Mitral Valve Disease and the Cavalier King Charles Spaniel

Mitral Valve Disease and
the Cavalier King Charles Spaniel


IN SHORT:

Mitral Valve LeakageHeart mitral valve disease (MVD) is the leading cause of death of cavalier King Charles spaniels throughout the world. MVD is a polygenetic disease which statistics have shown may afflict over half of all cavaliers by age 5 years and nearly all cavaliers by age 10 years, should they survive that long. MVD has been found to be 20 times more prevalent in CKCSs than in the average dog breed.  It is estimated to affect 10% of the entire dog population, but at a much older age of onset than for CKCSs. In the United States, out of 300,000 dogs, 5% died fo MVD while 50% of the cavaliers died of MVD. More ...

What It Is

Mitral Valve Cross-Section  Copyright © Cleveland ClinicMVD is a degeneration of the heart's mitral valve, one of four sets of valves in a dog's heart. A dog's heart valves' leaflets must open and close tens of thousands of times a day to maintain uni-directional blood flow through the heart.  When the valves open, they direct blood flow forward to where it is supposed to go, and when they close, they prevent blood from going backward to where it is not supposed to go. The mitral valve is located between the left atrium and ventricle. 

As the mitral valve degenerates, the valve no longer fully closes after each pumping action, allowing some blood to flow backwards through them from the ventricle back into the atrium. As the condition worsens, more and more blood is able to backflow through the valve as the leaflets of the valve begin to flail. In the final stages, the valve’s struts (chordae tendineae) sometimes break, causing the valve to collapse completely. In most dogs affected with MVD, the disease seldom progresses to heart failure. The estimates have varied from 20% to 30% of all dogs diagnosed with MVD eventually going into heart failure. However, MVD usually results in heart failure in the CKCS.

Heart failure (HF) is a condition where the heart is still working, but it can't pump enough blood to fully meet the dog's body's needs.  HF is determined by its symptoms, which include high rates of breathing (respiratory rates), exercise intolerance, shortness of breath (dyspnea), increase in respiratory effort, and/or fainting.  The term "congestive heart failure " (CHF) refers to the heart's dysfunction causing fluid buildups in the lungs (pulmonary edema) or elsewhere (effusions). Congestive heart failure (CHF) is the next step in the progression of MVD, following heart failure (HF).

About 10% of all dogs suffer from some form of heart disease. Mitral valve disease is the most common heart disorder in older dogs of all breeds. However, in the cavalier King Charles spaniel, the prevalence of MVD is about 20 times that of other breeds. Also in cavaliers, the onset of the disease typically is much earlier in the life of the dog. It has been reported that, once diagnosed, mitral valve disease is much more rapid in cavaliers than in other breeds, possibly reaching a life-threatening stage within as little as 1 to 3 years, rather than the average 3 to 5 years. To a lesser extent, cavaliers also suffer from deterioration of their tricuspid valves. More...

Diagnosis

Cavalier & CardiologistAll cavaliers should be screened for the sounds of tubulent blood flow, called heart murmurs, once a year beginning at age 1 year. Once MVD is detected, its progression can be monitored with stethoscopic examinations (auscultations), x-rays, echocardiograms, and color Doppler echocardiograms. If a heart murmur is detected, it should be confirmed in 3 to 6 months. If it still is detected, the dog is considered probable for MVD.  More...

Symptoms & Treatment

The progression of mitral valve disease can be rapid or slow. In most cavaliers, the disease shows a gradual progression in the loudness of the murmur and to more serious symptoms, in as little as 2 years after first detecting the murmur. Drugs may help to minimize the symptoms, but eventually the drugs may be unable to control them. The drugs prescribed for cavaliers with MVD can sometimes have severe adverse side effects, and blood chemistry should be done routinely to monitor their effects upon the kidneys, liver, and other internal organs. Severe symptoms of MVD in some cavaliers will appear more quickly, although previously having been stable. The ultimate consequence of the disease is heart failure.  More...

Breeders' Responsibilities

Early-onset mitral valve disease has been found to be "highly heritable" in the cavalier King Charles spaniel breed, and "selection against the disease should be successful.", according to an April 2011 research report.

Due to the pervasiveness of MVD in the breed worldwide, cavalier King Charles spaniels under the age of five years should not be bred (with one limited exception -- see MVD Breeding Protocol). Also, no cavalier should be bred after age five years if it developed an MVD murmur before the age of five years. Any littermates of breeding stock having early-onset MVD (mitral valve murmurs before age 5 years) should be taken into very serious consideration. All CKCS breeding stock should be examined by board certified veterinary cardiologists at least annually and cleared by the veterinary specialists for MVD, the closer the examination to the breeding the better. It is recommended that all cavaliers, breeding stock or not, be examined annually by board certified veterinary cardiologists after age one year. See the current list of health clinics for upcoming cardiologist examinations.

What You Can Do

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IN DEPTH:

Heart CavalierDegenerative mitral valve disease (MVD)* is the leading cause of death of cavaliers. It is a highly-heritable, polygenetic acquired heart disease which, statistics show, afflicts over half of all cavalier King Charles spaniels by age 5 years (by stethoscopic examination) and greater than 90% by age 10+ years, should they survive that long. It is estimated to affect 10% of the entire dog population, but at a much older age of onset than for CKCSs.

* MVD is also called cardiac valve disease (CVD) and medically known as myxomatous mitral valve disease (MMVD) chronic degenerative valvular disease, chronic valvular disease, chronic mitral valve insufficiency, myxomatous atrioventricular degeneration, endocardiosis, atrioventricular valve endocardiosis, chronic valvular fibrosis, acquired mitral regurgitation or insufficiency, and mitral valve defect.

Veterinary cardiologists began compiling statistics on cavaliers with MVD murmurs in the United Kingdom in 1990. Since then, cardiologists have examined the hearts of many thousands of cavalier King Charles spaniels at health clinics held by CKCS breed clubs in the UK, Canada, the USA, and elsewhere. From the data they have compiled, they have found that the percentage of CKCSs which develop MVD murmurs increases at a rate of about 10% per year. So, roughly 10% of cavaliers by age one year have MVD murmurs, and 20% aged between one and two years have murmurs, and so on for each age level. Specifically, the statistics show that more than half of all cavaliers aged five years have murmurs, and it is the very rare cavalier at age ten years which does not have, at the very least, a low grade MVD murmur.

A pair of September 2005 studies [1] [2] of Swedish cavaliers showed that 23% were dead by eight years, and 48% were dead by ten years. Those researchers stated:

"Heart disease in the Cavalier King Charles spaniel accounts for over 50% of deaths in that breed (in dogs under 10 years of age) and for over one-quarter of the heart deaths in the insured population [of all breeds]. Although heart disease in Cavalier King Charles spaniels is well recognized, these statistics give further insight into the impact of this cause of death in this breed."

 In the United States, out of 300,000 dogs, 5% died from MVD while 50% of the cavaliers died from MVD. In a 2006 study comparing the severity of MVD in cavaliers with six other breeds (Bichon, Dachshund, Lhassa Apso, poodle, Shi Tzu, and Yorkshire terrier), the researchers reported that in those other breeds, the age of onset of MVD is much later, and MVD is a well-tolerated disease with a long and slow progression, with most of the dogs not reaching heart failure.

* In a 1993 study of 394 cavaliers in the USA, 9% of puppies under age 12 months had MVD murmurs. 100% of CKCSs at age 10 years or older had MVD murmurs.  56% of cavaliers under age 5 years had MVD murmurs.

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What It Is

Mitral Valve Cross SectionMitral valve disease is a uniquely serious, life-shortening problem for cavalier King Charles spaniels and is their leading cause of death. About 10% of all dogs suffer from some form of heart disease. MVD is the most common heart disorder in older dogs of all breeds. Several smaller breeds of dogs typically are predisposed to suffer from MVD. However, in most all breeds, MVD does not result in heart failure (HF), causing death, because MVD does not develop early in a dog's life, and does not progress rapidly. See this January 2008 article, in which, of 302 MVD-affected dogs of various breeds with mild heart enlargement, over 60% were alive 70 months after initial diagnosis, and over 70% never reached the stage of heart failure.

In the cavalier King Charles spaniel, statistics have shown that the prevalence of MVD is about 20 times that of other breeds of dog. Also in cavaliers, the onset of the disease typically is much earlier in the life of the dog, with over half of all CKCSs having developing MVD by their fifth birthday (by stethoscopic examination), as noted above.

For nearly all other breeds, MVD is an old-age disease, and the age of onset is between 10 and 15 years of age. In most dogs affected with MVD, the disease seldom progresses to heart failure. The estimates have varied from 20% to 30% of all dogs diagnosed with MVD eventually going from heart enlargement into heart failure. However, MVD usually results in heart failure in the CKCS.

It has been reported that, once diagnosed, MVD is much more rapid in cavaliers than in other breeds, possibly reaching a life-threatening stage within as little as 1 to 3 years, rather than the average 3 to 5 years. Studies of cavaliers have concluded that it has an hereditary basis and is "polygenetic", meaning that more than one gene can be the cause.

Some research has indicated that MVD in the CKCS may be attributed to a chronic state of inflammation, as evidenced by measurements of immunoglobulin antibodies and glycoprotein and complement proteins particularly associated with immune responses to inflammation. See this 2014 Italian study. In a 2006 USA study, researchers found that, compared with controls, dogs with chronic valvular disease had higher plasma concentration of C-reactive protein (CRP). In veterinary medicine, CRP concentration has been shown to increase in inflammatory states, such as pancreatitis. Other research by Dr. Brendan Corcoran indicates that the damaging of the CKCS mitral valves is due to a life-long traumatic condition combined with the dog's inability to appropriately repair that damage. He has coined the term, "dyscollagenesis" (as opposed to fibrosis) meaning a chronic reduction in collagen production and a disorganization and failure of maturation. See his 2010 report.

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Mitral valve leaflets and chordae tendineae

Diseased Mitral ValveMVD is a degeneration and fibrosis of the heart's mitral valve, one of four sets of valves in a canine's (and a human's) heart. It is the valve which is designed to prevent the backflow of blood from the left ventricle into the left atrium (called mitral regurgitation -- MR). It consists of a set of double flaps, called "leaflets", that open and close like a set of one-way doors at appropriate times during each heart beat. Normal mitral valve leaflets consist of four layers of tissue (atrialis, fibrosa, spongiosa, and ventricularis), most of which are comprised of collagen and elastin fibers, and are very thin and nearly transparent. They are connected by tendons (chordae tendineae) to the muscles of the left ventricle. The normal mitral valve has a saddle shape.

Blood flows through the pulmonary veins from the lungs into the left atrium, one of the chambers of the heart. The mitral valve is located between the left atrium and the left ventricle, another chamber in the heart. The valve's action is governed by the movement of blood as it is pumped from the atrium and into the ventricle. The two leaflets of the mitral valve are controlled by the tendons -- the chordae tendineae -- which serve as thin "struts" shaped much like the chords of a parachute. Normal healthy chordae are smooth and symmetrical.

As the diseased mitral valve degenerates, myxomatous transformation -- the development of excess connective tissue that thickens the spongiosa and separates Healthy Valve versus Damaged Valvecollagen bundles in the fibrosa -- causes the valve to lose its flexibility, its leaflets thickening and shortening, its fibers stiffening, and its chordae tendineae elongating. The leaflets no longer fully close after each pumping action (see photo of a deteriorated mitral valve with thickened and shortened leaflets, at right above), allowing blood to jet backwards through them from the ventricle back into the atrium. This is the mitral regurgition (MR).  (In the photo at the left, a healthy mitral valve leaflet at the top is compared with a damaged valve leaflet below.)

(Photo credit to Dr. Brendan Corcoran, University of Edinburgh's Royal (Dick) School of Veterinary Studies.)

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Mitral valve shape (morphology)

Mitral Valve Annulus DiagramThe mitral valve's two leaflets are surrounded by a ring called the annulus (MVA). (See image at right.) The dog's MVA contracts (systolic phase -- when the heart is pumping blood the arteries) and expands (diastoic phase -- when the heart refills with blood). This is called the cardiac cycle. In most healthy dogs without MVD, their MVA is saddle-shaped or elliptical but during the diastolic phase, the annulus becomes rounder.

In an August 2021 study, Japanese cardiologists studied the shapes of the MVA in 59 healthy dogs and 371 MVD-affected dogs about to undergo mitral valve surgery. They reported finding that two-dimensional echocardiography revealed that the MVAs of the healthy dogs were elliptical and the annuluses of the MVD-affected dogs were larger than those of healthy dogs, and the annuluses remained rounder during the full cardiac cycle.

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Mitral valve prolapse

As the condition worsens, advanced lesions cause the leaflets to fold, invert, and stretch toward the left atrium. This is called mitral valve prolapse (MVP)*. In some cavaliers, MVP may be the first sign of possible MVD,  even before a mild mitral valve murmur is detected. On ultrasound (echocardiograph) examination, MVP appears as if the valve leaflets overlap backwards into the atrium.

In a 1999 study, echocardiographic screening of 75 cavaliers revealed that 82% (54/66) of those dogs aged one to three years had mitral valve prolapse (MVP)*, and 97% (84/87) of the dogs over three years had various degrees of mitral valve prolapse.  In a September 2021 Italian study, 51 of 52 cavaliers had MVP, including 25 CKCS which had no detectable mitral valve murmurs.

*Mitral valve prolapse (MVP) is defined 357. Peddle GD, Buchanan JW. Acquired atrial septal defects secondary to
rupture of the atrial septum in dogs with degenerative mitral valve
disease. J Vet Cardiol 2010;12:129-34.as the protrusion of one or both valve leaflets to the atrial side of the plane of the mitral annulus during systole (1999 study). The degree of MVP correlates with the severity of mitral valve regurgitation.

 MVP may cause the valve’s chordae tendineae to stretch. In the final stages, the valve’s chordae tendineae sometimes rupture, and if they are major chords, causing the valve to collapse completely. Rarely, a cavalier's mitral valve's major chordae tendineae may suddenly rupture earlier in the progression of the disease, before any enlargement of the heart takes place.

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Compensatory mechanisms

The initial effect of MVD upon the affected dog's body is a very mild reduction in the heart's output of blood (cariac output) along with reductions in blood pressure and dissolved oxygen (oxygen tension) in the blood stream. These signals prompt other regions of the dog's body to initiate compensatory mechanisms aimed at maintaining normal cardiac output, blood pressure, and oxygen tension levels. These mechanisms include:

(a) activating the sympathetic nervous system to increase the heart rate to normalize cardiac output and constrict the blood vessels to normalize blood pressure;

(b) activating the kidneys' renin-angiotensin aldosterone system (RAAS) to retain sodium and water and thereby further constrict the blood vessels to maintain normal cardiac output and blood pressure; and

(c) activating hormones, including natriuretic peptides, endothelin-1, and arginine vasopressin.
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Progression of MVD

In addition to the valve's leaflets and its chords, as more and more blood is able to backflow (regurgitate) through the damaged valve, both the left atrium (LA) and the left ventricle (LV) to enlarge. This process is called cardiomegaly or dilation. The LA is forced to enlarge (hypertrophy) by the increase in blood coming in two directions at once. The LV enlarges to increase the force of its contraction, to compensate for the lessened quantity of blood the LV is intended to pump though the arteries to the body.

Apart from the mitral valve itself, the disease has severe consequences for the rest of the heart and the lungs. The increased pressure in the left atrium decreases blood flow from the lungs to the heart, resulting in congestion in the pulmonary veins, ultimately causing fluid, called pulmonary edema, to leak out of the capillaries into the pleural cavity of the lungs. As the left atrium enlarges, cardiac output declines. 

Heart failure (HF) is a condition where the heart is still working, but it can't pump enough blood to meet the dog's body's needs. HF is determined by its symptoms, which include high rates of breathing (respiratory rates), exercise intolerance, shortness of breath (dyspnea), increase in respiratory effort, and/or fainting.

 Congestive heart failure (CHF) occurs when heart's dysfunction increases blood pressure in the pulmonary veins and capillaries, causing fluid buildups in the lungs (pulmonary edema) or elsewhere (effusions). (See the scientific definition of HF at this link.)

The left atrium usually enlarges first, followed by an enlarged left ventricle and the pulmonary veins. The heart enlargement may cause a tear in the left atrium, which usually results in immediate stoppage of blood flow. See a more detailed discussion of the progression of MVD at this section of this webpage.

To a lesser extent, cavaliers also suffer from deterioration of their tricuspid valves, called right-side heart disease or tricuspid valve disease. See this section of this webpage.

For an in-depth on-line seminar about the symptoms, diagnosis, progression, and treatment of mitral valve disease, watch Dr. Andrew Beardow, with his terrific active graphics, explain MVD. 

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Mitral valve dysplasia

MVD is a called an "acquired" disease because it is not present at or shortly after birth and instead develops and progresses thereafter. Another category of mitral valve disease is "mitral valve dysplasia", which is present at or shortly after birth and therefore is congenital. This category includes malformations of the mitral valve which cause blood regurgitation back through the valve.

In a January 2021 article, a team of Japanese veterinary clinicians reported discovering a congenital cleft Figure 3(split) in one of the two leaflets of the mitral valve of a 2-year-old male cavalier. The dog had mild mitral valve regurgitation of blood through the cleft's opening. The authors used 3-D echocardiography to reveal the position, shape, diameter, and width of the cleft's opening. (See Figure 3 at the left.) No heart enlargement was observed, and the dog was classified as Stage B1 of mitral valve dysplasia. The disorder is extremely rare, and only one other case has been reported in veterinary literature -- a 2012 report of a 7-month-old English toy spaniel (King Charles spaniel). In the cavalier's case, the owners opted for continued medication with oral temocapril hydrochloride (an ACE-inhibitor) and pimobendan. The CKCS's condition did not worsen until he died of lymphocytic leukemia. Ironically, the English toy spaniel in the 2012 report also died of lymphocytic leukemia, at the age of 8.5 years.

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Other types of heart disorders

MVD is not the only type of heart disorder which cavaliers may have. Others include:

Innocent flow murmurs: These sounds commonly heard in 15% to 25% of healthy puppies, by using a stethoscope, are caused by turbulent blood flowing through the heart valves while the puppies' hearts are still developing. They usually are low grade murmurs heard before the 9th week, which decrease as the dog matures and are not due to any congential heart disease. Such a murmur is "likely to be innocent if it is soft (with a maximal intensity of 2 of 6), systolic, has a musical character and the point of maximal intensity is located in the region of the left cardiac base." See this November 2015 article.

Systolic clicks: These are sounds heard with a stethoscope placed over the mitral valve of cavaliers not yet diagnosed with MVD murmurs. Veterinary cardiologist Dr. James Buchanan stated in 1998 that "systolic clicks occur twenty-five times more frequently in cavaliers than other breeds and may be a precursor to a murmur showing up a few years later ." Cardiologist Dr. Michele Borgarelli has stated in 2020 that such a click sound may be caused by vibration of the mitral valve leaflets and tensing of the valve's chordae tendineae as the leaflets slighty prolapse.

Pulmonic stenosis (pulmonary valve stenosis): This is a fairly common congenital heart defect in cavaliers. It is characterized by the narrowing and obstruction of blood through the heart's pulmonary valve, which connects the pulmonary artery to the right ventricle chamber. Read more details about this disorder here.

Patent ductus arteriosus (PDA): This is the most common congenital cardiovascular abnormality in dogs. Cavaliers have been shown to have a "high prevalence" for PDA. It occurs when a temporary blood vessel –- the arterial canal -– which is used to bypass the fetus’s undeveloped lungs in the womb and allows blood to pass from the right side of the heart to the left, fails to seal within a week after birth. Normally, this vessel will begin to seal once the puppy begins breathing. PDA compromises the circulation of blood through the heart. It is believed to be inherited as a polygenic threshold trait with a high rate of heritability in some breeds and is considered to be hereditary in the CKCS. Read more details about this disorder here.
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Symptoms

Until the MVD-affected dog reaches "heart failure" (HF or CHF), there usually are no visible signs or symptoms related to Enlarged Heartthe MVD. A murmur and an enlarging heart, which come before heart failure, are not considered symptoms, because they cannot be outwardly visible. A murmur is listened to with a stethoscope (auscultation), and enlargement is determined by comparing measurements taken from sets of x-rays or echocardiogram scans, none of which are observable externally. Prior to the dog reaching the MVD stage called heart failure, these signs -- murmurs and enlargement -- are referred to as "asymptomatic" indications of MVD.

"Heart failure" in this context does not mean that the dog's heart stops beating. It means instead that the dog shows signs that the heart is not functioning at full capacity and appears to be declining in its ability to pump blood throughout the dog's systems. "Congestive heart failure" (CHF) means that the dog's (pulmonary) veins in its lungs are congested with blood which no longer is flowing properly, causing the blood vessels to leak and release fluids into the lung tissue.

As noted above, what is not visible outwardly, before the dog reaches heart failure, is enlargement of the heart. As greater quantities of blood leak through the damaged mitral valve from the left ventricle back into the left atrium of the heart, the thin-walled atrium gradually begins to swell and enlarge (see x-ray image of a severely enlarged heart, above) -- called remodeling or cardiomegaly or dilation  -- to accommodate the overload of blood, and there is a reduction in the ability of the ventricle to provide sufficient blood to meet the demands of the rest of the body. The heart then has to pump harder and faster, to meet those demands. The shut-down of the distant blood vessels also has the effect of causing the left ventricle to beat against a higher resistance, causing another increase in mitral valve leakage.

Heart enlargement due to mitral regurgitation also has been shown to cause cardiac arrhythmias. See this January 2019 article.

Pulmonary Edema DiagramAlso, the overload of blood in the left atrium creates increased pressure back into the pulmonary veins, which drain into the left atrium from the lungs. When a critical pressure is reached, flooding of the lungs can occur, causing pulmonary edema.

Edema results when blood vessels leak and release fluids into nearby tissues. The extra fluid accumulates, causing the tissue to swell. Edema is a normal response of the body to inflammation or injury. When the heart weakens and pumps blood less effectively, fluids can slowly build up, creating edema. If fluid buildup occurs rapidly due to damage to the left side of the heart, fluid in the lungs -- pulmonary edema -- can develop. If there is heart failure of the right side of the heart, edema can develop in the abdomen.

For an in-depth on-line seminar about the symptoms, diagnosis, progression, and treatment of mitral valve disease, watch Dr. Andrew Beardow, with his terrific active graphics, explain MVD.

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-- early symptoms of heart failure:

The closer the MVD gets to heart failure, the more rapid the dog's breathing becomes.  Usually more than 30 breaths per minute while sound asleep or resting indicates the onset of congestive heart failure, due to the build-up of fluid in the dog's lungs (pulmonary edema). Breathlessness also is a most common sign, starting as excessive panting on exercise.

A dog with fluid in its lungs may have difficulty finding a comfortable position when lying down.

Note that some cardiologsists refer to two categories of heart failure -- the traditional symptomatic one which they call the "decompensated phase", and an earlier "compensatory phase" which displays no symptoms. See this January 2018 article.

        --- coughing

Most MVD-affected dogs with a cough are not yet in heart failure. However, many veterinarians associate a dry, hacking cough with an enlarged heart due to MVD or even to heart failure. They call it a "cardiac cough" and attribute it to either the enlarged left atrium conpresising against the dog's bronchus or trachea, or, fluid build-up in the lungs due to CHF (pulmonary edema). In most all cases, however, the term cardiac cough is a misnoner because the true cause of the cough probably is respiratory related and completely independent of any heart disorder.

One of the most common -- and potentially dangerous -- misjudgments some veterinarians tend to make is to assume that such a cough indicates the onset of CHF and the need for immediate treatment with a diuretic. Cardiologist Dr. Michele Borgarelli has warned:

"It should be stressed that cough is a general clinical sign of respiratory disease and its presence in a dog with a murmur is not an indicator for starting treatment for CHF."

The cough could be due to a combination of factors, which include the enlarged left atrium of the heart pressing against and compressing the left mainstem bronchus or trachea, but more likely to airway disorders independent of any relationship with the heart, such as bronchomalacia and airway inflammation (possibly with the large left atrium merely highlighting the bronchial narrowing). It may even cause the trachea to collapse*. However, if the dog coughs up a pink-tinged fluid, it would indicate that may have very severe pulmonary edema which is filling the airways.

* Trachea collapse also may be due to Brachycephalic airway obstruction syndrome (BAOS).

In a March 2012 article, USA researchers found no association between left atrial enlargement (LAE) and bronchial collapse in MVD-affected dogs with moderate-to-severe LAE and chronic coughing, but they did find that airway inflammation is common in dogs with airway collapse.

In a January 2019 article, a pair of experts concluded that a cough in the absence of rapid and labored breathing would indicate that it is due mainly to a respiratory disease rather than a cardiac disease. Coughing is a hallmark sign of bronchitis. Dogs with severe pulmonary edema can cough but coughing is much more common with primary lung disease. By severe pulmonary edema, they mean that the fluid has completely filled the lungs and also has started to fill the upper airway passages, as well.   (The x-ray below shows the heart's enlarged left atrium impinging upon the left main bronchus.).

In an April 2021 article, a team of French and US investigators used computed tomography (CT) to study the association between left atrium enlargement causing bronchial narrowing in 21 coughing dogs (2 cavaliers -- 9,5%) diagnosed with heart murmurs due to MVD. They measured each dog using chest x-rays, echocardiography, and chest CT scans. They calculated bronchial narrowing using the bronchial-to-aorta ratio. They report finding "significant narrowing" of the bronchi in the coughing dogs, compared to 10 control group non-coughing, healthy dogs. They noted that as the left atrium size (LA/Ao) and vertebral heart size (VHS) increased, the diameter of all left-sided and most right-sided bronchi decreased. The LA/Ao range was from 1.5 to 3.5, and three dogs (14%) had a LA/Ao ratio below 1.6.

So if a dog has had a cough for months and unchanged and the dog is not being treated with a diuretic, the cough is very unlikely due to heart failure. Some cardiologists may prescribe a bronchial dilator (bronchodilator), such as a methylxanthine, for example, aminophylline, millophyline, oxtriphylline, theophylline* (Corvental, Apo-Theo-LA, Theo-Dur), or terbutaline (Brethine, Bricanyl) which are human grade prescription medications which relax and open air passages in the lungs, making breathing easier.** A narcotic, hydrocodone bitartrate with homatropine MBr or guaifenesin  (Hycodan, Hydromet, Tussigon, Mycodone), or butorphanol tartrate (Torbutrol, Stadol, Torbugesic)  may be prescribed to suppress the coughing by affecting the brain's cough centers.

* Theophylline is a PDE inhibitor which should not be given concurrently with pimobendan, which is another PDE inhibitor, unless the combination of those two drugs is carefully balanced.
** Fluoroquinolone antibiotics should not be given concurrently with any methylxanthines.

X-ray showing enlarged heart causing coughing

There is a possibility that a particular angiotensin-converting enzyme inhibitor (ACE-inhibitor) may have cough-suppressant effects on MVD-affected dogs with a cardiac cough. In an August 2018 article, a team of Japanese researchers tested the ACE-inhibitor alacepril on 36 dogs, including four cavalier King Charles spaniels, which were in Stage B2 of mitral valve disease (having an MVD-murmur and an enlarged heart but prior to heart failure) and all displaying an MVD-related cough. They primarily were testing the cough-suppression efficacy of alacepril over a period of four weeks. They report finding that alacepril resolved or lessened the cough in 20 (55.6%) of the dogs and had no cough-suppressant effect upon the remaining 16 (44.4%). They observe that alacepril is among a sub-group of ACE-inhibitors (including captopril and zofenopril) which contain sulfhydryl, which may confer properties additional to ACE inhibition and which may explain the cough-suppressant qualities.

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-- later symptoms of heart failure:

Once congestive heart failure has been diagnosed, look for these additional signs: exercise intolerance, lack of appetite, restlessness at night, weight loss, and fainting (called syncope). As breathing difficulties become more severe, the dog may sit or stand, holding its elbows away from the chest, and it may be reluctant to sit down. In some cases, any of these symptoms may appear even before the onset of congestive heart failure.

    --- exercise intolerance and loss of skeletal muscle mass (cardiac cachexia)

The inability to withstand normal levels of exercise is a classic sign of the progression of the MVD. This is attributed to a variety of systemic changes which take place in the dog's body, including pulmonary hypertension and the loss of skeletal muscle mass, especially in the hindquarters (cardiac cachexia). Research has shown that loss of muscle mass is due to:

• an insufficiency of oxygen getting to the dog's muscles;
• reduction in capillary length density, leading to inadequate capillary blood per unit volume of skeletal muscle;
• reduced  mitochondria* mass in the skeletal muscles, resulting in more limited oxidative capacity; and
• transformation of muscle fibers from type I (slow twitch) to type II (fast twitch), particularly type IIB, which possess less oxidative capacity than type IIA or type I fibers. Type IIB fibers have a low aerobic potential, and are easily fatigued.

*Mitochondria in each cell of the dog's body are organelles which take in nutrients, break them down, and create energy rich molecules for the cell.

For more information about the effects of heart failure upon skeletal muscles, see this November 1989 article and this May 1992 article, both of which are about human patients, and this May 2017 article, specifically pertaining to dogs in heart failure. See our discussion of treating exercise intolerance and loss of muscle mass in our Treatment -- Stage C -- heart failure subsection, for more information.

The dog may also display episodic weakness of the hindquarters, ataxia (lack of coordination), involuntary shaking of a hind leg, or collapse (presyncope), or combined with loss of consciousness (syncope), due to a sudden decline in blood flow to the brain. See Syncope for a discussion of this disorder and its causes.

Cardiac cachexia also includes a loss of appetite, resulting in possibly severe weight loss. Over half of all dogs in CHF due to MVD will develop cardiac cachexia. In a July 2019 article, a team of researchers at Tufts University's Cummings veterinary school examined 218 MVD-affected dogs in heart failure (CHF), including 20 cavalier King Charles spaniels, to determine the role of muscle loss -- called cardiac cachexia -- in life expectance of the dogs. Cardiac cachexia is defined as the loss of muscle mass associated with CHF. A second definition is the rapid loss of overall weight (≥5%) within 12 months. They found that dogs with cachexia had a significantly shorter survival time compared with dogs without cachexia. They also report that cachexia is common in dogs with CHF. They emphasize "the importance of preventing, diagnosing, and treating muscle loss in dogs with CHF".  Tufts provides this chart (below) to detect muscle loss in MVD-affected dogs in CHF.

Muscle Condition Score Chart

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       --- syncope or pre-syncope

Fainting or the loss of consciousness in MVD-affected dogs in the late stages of the disease is called syncope; absent the loss of consciousness, it is called presyncope.  For more information, see our Syncope webpage.

    --- fluid in the abdomen

Ascites - Mount Pleasant Vet ClinicIf the tricuspid valve is also affected, the retained fluid, called ascites (or abdominal effusion), is squeezed into other body tissues, the liver, chest, and peritoneal cavity of the abdomen, giving the dog a heavy, pot-bellied appearance. This is also known as right-sided heart failure. See photo at right of cavalier, Kopi, with ascites (courtesy Mount Pleasant Vet Group).




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       --- near death signs

As the cavalier nears death from MVD, often the dog will display a severe air hunger and uses all of its remaining energy just trying to breathe.

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-- assessment of quality of life

In a 2005 report, cardiac researchers at Tufts University's Cummings School of Veterinary Medicine devised a survey that may prove to be similarly useful in evaluating the quality of life for dogs with heart disease. Known as "FETCH" (Functional Evaluation of Cardiac Health), the survey asks the dogs' owners to rank aspects of their dog's health on a scale of 0 to 5. Veterinarians are then able to assess the animal's perceived quality of life, which may inform decisions about treatment, nutrition or even euthanasia. Researchers found that the FETCH scores correlated well to the International Small Animal Cardiac Health Council (ISACHC) classification for disease severity. See our in depth discussion of this quality-of-life questionnaire, below.

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Diagnosis

-- auscultation (stethoscope)

The sound of tubulent blood flow over the mitral valve, called a heart murmur, heard by means of a stethoscope, is the first indication that the dog may have mitral valve disease (MVD). Cavaliers should be Auscultation of a cavalierscreened for heart murmurs annually, beginning at age one year. Once MVD is detected, its progression can be monitored with stethoscopic examinations (auscultations), x-rays, respiratory rates (breaths per minute while resting or asleep), echocardiograms, and color Doppler echocardiograms. If a cavalier's heart murmur is first detected by a general practice veterinarian, it should be confirmed within 3 to 6 months by a specialist, preferably a board certified veterinary cardiologist. If it still is detected, the dog has MVD.

Not all heart murmurs are due to blood backflowing through the mitral valve. See "Other Types of Heart Disorders" above for details of other types of heart murmurs.

Heart murmur grades

The first indication of MVD which is detectible apart from an echocardiograph (ultrasound) examination, is the presence of a soft whistling sound, called a "murmur", which can be heard by a veterinarian using a stethoscope, which is called auscultation. The murmur sound is caused by the turbulent flow of blood jetting backwards through the damaged leaflets of the mitral valve from the left ventricle, into the left atrium. This reverse flow of blood through the mitral valve is called mitral regurgitation (MR). (Photo above is of veterinary cardiologist Dr. Michele Borgarelli auscultating a cavalier's heart with a stethoscope.)

As simple a device as the stethoscope may seem to be, many cardiologists consider that auscultation is the best screening test there is for the identification of the presence of mitral valve regurgitation. The loudness of the murmur determines its "grade". (See the "Grades of Mitral Valve Disease Murmurs" below.)  An alternative method of grading murmurs, discussed in this November 2014 article, provides:

• Soft (quieter than heart sounds) = Grades I and II
• Moderate (as loud as heart sounds) = Grade III
• Loud (louder than hart sounds) = Grade IV
• Thrilling (very loud, heard with stethoscope removed from chest) = Grades V and VI

MR usually is classified as mild, moderate, or severe. However, there is not necessarily a direct correlation between the loudness of the murmur and the amount of blood flowing backward through the mitral valve. While soft mitral murmurs -- Grades 1 or 2 -- almost always indicate mild MR, once the murmur edges upwards from there, there often is no correlation between the murmur's grade and the degree of mitral regurgitation. However, However, two studies -- November 2014 and December 2018 -- have concluded that thrilling murmurs (grades V and VI) are associated with more severe MVD.

Grades of Mitral Valve Disease Murmurs

Ask the cardiologist to use this standardized report form. A list of upcoming heart testing examination clinics is on our Health Clinic webpage.

Also, ask the cardiologist about the American College of Veterinary Internal Medicine (ACVIM) Registry of Cardiac Health (ARCH), a registry and database for canine hearts examined by board certified cardiologists. See the details on the ARCH website.

In a 2009 "Consensus Statement" published by a panel of the board certified veterinary cardiologists of the American College of Veterinary Internal Medicine (ACVIM), they state:

"Consensus recommendations:

"Small breed dogs, including breeds with known predisposition to develop CVHD [chronic valvular heart disease] (e.g., Cavalier King Charles Spaniels, Dachshunds, Miniature and Toy Poodles) should undergo regular evaluations (yearly auscultation by the family veterinarian) as part of routine health care.

"Owners of breeding dogs or those at especially high risk, such as Cavalier King Charles Spaniels, may choose to participate in yearly screening events at dog shows or other events sponsored by their breed association or kennel club and conducted by board-certified cardiologists participating in an ACVIM-approved disease registry."

For an in-depth on-line seminar about the symptoms, diagnosis, progression, and treatment of mitral valve disease, watch Dr. Andrew Beardow, with his terrific active graphics, explain MVD.

Listen to the sound of a Grade 3 MVD heart murmur here. Other levels of murmurs may be heard here.

Our Blog: "So your cavalier has a heart murmur. What do you do next?"

Clicks

Even if the veterinarian does not hear a murmur, he might report hearing a "systolic click" when he examines the dog with his stethoscope. Veterinary cardiologist Dr. James Buchanan stated in 1998 that "systolic clicks occur twenty-five times more frequently in cavaliers than other breeds and may be a precursor to a murmur showing up a few years later ." Cardiologist Dr. Michele Borgarelli has stated in 2020 that such a click sound may be caused by vibration of the mitral valve leaflets and tensing of the valve's chordae tendineae as the leaflets slighty prolapse.

Fluid in the lungs

Veterinarians also use the stethoscope to listen to the dog's lungs if congestive heart failure (CHF) is suspected. One of the signs of CHF is fluid in the lungs (called edema), and that fluid tends to make crackling noises when heard with a stethoscope. Cardiologist Dr. Dave Dickson  has described the sound of fluid in the lungs as "like Velcro unpeeling". However, hearing those sounds is not definitive of CHF, and other devices should be used to confirm edema, including high sleeping respiratory rates, chest x-rays, and lung ultrasound.

Other types of heart murmurs

MVD is not the only type of heart disorder which may produce heart murmurs in cavaliers. Others include:

Innocent flow murmurs: These sounds heard in puppies, by using a stethoscope, are caused by turbulent blood flowing through the heart valves while the puppies' hearts are still developing. They usually are low grade murmurs which decrease as the dog matures and are not due to any congential heart disease.

Pulmonic stenosis (pulmonary valve stenosis): This is a fairly common congenital heart defect in cavaliers. It is characterized by the narrowing and obstruction of blood through the heart's pulmonary valve, which connects the pulmonary artery to the right ventricle chamber. Read more details about this disorder here.

Patent ductus arteriosus (PDA): This is the most common congenital cardiovascular abnormality in dogs. Cavaliers have been shown to have a "high prevalence" for PDA. It occurs when a temporary blood vessel –- the arterial canal -– which is used to bypass the fetus’s undeveloped lungs in the womb and allows blood to pass from the right side of the heart to the left, fails to seal within a week after birth. Normally, this vessel will begin to seal once the puppy begins breathing. PDA compromises the circulation of blood through the heart. It is believed to be inherited as a polygenic threshold trait with a high rate of heritability in some breeds and is considered to be hereditary in the CKCS. Read more details about this disorder here.

Quadricuspid aortic valve: The aortic valve is the gateway for blood to exit out of the ventricle and pass through the aorta artery for the body to receive oxygenated blood. Normal aortic valves have three equally sized leaflets, called (1) the right coronary cusp, (2) the left coronary cusp, and (3) the non-coronary cusp. Quadrisupid aortic valve (QAV) is a rare congenital heart disease in which a fourth cusp develops, resulting in regurgitation through the aortic valve, causing the sound of a murmur detected by auscultation. Read more details about this disorder here.
Phonocardiogram

Phonocardiogram-fakhryA phonocardiogram (PCG) is a graphic recording of heart sounds detected using an electronic stethoscope. The phonocardiogram appears as a digital image on a computer screen. Phonocardiograms can produce sound recordings of the heart beats and murmurs, as well as display images showing "waveforms" (see image at right) which enable the clinician to distinguish between normal heart beats and abnormal sounds, such as murmurs, in a more objective manner than the clinician listening to those sounds using a non-electronic (acoustical) stethoscope.

Phonocardiograms are used to detect heart murmurs and to distinguish between mitral valve murmurs due to mitral regurgitation and others, including innocent flow murmurs, aortic regurgitation, aortic and mitral stenosis, and valvular lesions.

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-- x-rays (radiography)

Measuring Vertibral Heart ScoreRadiography (x-ray) is used to determine if the heart is enlarged (particularly the left atrium and left ventricle), if the veins from the lungs to the heart are distended, or if fluid is beginning to develop in the lungs.* X-rays also will show any enlargement of the pulmonary vein, a classic symptom of congestive heart failure (CHF).

*X-ray is the best diagnostic device for detecting fluid in the dog's lungs. See below.

 Once a mitral valve murmur is detected by auscultation, annual x-rays are very useful in charting the progression of the disease. The 2009 ACVIM  "Consensus Statement" on degenerative MVD recommends baseline thoracic radiography for dogs with a new mitral valve murmur, then annually thereafter. However, if auscultation by stethoscope indicates that a murmur has remained mild -- Grade 1 or 2 -- and has not progressed in loudness since the murmur was first detected, a set of follow-up x-rays the next year usually is not necessary. 

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• Using radiography to diagnose heart enlargement

Mild to moderate heart enlargement indicates mild to moderate progression of mitral regurgitation (MR), with the heart compensating for the effects of mitral regurgitation by enlarging. Usually the dog displays no outward signs or symptoms of MVD when moderate to severe heart enlargement develops, until the dog reaches the stage of heart failure.

In a May 2020 article, a team of Korean veterinary investigators  compared chest (thoracic) x-rays of MVD-affected dogs both at full inspiration (inhalation) and full expiration (exhalation) when measuring the apparent sizes of the dogs' hearts. The study included 20 beagles with normal-sized hearts and 100 MVD-affected dogs of unidentified breeds. They measured the vertebral heart scale (VHS), vertebral left atrial size (VLAS), position of the trachea, and bulging of the left atrium (LA), and appearance of the left ventricle (LV). They compared this data to each dog's left atrium to aorta echocardiographic ratio (LA/Ao). They concluded:

“In dogs with MR [mitral regurgitation], LA enlargement was subjectively more apparent when thoracic radiography was taken during the expiratory phase compared to the inspiratory phase. These findings supported the use of both inspiratory and expiratory radiographs for assessment of left heart enlargement in dogs with MR, although measures of LA enlargement in dogs with MR can be overestimated in expiratory radiographs.”
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• VHS measurements to detect enlargement

Cardiologists use x-rays to evaluate the size and shape of the heart in order to assess the severity of MVD. The Vertebral Heart Size or Scale or Sum (VHS) is an objective means of measuring heart size. Cavaliers with episodic falling on YouTubeAs the x-ray image above shows, using calipers, they measure the length (from the apex to the bottom of the left mainstem)  and width (at its widest point perpendicular to the lemgth measurement) of the heart on a lateral x-ray and compare those dimensions to the number of veterbrae from T4 to T12, to calculate the VHS value. Since the dog's own vertebrae are used for comparison, each VHS vamue is normalized to the dog's overall body size.  VHS misses enlarged left atriumSee this YouTube video for details. A diagram showing how the VHS is calculated is here. This is called the Buchanan VHS method, devised by Dr. James W. Buchanan, a pioneer in the research of MVD in cavaliers, in 1995. See his 1995 article.

In a 2001 study and a 2005 study, researchers found that the normal range of VHS values for cavaliers was from 10.0 to 11.7. In an October 2018 article, a cavalier with a normal sized heart with a VHS value of 11.9 was reported.

 The VHS is not intended to diagnose CHF. It's purpose is to enable veterinarians to more accurately determine enlargement of the heart (called cardiomegaly or dilation) and the progression at which the enlargement is occurring, which usually is due to MVD. However, since MVD normally initially causes only the left atrium (LA) to enlarge, the VHS method is not precise enough to measure only the size of the LA. See for example, the x-ray at left, which shows that the VHS measurements entirely miss the bulbous enlarged LA in the upper right corner of the heart. (Image from Hezzell, 2018.)

The VHS method is most effective when it is used to compare two x-rays of the same dog's heart, taken over time, to see if the later x-ray's VHS value is higher than the earlier one, thus indicating that an enlargement of the heart has occurred. Therefore, once an MVD murmur is first detected, it is advisable to obtain an initial set of chest x-rays (called a "baseline" set) for comparison with subsequent x-rays once progression of the MVD is suspected.

In a June 2020 article, University of California at Davis veterinary researchers performed fluoroscopic scans of the hearts of 49 dogs during their cardiac cycles to determine what impact the heart's pumping action may have upon x-ray image measurements to determine the dogs' VHS. Fluoroscopy is a series of low dose x-ray images that show internal organs in motion. Fluoroscopy produces poorer quality images than x-rays and therefore is not as accurate for diagnostic purposes. However, since fluoroscopic images can show a series of images of the heart during its cycling, they were useful in this study in assessing changes in the quantitative measurements of the heart during its cycle. In this study, the investigators measured VHS at the point of end-diastolic volume (the maximum amount of blood in the left ventricle just before the heart contracts) and end-systolic volume (the minimum volume of blood in the ventricle at the end of contraction). They report finding that the cardiac cycle had a significant impact on VHS (mean difference: 0.36 ± 0.14 vertebral units between systole and diastole). They concluded that "The cardiac cycle has a significant effect on VHS... . These findings should be taken into consideration during clinical use of these measurements, especially if a patient is being monitored for cardiac changes over time via serial radiographs."

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• VLAS measurements of left atrium

In an October 2018 article, a more highly accurate x-ray measurement of the left atrium (LA) to determine if MVD-affected dogs have LA enlargement, has been introduced. It is called  "vertebral left atrial size (VLAS)". The lower broken line of the x-ray in Figure 1 (left below), labeled #, shows the location of the measurement of the LA, and the upper broken line, labeled *, shows how that length is compared to the dog's vertebrae, begining at vertebra T4. Technically, the measurement is described as:

"First, a line was drawn and measured (in arbitrary units) from the center of the most ventral aspect of the carina to the most caudal aspect of the left atrium where it intersected with the dorsal border of the caudal vena cava. For the purpose of this study, the carina was defined as the radiolucent circular or ovoid structure within the trachea that represented the bifurcation of the left and right mainstem bronchi. Similar to the vertebral heart size method, a second line that was equal in length to the first was drawn beginning at the cranial edge of T4 and extending caudally just ventral and parallel to the vertebral canal (Figure 1 below). The VLAS was defined as the length of the second line expressed in vertebral-body units to the nearest 0.1 vertebra."

The researchers compared these x-ray dimensions in 103 dogs divided into four categories determined by Visser VLAS Measurement -- Fig 1echocardiographic scans: (1) control group of 15 heart-healthy dogs; (2) 40 dogs, including 2 cavalier King Charles spaniels, in Stage B1 (MVD-affected but without enlargement); (3) 26 dogs (2 CKCSs) in Stage B2 (MVD with enlargement); and (4) 22 dogs (4 CKCSs) in Stages C or D (in congestive heart failure). The investigators compared these x-ray measurements with echocardiographic measurements of the left atrium of each dog, using two standard echo images of the LA: (a) left atrium-to-aortic root ratio acquired from short-axis (LA:AoSx) and (b) long-axis (LA:AoLx). They conclude:

"Results of the present study indicated that there was a significant positive correlation between VLAS and both LA:AoSx and LA:AoLx, and VLAS cutoffs of 2.3 to 2.5 vertebrae were associated with an LA:AoSx ≥ 1.6 and LA:AoLx ≥ 2.6 (or both). Thus, a VLAS ≥ 2.3 vertebrae can be used as a radiographic indicator of LA enlargement, and dogs with a VLAS ≥ 2.3 vertebrae likely have hemodynamically important MMVD. ... Results of the present study indicated that VLAS was an accurate predictor of LA enlargement in a large and diverse population of dogs with MMVD of varying severity. There was a moderate positive correlation between VLAS and echocardiographic estimates of LA size by linear measurement methods in both the long (LA:AoLx) and short (LA:AoSx) axes. Results also indicated that VLAS was a readily repeatable measurement, with a high level of agreement among measurements obtained by the same individual on multiple occasions as well as by multiple individuals.

In a June 2020 article, University of California at Davis veterinary researchers performed fluoroscopic scans of the hearts of 49 dogs during their cardiac cycles to determine what impact the heart's pumping action may have upon x-ray image measurements to determine the dogs' VLAS. Fluoroscopy is a series of low dose x-ray images that show internal organs in motion. Fluoroscopy produces poorer quality images than x-rays and therefore is not as accurate for diagnostic purposes. However, since fluoroscopic images can show a series of images of the heart during its cycling, they were useful in this study in assessing changes in the quantitative measurements of the heart during its cycle. In this study, the investigators measured VLAS at the point of end-diastolic volume (the maximum amount of blood in the left ventricle just before the heart contracts) and end-systolic volume (the minimum volume of blood in the ventricle at the end of contraction). They report finding that the cardiac cycle had no significant impact on VLAS. They concluded that "The cardiac cycle ... does not impact VLAS."

In a July 2020 article, a team of Italian veterinary investigators compared measuring the vertebral heart size (VHS) method with the vertebral left atrial size (VLAS) method on x-rays of 80 healthy dogs (including only one cavalier King Charles spaniel and 23 Chihuahuas [29%]) and also to determine VLAS reference intervals for healthy dogs. They used right lateral x-rays and reported finding a positive correlation between VHS and VLAS values and no effect of body weight, sex, or age on VLAS. They concluded that VLAS was a repeatable (meaning, different examiners reached the same measurements) method to quantify left atrial size. The main limitation they acknowledged was that:

"[N]o brachycephalic “screw-tailed” breeds (eg, English Bulldog, French Bulldog, Pug, Boston terrier) were included. These breeds present a typical barrel-shaped thoracic conformation in comparison to other dogs, and a greater occurrence of thoracic vertebral body anomalies that could alter the measurement of vertebral-based methods. The reference interval for VLAS determined in this study may thus not be applicable to brachycephalic dogs."
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• Modified-Vertebral Left Atrial Size (M-VLAS)

 In a February 2021 article, a team of Australian cardiology investigators devised a modification of the Vertebral Left Atrial Size (VLAS) method of measuring the size of the left atrium from x-rays of dogs diagnosed with mitral valve disease (MVD). As they explain it:

"The original VLAS method aimed to quantify LA [left atrium] size radiographically based on a single-dimensional measurement that roughly represented the transverse diameter of the LA body. Yet, LA functional anatomy and geometry is complex, with the left atrium described as a cylinder with an almost fixed head and distensible walls attached to a piston (ie, mitral annulus). The process of LA remodeling is equally complex and non‐uniform. Recognizing the limitations of only using a single 2D lateral radiograph to quantify the complex LA anatomy, the M-VLAS method aimed to complement the existing VLAS method with an additional aspect of measurement, incorporating the dorsoventral dimension of the LA chamber. The goal was to capture dogs with LA remodeling secondary to MMVD that would have otherwise been missed by the VLAS method given its potential limitations as a single-dimensional measurement."

They examined the x-rays of 64 MVD-diagnosed dogs, including 12 cavalier King Charles spaniels (18.75%). They categorized them according to the ACVIM's 2019 stages of MVD (Stages B1, B2, and C). They then measured their new M-VLAS method of calculating the size of the LA and compared it to the VLAS method as well as the Vertebral Heart Size (VHS) and Radiographic Left Atrial Dimension (RLAD) methods, to determine the most accurate in detecting enlargement of the LA. (See Figure 1.) They concluded that:

"M-VLAS, which is superior to VHS, offers an accurate and repeatable way to radiographically identify LA enlargement in dogs with MMVD [myxomatous mitral valve disease]."

M-VLAS Figure 1

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• Radiographic Left Atrial Dimension (RLAD)

In a December 2018 article, a team of European Figure 1cardiology researchers report having devised an addendum to the verterbral heart size (VHS) method of measuring heart size using x-rays in order to measure just the size of the left atrium. The method, called Radiographic Left Atrial Dimension (RLAD), extends a diagonal line from the from the intersection of the long and short VHS axes to the tip of the left atrium. See Figure 1, rght. They performed these measurements on the x-rays of 77 dogs, 31 in group 1 of which had no left atrial enlargement (and included one cavalier King Charles spaniel), and 46 mixed breed dogs in group 2, all of which reportedly did have enlargement of the left atrium. They compared the resulting RLAD measurements with echocardiographic calculations of left atrium size using the ratio of the left atrium width measurement over the aorta width measurement (LA/Ao) and found a "strong correlation" between the two resulting values. They concluded:

"The new radiographic measurement named RLAD demonstrated high sensitivity and specificity for detecting LAE [left atrial enlargement] with a strong correlation with LA/Ao ratio. The proposed optimal cut-off value for RLAD to detect LAE is 1.8v. RLAD would provide clinicians with a simple and cost-effective tool for the detection and monitoring of LAE in dogs with MVD and possibly dogs with other cardiac diseases presenting with LAE."
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• Subjective analysis of x-rays of MVD-affected hearts

A more subjective method of determining heart enlargement from x-rays is to compare the shape of the left artium (LA) and left ventricle (LV) to the known customary shapes of normal canine hearts, particularly of the same breed. Enlarged left atrium on x-rayThe cardiologists look for a more rounded appearance, bulging, and other deviations from the typical normally shaped heart, and whether the heart is impacting the trachea, in addition to the size of the heart.

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• Left Atrium Enlargement (LAE)

Mild left atrial enlargement (LAE) is indicated by a small bump. For moderate LAE, that bump would be clearly enlarged but not huge.  For severe LAE, the bump would appear to be huge on the x-rays. Commonly used criteria for LAE include what are called "Roentgen signs" (named after the discoverer of the x-ray). These signs are: (1) elevation of left mainstem bronchus, (2) loss of curvature of the caudal heart, (3) straightening of the caudodorsal margin of the cardiac silhouette, (4) increased height of cardiac silhouette, (5) divergence of mainstem bronchi, (6) double opacity LA, and (7) enlarged (bulging) left atrium.

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• Left Ventricle Enlargement

The increase in size of the LV does not include a bump. Instead, the enlarged LV is more rounded than a flatter, normal sized LV. In the x-ray above (Fig. 5), the LA is outlined in red. In the x-ray at right, the severely enlarged heart is in the center of the photo, beneath the horizontal spinal column. The LA is the bulging upper right corner. The LV is the rounded portion on the right side, beneath the LA. Comparison of Left VentricleTo compare x-rays of the left ventricle (LV) in a better perspective, here at the left are computer-designed models of a normal sized LV on the left and an enlarged LV on the right. Note that the healthy LV is flatter (elliptical), and the enlarged LV is wider and rounded (globular). (Image from Ljungvall, et al. 2011.)  Dr. John Bonagura has described the appearance of an enlarged LV as a "squashed mushroom".


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• Quality and standardization of x-rays

A downside of relying upon x-rays to detect heart enlargement is the necessarily subjective analyse of the films. Even experienced board certified cardiologists will argue over whether a single set of x-rays shows left side enlargement or not, and if so, its degree. This usually is due to poor positioning of the dog during the x-rays, which is not uncommon.

Two x-rays of the same dog, even taken at the same session, can vary the appearance of the heart. Variations can be due to (1) the stage of the dog's respiration (inhaling versus exhaling), (2) the stage of the heart's contraction, (3) the centering of the x-ray beam, and (4) the position of the dog on the x-ray table, among a few causes. Ideally, all x-rays should be taken as close to the dog's peak inhalation of its breath as possible. This may be very difficult when the x-rays are taken digitally, because there may be a delay between pushing the button and the actual x-ray beam. Even with perfect timing, the heart size changes with each beat -- systole (contraction) and diastole (relaxation). Standardization of x-rays of MVD-affected dogs is very important to assure that when two sets of x-rays of the same dog are compared, the cardiologist is looking at the same position and timing of the dog's heart.  

Maybe a board certified cardiologist can tell from x-rays alone that the LA or LV is enlarged, but as noted above, even they will disagree from time to time, and especially if the positioning of the dog (even flexing the neck can cause misleading shadowing) and quality of the films are less than perfect, or the dog was inhaling in one view and exhaling in another or sedated in one and not in the other. See e.g., Why Is Cardiac Radiology So Difficult? a 2004 article:

“In a recent study two experienced observers examined the radiographs of 57 dogs with common congenital cardiac anomalies without access to any clinical information in order to avoid biasing their interpretations. Under these conditions, the observers reached the correct diagnosis in less than 40% cases. This poor result reflects the difficulty observers had identifying shape changes that can occur in radiographs of dogs with enlarged cardiac chambers. Radiographic signs of specific cardiac chamber enlargement (or pulmonary vascular abnormalities) were recognised by both observers in only 20% instances in which they might be expected.”

See also, this November 2001 article, which concluded:

"Even in the hands of experienced clinicians, survey radiography is an inaccurate method for diagnosing canine congenital cardiac anomalies because of the difficulty in recognising the classic radiographic signs, which are not present in every case. ... The results of radiography should be considered as only one part of the clinical assessment and an attempt should be made routinely to reconcile the clinical signs with radiographic findings in order to avoid placing unwarranted emphasis on the perceived size or shape of the cardiac silhouette alone. ... Clinicians should be very cautious about diagnosing congenital cardiac disease based on survey radiographs and it is not recommended that owners are given advice about the potential for treatment or the prognosis for suspected congenital cardiac anomalies on the basis of survey radiographs alone."

In a 2012 study, a team of Spanish researchers, issued a new VHS measurement, called Objective VHS.

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• Baseline and periodic x-rays

Baseline x-rays are a set of radiographs taken either before or immediately after an MVD murmur is detected. The baseline x-rays are used to compare to later sets to determine if the heart as enlarged. Heart Size Increase Over Time - RVC PhotoPeriodic x-rays of the cavalier's heart, showing the rate of its enlargement, are viewed by many cardiologists as an effective way to anticipating the onset of heart failure (HF). (The series of x-rays at left shows the increase in heart size of one cavalier over 5 years. -- Courtesy of the Royal Veterinary College.)

The amount of enlargement of the left atrium (mild, moderate, or severe enlargement) usually correlates with the degree of mitral regurgitation (MR) -- mild, moderate, or severe MR.

In a September 2011 study of 94 CKCSs*, an international team of cardiologists concluded that the difference in the vertebral heart scale (VHS) per month was a useful measurement for detecting the onset of HF. A formula used by cardiologists to predict when onset of heart failure will occur, is to determine the change in the vertebral heart scale between two x-rays taken within a year of each other, divided by the number of months between those two x-rays. If that number is equal to or higher than 0.08, then the dog likely will be in heart failure within 12 months. However, this formula is not error-proof and should not be the sole determining factor in predicting or diagnosing the onset of heart failure.

* See follow up letters to editor by Dr. Mark A. Oyama and by the authors regarding this study.

In a January 2013 article, the average VHS measurements of eight other dog breeds -- pug, Pomeranian, Yorkshire terrier, Dachshund, bulldog, Shih Tzu, Lhasa Apso, and Boston terrier -- were studied and listed. See also this November 2017 article which focused specfically on the Dachshund.

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• Diagnosing pulmonary edema and heart failure

Chest x-rays also are the only diagnostic imaging modality that can accurately tell if the MVD-affected dog has pulmonary edema (fluid building up in the lungs)or pleural effusion, meaning has reached the point of congestive heart failure. Thus, they are called the "gold standard" for detecting pulmonary edema.

 Identifying pulmonary edema on an x-ray alone (without a high respiratory rate)  does not confirm a diagnosis of heart failure, because pulmonary edema may have other causes. Therefore, to confirm heart failure as the cause of the edema, there must also be mitral valve regurgitation and enlargement of the left side of the heart. Pulmonary edema is shown on x-rays as an in the interstitial density of the lungs. The more severe the edema, the more dense will be the interstitial markings.

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• Angiography and Angiocardiography

Angiocardiograms are x-rays made while a radioactive fluid is inected and is circulating through the heart. The fluid is injected through a catheter into the left ventricle, to observe regurgitation through the affected valve. This procedure has been utilized in MVD-affected dogs since the mid-1960s. See this January 1965 article authored by Dr. Buchanan. (See this comparison between a standard x-ray of a dog's heart at leftand an angiogram of the same heart at right, below.)

Angiogram comparison

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• Cardiothoracic Ratio (CTR)

Another radiographic method of measuring heart enlargement is called the Cardiothoracic Ratio (CTR), a two-dimensional ratio. The CTR is calculated as the percentage of the cardiac silhouette related to the thoracic area.

Cardiothoracic Ratio measurementsThe CTR was proposed in a September 2016 article by a team of Brazilian researchers, using a scheme previously proposed by others for assessing human heart enlargement. Using the "dorsoventral" x-ray of the dog's heart (see the photo at right here, from the article), the CTR is calculated by adding the largest distance from the heart's vertical center line to the right side of the heart (MR) and the largest distance from that line to the left side (ML). Then divide that combined amount by the greatest thoracic diameter (MTD).

CTR = MR + ML
                  MTD

In that article, the Brazilian researchers compared the VHS with the CTR in poodles and concluded:

"Our results demonstrated that VHS and CTR showed strong correlation in their measurements, suggesting that CTR, constantly used in humans, could be considered as a tool to assess the size of the heart silhouette in dogs of the poodle breed."

In a January 2016 article, Romanian researchers reported that the CTR method can discriminate the normal from modified heart size, diagnosed according to the VHS score, in small breed dogs.

In a June 2020 article, University of California at Davis veterinary researchers performed fluoroscopic scans of the hearts of 49 dogs during their cardiac cycles to determine what impact the heart's pumping action may have upon x-ray image measurements to determine the dogs' CTR. Fluoroscopy is a series of low dose x-ray images that show internal organs in motion. Fluoroscopy produces poorer quality images than x-rays and therefore is not as accurate for diagnostic purposes. However, since fluoroscopic images can show a series of images of the heart during its cycling, they were useful in this study in assessing changes in the quantitative measurements of the heart during its cycle. In this study, the investigators measured CTR at the point of end-diastolic volume (the maximum amount of blood in the left ventricle just before the heart contracts) and end-systolic volume (the minimum volume of blood in the ventricle at the end of contraction). They report finding that the cardiac cycle had a significant impact on CTR (mean difference: 2.2 ± 1.2% between systole and diastole). They concluded that "The cardiac cycle has a significant effect on ... CTR ... . These findings should be taken into consideration during clinical use of these measurements, especially if a patient is being monitored for cardiac changes over time via serial radiographs."

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• Manubrium Heart Score (MHS)

Manubrium Heart ScoreIn a February 2017 article, researchers proposed assessing cardiac enlargement based upon comparing the length of the dog's manubrium (the handle-shaped, broad upper part of the sternum, from which the clavicles and first ribs extend). The manubrium of the sternum was selected because, the article stated, "it is a relatively prominent, regularly elongated, bullet-shaped or rectangular bone segment that is easily identified and can be readily measured on lateral thoracic radiographic views." The researchers criticized the reliability of the VHS, stating:

"Additionally, on the basis of the right lateral radiographic findings in this study, the possible variation in the intervertebral disk spaces (eg, intervertebral disk space narrowing) may be another possible factor contributing to the relative weak correlation between the VHS and the corresponding cSAL [cardiac short-axis length] and cLAL [cardiac long-axis length]. However, the canine manubrium is rarely affected by disease, and it is a single prominent, elongated bone segment that can be easily identified on lateral thoracic radiographs. In addition, in the present study, there were strong correlations between the cSAL and cLAL and the corresponding ML. Therefore, we propose that the ML can be used as an appropriate reference value for assessment of the corresponding cSAL and cLAL in dogs."

In an April 2020 article, the same team reported on their study of 184 dogs to evaluate the usefulness of the manubrium heart score (MHS) in distinguishing between dogs with and with cardiac disease. Five cavaliers were included in this MHs study, including one in the healthy control group of small dogs and four in the affected group of small dogs. Their findings included an indication that MHS and VHS were greater in dogs with left-sided cardiac disease, compared to the control group dogs. They concluded that:

"Results indicated that MHSs could be useful, objective radiographic values to help assess dogs for potential heart disease, and we recommend that MHSs be added to the diagnostic tools used by veterinarians when screening for heart disease in dogs."
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• Dexmedetomidine

Dexmedetomidine often is used to sedate dogs before heart x-rays and echocardiographs. In a January 2016 report, researchers examined the effects of dexmedetomidine on six heart-healthy dogs undergoing chest x-rays and echocardiograms to determine if the sedative caused any changes in the resulting measurements. They found that the x-rays and echos performed after dosing dexmedetomidine resulted in significantly higher measurements of the vertebral heart size and cardiac size, and that moderate to severe mitral regurgitation and mild pulmonary regurgitation occurred in all six dogs. They concluded:

"Findings indicated that dexmedetomidine could cause false-positive diagnoses of valvular regurgitation and cardiomegaly in dogs undergoing thoracic radiography and echocardiography."

View other radiographs of dogs with various stages of MVD here, on the website of the Cardiac Education Group.

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-- respiratory rates (breaths per minute)

Sleeping CavalierAn ever increasing respiratory rate (called tachypnea), while the dog is asleep, which approaches or exceeds 30 breaths per minute (bpm), is an indication that the dog is approaching heart failure. This is because the rise in the bpm is due to fluid accumulating in the lungs (pulmonary edema).

Once a dog is diagnosed with MVD and the disease has been progressing, the treating veterinarian may ask the dog's owner to periodically count the number of breaths the dog takes per minute while asleep, and to keep a record of those counts. In an October 2012 study, researching cardiologists found that healthy adult dogs generally have mean sleeping respiratory rates (SRR) or resting respiratory rates (RRR) of less than 30 bpm and rarely exceed that count in the home environment.

While the dog is sound asleep (but not showing signs of dreaming), count the number of breaths the dog takes in 15 seconds. A rise (inhale) and fall (exhale) of the chest count as one full breath or respiration. Then multiply that number by four to get the number of breaths per minute (bpm). If that sleeping respiratory rate (SRR) increases by more than 20 percent over 2 to 3 days, or regularly exceeds 30 breaths per minute, many treating veterinarians would advise the dog's owner to report to them.

Infrequent, extremely rapid breathing rates above 100 bpm are commonly called "panting" (usually over 100 bpm) and should not be counted in this test.

In a 2011 study which compared the effectiveness of (a) respiratory rate, (b) natriuretic peptide concentration, and (c) echocardiogram, in predicting heart failure, the respiratory rate count was more accurate than both of the other procedures. The researchers stated:

"Only respiratory rate predicted the presence of CHF ... with high accuracy. ... Home monitoring of respiratory rate is simple and very useful in the assessment of CHF in dogs with either DCM or MVD."

Every cavalier owner can and should learn this very simple procedure of how to count the breaths of their MVD-affected dogs while they are sleeping. Several cardiologists are recommending that owners become familiar with their MVD-affected cavaliers’ normal sleeping breathing rate and effort and keep logs of their sleeping respiratory rates, to establish a baseline rate for each dog, and report when the dogs’ rates increase to consistent rates approaching or above 30 to 40 breaths per minute. For example, the University of Pennsylvania’s veterinary school advises in a handout available on-line

“When your dog is at rest, watch their sides rise and fall as they breathe normally. One rise and fall cycle is equal to one breath. Count the number of breaths they take in 15 seconds, then multiply this number by 4 to get total breaths per minute. For example, if you count 8 breaths in 15 seconds, that is equal to 32 (8 x 4) breaths per minute. Texas A&M Respiratory Rate BrochureA normal dog at rest should have a respiratory rate less than 40. If you notice this number increasing consistently, or notice an increase in the effort it takes to breathe, contact your veterinarian.”

The vet school at Texas A&M University also has published a handout (right) explaining how to keep track of dogs’ respiratory rates. An excellent YouTube video shows when How to measure a respiratory heart rate in your dogand how every cavalier owner can count the breaths of their MVD-affected dogs while they are sleeping or at rest.

A smart phone app, called Cardalis App, is a useful device for counting respiratory rates. The Android version is available on Google Play, and the Apple version is on iTunes' App Store.

Once the heart failure is controlled by appropriate medication, the respiratory rate may be expected to reduce to a level below 30 breaths per minute. See this January 2016 article.

 Bottom Line: Ask your cavalier’s cardiologist (you do have one, don’t you?) whether and how you should monitor your dog’s respiratory rate for congestive heart failure.

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-- heart beat rates

The "cardiac cycle", or heart beat, consists of the two phases -- contraction and relaxation -- of the heart pumping. When the left ventrical chamber (LV) contracts, the phase is called "systole", and when the LV relaxes, it is called "diastole". The heart rate (HR) is the number of contractions of the heart -- beats -- per minute (bpm).

Changes in the dog's heart rate are tied to changes in cardiac output. Heart rate variability (HRV) reflects variations in the time periods between heart beats. Generally, a low HRV indicates that the dog is under stress, which may be due to exercise, psychological events, or other internal or external events. A higher HRV usually means that the dog has a strong ability to tolerate stress or is strongly recovering from prior accumulated stress. A reduction in HRV in MVD-affected dogs reflects a "sympathovagal imbalance", which has been identified as a risk factor for sudden cardiac death. "Sympathovagal" refers to an interaction between the dog's sympathetic nervous system and its vagus nerve. HRVs reflect the output of the heart as regulated by the sympathetic nervous system. HRV may be determined by using Holter recording devices.

In a February 1996 article in which 107 cavaliers were studied, the Swedish cardiologists found that HRV decreased in MVD-affected cavaliers when compared to healthy CKCSs. They also reported that heart rates were significantly increased in cavaliers in CHF.

In a January 2012 study comparing 70 cavaliers with a variety of MVD severity and 20 non-CKCSs in heart failure (CHF) due to MVD, the investigators report that HRV variables decreased in cavaliers with increasing severity of MVD, while the heart rate (HR) increased with increasing severity. Among dogs of all breeds in CHF, HRV variables did not differ.

In a July 2017 study of 34 asymptomatic MVD-affected dogs, compared to 13 healthy dogs, the results showed that MVD dogs had significant higher heart rate (HR) than the control dogs.

In a November 2010 article studying 33 cavalier King Charles spaniels, increased heart rate  was been identified as having diagnostic value in identifying cavaliers in congestive heart failure (CHF).  However, in a January 2012 study of 256 dogs of several breeds with MVD, heart rate was not among the variables associated with a progression to heart failure.

In a July 2014 report, a Swedish/Finnish/Danish team  examined 78 cavaliers with MVD and found that the risk of the onset of congestive heart failure (CHF) increased with a heart rate greater than 130 beats per minute (and a mitral valve murmur grade of 4 to 6). They noted, however, that relying upon increases in heart rates is not always a reliable indication of the onset of CHF.

The Vasovagal Tonus Index (VVTI), a time-domain indicator of heart rate variability obtained from standard electrocardiographic (ECG) recordings, is used to estimate heart rate variability (HRV). In a June 2004 article, the VVTI of four cavaliers in congestive heart failure were significantly lower than those of the eight other CKCSs in ths study. In an October 2017 article, Brazilian researchers  report finding from ECG and echocardiographic examinations of 120 MVD-affected dogs, that lower VVTI values were found in dogs in congestive heart failure (CHF -- ACVIM Stage C) compared with MVD-affected dogs not yet in CHF (Stages B1 and B2). They found that values were also lower in dogs with severe cardiac enlargement. They stated:

"When a cut-off value of 6.66 is used, VVTI was able to discriminate MMVD patients in stage C from B1 and B2 dogs with a sensitivity of 70 per cent and a specificity of 77 per cent. MMVD dogs in which VVTI is lower than 6.66 are 30% more likely to develop congestive heart failure (CHF)."

Heart rate variability (HRV) is a measure of the oscillations in the intervals between successive, normal heart beats. Poincaré plots are a complicated geometrical method of HRV analysis which is being utilized by some researchers.

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Color Doppler Ultrasound-- ultrasound (echocardiography)

Echocardiography (ultrasound scanning of the heart and connected blood vessels) is a beam of ultra-high frequency sound directed at the heart, and is used to evaluate heart size, function, and valve appearance. The earliest indications of MVD are outwardly invisible and silent and can only be observed by the ultrasound. Echo scans can demonstrate the thickened valve leaflets and their abnormal movement, such as "tethering", "tenting", and  prolapse (MVP). In one study, 26% of dogs diagnosed with MVD by echocardiography did not have a murmur.

Echocardiographing a cavalier's heartEchocardiography enables the cardiologist to assess the size and functioning of the heart chambers. Since MVD affect the size and function of the chambers, particularly the left ventricle (LV) and left artial (LA) chambers, the values determined from echocardiographic scanning are used by the cardiologist as a tool in diagnosing MVD and its progression and severity. There currently are one-dimension (M-mode, or  motion-mode or 1-D), two-dimension (2-D), and three-dimension (3-D) echocardiographic devices used in veterinary cardiology, with the 3-D measurements being most accurate and 1-D the least. because the 1-D and 2-D devices require estimates of chamber volumes, while the 3-D device measures the volumes without requiring estimations. (Photo at right is of veterinary cardiologist Dr. Michele Borgarelli viewing on a computer screen an echocardiographic image of a cavaliers's heart which he is scanning with the probe [transducer] he holds next to the dog's chest.)

Echocardiography cannot diagnose MVD heart failure, because it cannot visualize lung congestion -- pulmonary edema -- which is the hallmark of Stage C mitral valve disease, called congestive heart failure (CHF). To detect pulmonary edema, the veterinarian needs to examine chest x-rays or perform a lung ultrasound (LUS), also called a point-of-care ultrasound (POCUS).  See Lung Ultrasound, below.

Echo can  identify findings that are compatible with MVD heart failure, such as a severely enlarged left atrium or ruptured chordae tendineae. Although a mis-nomer, the so-called gold standard* test to assess left atrium (LA) size in dogs is the 2-dimensional echocardiography (2DE).

* Elevated left atrial pressure (LAP) is the most common sign of MVD in affected dogs. Cardiac catheterization may be called the "platinum" standard because it is the most accurate method of measuring the elevation of LAP. However, catheterization is very invasive and requires anesthesia.

Echocardiography should be considered a complementary technique to radiography (x-ray) and not a substitute. X-rays provide more information regarding overall heart size and shape, while ultrasound enables assessment of the cardiac structures and function. Echo examinations normally are performed on unsedated, restrained dogs, which may cause increased stress levels and higher heart rates in some dogs. Also, echocardiography is not a totally reliable means of diagnosing the condition of the dog's heart. To effectively verify changes in a dog's heart by echocardiography, such as increases in the sizes of heart chambers, repeat echos should be performed over a period of months or even years. This is called serial echocardiograhic variables. Ideally, the same cardiologist should perform any and all repeat echos of an individual patient. Cardiologists Drs. John Bonagura and Virginia Luis Fuentes stated in an October 2020 book:

"Most echocardiographic studies are repeatable in experienced hands; however, results can be highly operator and equipment dependent. Foremost, all clinicians should practice within their level of knowledge, training, experience, and expertise, and should not hesitate to send patients to cardiac specialists when referral will serve the best interests of the patient and client." (Emphasis in original.)

In a 1999 study of cavaliers which had no MVD murmur, echocardiographic screenings showed that 82% (54/66) of those dogs aged one to three years had mitral valve prolapse (MVP), and 97% (84/87) of the dogs over age three years had MVP. In a 2015 echocardiographic study of 126 CKCSs in the UK, all aged from 8 to 16 years of age, all dogs had mitral valve thickening and regurgitation; mitral valve prolapse was found in 111/126 (88%), of which 20/111 (18%) were severe; 100% showed echocardiographic evidence of MVD, however a low prevalence of markers of disease severity were found.

Chronic degenerative valvular disease in a dog, heart, echocardiogram, right parasternal long-axis view; LA-left atrium; LV-left ventricle; MV-mitral valve, septal leaflet. Note the thickened free end of the mitral valve leaflet.Echocardiogram Diagram

The echo image at left shows a dog's heart with MVD. LA-left atrium; LV-left ventricle; MV-mitral valve, septal leaflet. Note the thickened free end of the mitral valve leaflet at the left of the valve. The diagram at right shows the view more clearly.

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Mitral Regurgitation (MR)

 An important part of an echocardiographic examination is an assessment for the presence and measurement of mitral regurgitation (MR). The amount of enlargement of the left atrium (mild, moderate, or severe enlargement) usually correlates with the degree of MR -- mild, moderate, or severe MR.  MR is the ratio of regurgitant jet area (RJA) to LA area (RJA/LAA) is commonly used as a method to assess the severity of MVD.

 The severity of mitral regurgitation (MR) can be assessed on color flow Doppler recordings and has been and classified (see this  July 2017 article) as:

 • No MR = 0%
• Mild MR = 1% to 20%
• Moderate MR = 20% to 50%
• Severe MR = over 50%
• Intermittent MR = no or mild MR in the majority of cardiac systoles but with some MR jets ≥20%.

In a June 2019 article, the severity of MR was classified thusly:  

• Mild MR: <20%
• Moderate MR: 20% to 50%
• Severe MR: >50%

In that July 2017 article, cardiologists who studied the echos of 1,125 cavaliers aged between 1 and 3 years reported that CKCSs in that age group with moderate to severe MR and intermittent MR had significantly increased hazard of cardiac death compared to dogs with no MR. This may seem obvious, but with a 1,000+ group of dogs, it makes it pretty much conclusive for cavaliers.  However, this finding was not the case when MR was based on murmur intensity on auscultation. Thus, this emphasizes the importance of assessing MR using echocardiograph.

In a September 2017 article, Virginia-Maryland Veterinary School cardiologists Giulio Menciotti and Michele Borgarelli and Utrecht University cardiologist Sandra Müller utilized measurements of the size of the regurgitant gap in the mitral valve -- called the "anatomic regurgitant orifice area" (AROA) -- to determine if that measurement compares to the severity of mitral regurgitation (MR) assessed by an echocardiographic scoring system (MRSS). They devised four classes of the MRSS -- normal, mild, moderate, and severe. They used "real-time three-dimensional transthoracic echocardiography" (RT3DE) to arrive at the AROA dimensions. Eleven cavalier King Charles spaniels were included in the 60 dog, 25 breed, study. They found that The AROA was significantly greater in dogs with a severe MRSS compared with dogs with mild MRSS, and that there was no difference between the AROA of dogs in different ACVIM clinical stages (i.e., Stages B1, B2, C). They concluded that it is feasible to obtain the AROA in dogs with MVD using RT3DE, and that the AROA of dogs with severe MR is greater than the AROA of dogs with mild MR.

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• Left Ventricle Shape

It is possible for some well-experienced echocardiographers to recognize enlargement of the left ventricle (LV) on the device's screen, especially if the enlargement is moderate to severe (as opposed to mild). An enlarged LV will have a more spherical shape than a normal one, with rounding at its apex and a squashed appearance of the mushroom-shaped LV lumen at the papillary muscle level. See this October 2020 article.

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• Measurements Taken

 During echo exams, the operator typically also will take measurements of the heart to determine if it has enlarged and the likely onset of heart failure (HF). Measurements typically include:

(1) the interventricular septal end diastole (IVSd) and end systole (IVSs) in millimeters (mm);
(2) the left ventricular internal diameter end diastole (LVIDd) and end systole (LVIDs) in mm;
(3) the left ventricular end-systolic diameter normalized for body weight (LVIDSn) in mm;
(4) the left ventricular internal diameter end diastole (LVPWd) and end systole (LVPWs) in mm;
(5) the left atrial (LA) in mm, and the aortic root (AO) in mm, to determine that ratio (LA:AO); and
(6) the left ventrical (LV) diastolic volume and the LV systolic volume, from which the operator may calculate the fractional shortening percentage (FS%); and
(7) mitral E wave velocity, which is the peak velocity flow in early diastole.

Canine Normal Echocardiographic Values

In a November 2014 article, cardiologists comparing mitral valve murmur intensity with the severity of MVD defined cardiac enlargement "as an increase in at least two of the three echocardiographic variables (LA:Ao, wLA and wLVID) above previously established reference intervals."

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• Left Atrial-to-Aortic ratio

In MVD-affected dogs, enlargement of the left atrial (LA) chamber is usually LA/Ao measurementsassessed by the "left atrial-to-aortic ratio" (LA:Ao or LA/Ao). The LA:Ao uses the relatively fixed diameter of the aorta to assess the degree of left atrial volume loading.

While the LA:Ao ratio, if carefully and accurately calculated, unquestionably can be used to determine the linear width of the LA, that ratio by itself does not determine whether the width of the LA means that the dog's LA is enlarged or not. A comparison of two sets of LA:Ao measurements -- a baseline set taken previously and a current set taken months or years later -- will show whether the LA has enlarged in the interim. But a single measurement of the LA:Ao is static and only tells what the current dimension is and not whether it is larger than it has been in the past.

Nevertheless, several veterinary cardiologists have arbitrarily equated an LA:Ao ratio of 1.6 as the definitive dividing line between a normal sized heart and an enlarged one on a species-wide basis. This assumption appears to have begun with the 2012 PREDICT Cohort Study in which the authors state, without any statistical support whatsoever: "We defined cardiac remodeling as an LA:Ao of 1.6 based upon 2D echocardiographic examination." That arbitrary and un-scientific tactic has been followed by the 2016 EPIC Study, the 2019 ACVIM Consensus Guidelines, and several others.

Interestingly, the only piece of veterinary literature which any of these articles reference to support their species-wide choice of LA:Ao = 1.6 is a November 2002 article, in which researchers Drs. Jens Häggström, Kjerstin Hansson, and Clarence Kvart measured the LA:Ao ratio of 166 CKCSs (that is, only CKCSs and no dogs of any other breed), 56 of which were normal and 110 having varying degrees of severity of mitral regurgitation due to MVD. They found that the LA:Ao ratio for the normal dogs was 1.03 ± 0.09 in 2-D mode, and that the ratio for cavaliers with MVD was 1.61 ± 0.57 in 2-D mode. In that November 2002 study of only cavaliers, the researchers stated:

"In this study, we have deliberately refrained from introducing index ranges for mild, moderate, and severe enlargement, because the grading would be arbitrary and was not included in the study design."

In a March 1995 study by these same researchers, of 79 CKCSs in varying stages of MVD, at least one cavalier with an enlarged left atrium had an LA:Ao as low as 1.31, significantly lower than this new arbitrary species-wide definition of enlargement starting at LA:Ao ≥1.6.

In a November 2019 article, the cardiologists-researchers reported that 28 (12%) of the 233 dogs in their study, all with normal-sized left atriums, had LA:Ao ratios above 1.6, including Jack Russell terriers, Italian hounds, English setters, collies, Cocker spaniels, boxers, Beagles and mixed breeds. Seven of those healthy dogs had LA/Ao ratios over 1.7.

This LA:Ao method has been discredited for accuracy in diagnosing LA enlargement since a July 2014 article, in which the researchers observed that LA:Ao measurements were far inferior to the bi-plane volumetric assessment, called LA volume indexed to body weight measurements (LA Vol/BW), when comparing the two methods in 82 dogs, including 9 cavaliers. Nevertheless, the LA:Ao measurements continue to be relied upon in many echo examinations of MVD-affected dogs suspected of having enlarged hearts.

In a January 2008 article, an Italian team of researchers, led by Dr. Michele Borgarelli, studied 558 MVD-affected dogs among 36 breeds, with various degrees of mitral valve regurgitation. Among the variables, for cardiac-related death, the only significant variable was LA/Ao >1.7.

In a July 2017 article, cardiologists who studied the echos of 1,125 cavaliers* aged between 1 and 3 years unexpectedly found that CKCSs in that age group with a lower value of LA/Ao significantly increased the hazard of cardiac and all-cause mortality. They noted:

"This was not expected and counterintuitive as it is generally accepted that increasing LA/Ao is a risk factor in MMVD. Again, it should be kept in mind that the dogs are very young and that all LA/Ao values were within a very narrow range and all within reference ranges of normal dogs and thus could represent a finding occurring at random."

*These dogs were privately owned and chosen from a database of CKCS used primarily for breeding purposes.

In a January 2017 article, Bulgarian cardiologist Atanas Pankov compared LA/Ao measurements of 20 MVD-affected dogs with weight idealized aortic size (LA/Aow). He pointed out that weight loss in MVD patients is associated with the progression of the cardiac decompensation and should not be excluded when reporting the progression of the process. He reported that the results from echocardiographic measurements with the weight idealized measured aortic size have h a higher reliability in comparison with the LA/Ao ratio method. He concluded that the indexing of M-mode echocardiographic measurements with weight aortic size is more suitable in comparison to the indexing with the linear aortic size, where in the case of this indexing the weight loss with progression of the heart failure is also noted.

In an August 2018 article, Oregon State Univ. researchers discourage the continued reliance upon LA:Ao measurements to determine enlargement. They state:

"Our results also suggest that there are limitations to using a single linear dimension (LA:Ao) to assess LA size. The LA is a complex cardiac structure that can enlarge in multiple planes, so single measurement may not accurately reflect actual LAE. This is supported by the stronger agreement of radiographic LAE with LAV, rather than LA:Ao. Owing to the eccentric manner in which atrial enlargement occurs, large differences in overall LA size may be misrepresented by a small range of LA:Ao values. Enlargement of the LA primarily in the dorsal-ventral orientation may not be apparent in the single plane LA:Ao measurement, while enlargement in multiple directions is incorporated into the LAV value by tracing the LA border. In addition, dividing by the aortic dimension is an attempt to index LA size to a cardiac structure that theoretically does not change much in disease states. However, the size of the aorta may vary throughout the cardiac cycle. While LA:Ao is less time consuming than volumetric measurements, this study and other recent veterinary studies emphasize the limitations of the LA:Ao measurement. Furthermore, the American Society of Echocardiography guidelines recommend that LA size be measured by biplane LAV using the MOD in people. Consequently, we used LAV in addition to conventional LA:Ao measurements to categorize echocardiographic LAE. As there is no established veterinary consensus among cardiologists to delineate degrees of LAE to the authors’ knowledge, our results may have differed with the use of different LA:Ao and LAV classification schemes."
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• Simpson's Method

Another means of measuring the sizes of the left atrium and left ventricle is the "biplane Simpson's method of discs" (SMOD), also known as the "modified Simpson's rule". This is deemed a more accurate measurement method of left atrium and left ventricle volume than the two-dimensional left atrial to aortic ratio (LA:Ao) and left ventricular internal diameter in diastole, normalized for body weight (LVIDDN) because it consists of the summation of measurements of the heart chamber as if it was a stack of elliptical disks.

In an October 2018 article, the investigators found that the Simpson's method was in agreement with the LA:Ao ratio and demonstrated a good assessment of atrial function. In a February 2020 article, members of that same research team found that The Simpson's method was sensitive to the early detection of left atrial dysfunction and can measure atrial deformation even in asymptomatic dogs, as well as the progressive decline in atrial function as the MVD progresses.

In a March 2021 article, a team of German cardiology investigators  applied the Simpson's method a linear method in measuring the left ventricles (LVs) of 1,331 dogs of 128 breeds, including 16 (0.01%) cavalier King Charles spaniels. They produced a single set of reference intervals (the range from the lowest to the highest measurements) for healthy LVs in non-sighthound breeds (see Table 4, below). They conclude:

"Our study provides echocardiographic RIs [reference intervals] for SMOD, independent of breed and size and might enable veterinary cardiologist to use this method for all dogs, using the PLAX [parasternal long axis] or A4C view {apical 4-chamber view] or both."

Simpson Method Reference Intervals

In a June 2021 abstract, University of California-Davis cardiologists used Simpson’s method of disks (RF_SMOD) to estimate total stroke volume (TSV) in 81 dogs with MVD and compare it to regurgitant fraction (RF) using M-mode to estimate TSV (RF_M-mode). They also evaluated the effect of pimobendan on RF and the reproducibility of RF. They concluded that RF_SMOD might aid the echocardiographic assessment of MMVD and should be considered for multifactorial approaches to determine disease severity.

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• Mitral E wave peak velocity

 The peak velocity of the Doppler E wave in early diastole is considered a measure of mitral regurgitation (MR) severity. E wave usually is measured using pulsed wave Doppler but can be measured using continuous wave Doppler. An E wave velocity (Emax) >1.2m/s is a measure of severe MR. See this January 2008 article.

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• Color Flow Doppler

Color flow Doppler echocardiography provides information regarding mitral valve regurgitation, including the size of the regurgitant jet, its width and spatial orientation, as well as flow convergence into the regurgitant orifice. The color Doppler can evaluate the direction and velocity of blood flow, quantifying blood leakage. It can be used to distinguish MVD from benign murmurs in ambiguous cases. The Doppler may detect leakage before it is audible as a murmur. However, trivial regurgitation of blood through the mitral valve may be present in as many as 50% of normal dogs. In such cases, however, there is no MVP or valve thickening present. Trivial regurgitation ranges up to less than 15% of left atrial area; mild regurgitation ranges from 15% to 50%; modeate to severe regurgitation is greater than 50%.  (The color Doppler view below shows red blood at the top, regurgitating from the mitral valve of this CKCS.)

Haggstrom Color Doppler of Mitral Regurgitation

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• 3-D Echocardiograms

Mitral Valve Annulus Diagram3-D echos* have enabled cardiologists to more clearly observe  the functioning of the mitral valve, including "tethering" of the valve's leaflets, and the dimensions of the "tenting" area created during the tethering. In some instances, 3-D echo measurements of cavaliers' mitral valves have shown that CKCSs' valves structural features differ from those of other breeds, which may explain why the onset of MVD in cavaliers is earlier and progresses more rapidly than in the average canine. In a September 2016 abstract, an international panel of cardiologists used 3-D echocardiography to compare the mitral valves of 22 cavalier King Charles spaniels with 41 other dogs of 18 different breeds. They measured the dimensions of the mitral valve's annulus (see diagram at right), tenting (see diagram at left below), leaftet areas, and several other categories.

* 3-D echos are technically referred to as real-time transthoracic three-dimensional echocardiography analysis (RT3DE).

They found that cavaliers had significantly smaller annulus diameter, annulus height, tenting height, tenting area, normalized tenting volume, posterior leaflet length, normalized posterior leaflet area, and a greater annulus sphericity index. They concluded that the mitral valve of healthy CKCSs was more circular and had less tenting, compared to other Mitral Valve Tentingbreeds.

The echocardiograph examination shows the dimensions of the heart chambers, wall thickness and movement, valve movement and lesions, fractional shortening, among other characteristics. The echo screen shows the amount of wall contraction, which enables the operator to determine contractility, preload, and afterload. These factors are used to calculate "fractional shortening" (FS%) which is used as an indication of ventricular performance and of myocardial contractility.

 See, also, this March 2017 article, in which the same investigators used 3-D echocardiography analysis on 113 dogs, including 13 cavaliers affected in varying stages of MVD. The 3-D echos enabled the investigators to compare the morphology of the mitral valves (MVs) of healthy dogs (none were CKCSs) and MVD-affected dogs. They report that the study demonstrated that the MVs of MVD-affected dogs differed from those of healthy dogs in several morphological aspects. In particular, the affected dogs had an increased sphericity and a decreased saddle shape of the MV annulus, as well as a decreased tenting height, area and volume. See Figure 1. The study also reportedly demonstrated significant differences in multiple 3-D echo MV measurements between dogs in varying stages (B1, B2, C) of MVD.

Figure 1

In an April 2021 article, Japanese cardiology researchers used three-dimensional transesophageal echocardiography (TEE) to examine 31 MVD-affected dogs, including 9 in Stage B2, 15 in Stage C, and 7 in Stage D. The TEE was performed while the dogs were under anesthesia prior to mitral valve repair surgeries. They found that the annulus height to commissural width ratio of Stage D dogs had significantly lower values than Stage B2 dogs, and that the aortic-mitral angle of Stages C and D dogs were significantly flatter than those in Stage B2. They concluded that the saddle shape of the mitral annulus and aortic-mitral angle were flatter in Stage D than those in the other two stages.

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• Tissue Doppler Imaging

An advanced version of the Doppler ultrasound, called Tissue Doppler Imaging (TDI), has been found to be more sensitive than conventional ultrasound in human medicine. TDI reportedly has been able to detect early myocardial dysfunction in patients with a left ventricular (LV) volume overload induced by mitral regurgitation (MR). TDI also has been tested on dogs and also has been found in a December 2005 study to detect congestive heart failure (CHF). A still more advanced version, known as color Doppler (CD) TDI, was tested in a study published in January 2015 by South Korean researchers. They found that CD TDI was more useful in detecting CHF and that one TDI variable (TDI-derived E/Em sept), which evaluated diastolic function, could be an important predictor of CHF in dogs with MVD.

Contrast echocardiography is a technique for improving echocardiographic resolution in order to assess blood flow. An agitated saline solution provides contrast in the left ventricular (LV) cavity, improving assessment of the left ventricular dimensions, wall motion, and mitral regurgitation.

For cavaliers' hearts, it is recommended that ultrasound scanning be conducted by specialists, preferably board certified veterinary cardiologists.

In an October 2015 report, Drs. Julia Sargent, Virginia Luis Fuentes, and Holger Volk, of the Queen Mother Hospital for Animals at the Royal Veterinary College in the UK, have developed a new echocardiographic scoring system to grade the severity of mitral regurgitation in chronic mitral valve disease, based upon a number of different measurements that they believe can offer more reliable information on the severity of MVD. They are testing their new scoring system by comparing it to cardiac magnetic resonance imaging (cMRI), which is considered the most reliable test for quantifying valve disease in humans. They have determined that the echocardiographic measures that correlated most closely with cardiac magnetic resonance imaging-derived mitral regurgitant fraction were vena contracta/aortic diameter and E-wave velocity.

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• The Tei Index

The Tei Index (RVTX)In a January 2016 article, a team of Hokkaido University, Japan, veterinary researchers calculated the "right ventricular Tei-index" (RVTX)* of 30 dogs diagnosed with MVD by echocardiograph. The dogs were included in Group A (19 dogs) if they survived a year from their first echo, and in Group B (11 dogs) if they suffered cardiac-related death within that year. A lack of tricuspid regurgitation (TR) velocity in 2 of the 11 dogs in Group B disqualified them. All of the remaining 9 Group B dogs (which died during the first year) had increased RVTX (≥0.61). Three of the dogs with lower RVTX (<0.61) died before the study ended but after the first year, and the 18 other dogs with lower RVTX were alive when the study ended.

Notwithstanding the small number of dogs involved, the researchers concluded:

"The results of the present study indicate that RVTX is strongly correlated with early death in dogs with MMVD. Although several echocardiographic variables were significantly different between the two groups, we found that RVTX, a variable that corresponds to the RV function, was the most significant independent predictor of mortality. This study demonstrates that RV function analysis may be the most reliable prognostic indicator for dogs with MMVD."

* Dr. Chuwa TeiIn 1995, Dr. Chuwa Tei (right) devised an index of myocardial performance (the Tei index) that evaluates the left ventrical (LV) systolic and diastolic function in combination. The Tei index reportedly is a reliable method for the evaluation of LV systolic and diastolic performance, with advantages over previous indexes and prognostic value in many kinds of heart disease. Calculation of the Tei index is a number calculated from the ratio of time intervals (a-b/b) determined by pulsed Doppler echocardiography. See this December 1995 article, this November 1996 article, and this January 2005 article.

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• Left ventricular torsion (LV-Tor)

Another function of the heart which is observable via echocardiograph  Contraction Torsionis its contraction, measured by left ventricular torsion (LV-Tor). In human MVD, cardiac surgeons have been focusing on the relative amounts of LV-Tor in patients slated for heart surgery. When the heart contracts, it essentially is a "wringing" or "twisting" motion by which the top half of the heart rotates counterclockwise and the bottom half rotates clockwise. (See diagram at right.) The net difference of the degrees of rotation of the two halves of the heart is referred to as "torsion". This activity is observable by echocardiograph. Normal human hearts show a net torsion of approximately 15º, and as the ejection fraction decreases and the heart enlarges, torsion also decreases. Therefore, a reduction in torsion may be a marker of enlargement of the left ventricle. See this June 2016 article.

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• Speckle-tracking echocardiography (STE)

Two-dimensional speckle-tracking echocardiography (STE) is a novel, angle-independent imaging method that allows assessment of strain and strain rate in heart chambers, using the tracking of acoustic speckle patterns. Speckle-Tracking EchocardiographyIt is based upon software which tracks speckles (natural acoustic markers in the myocardium) during the cardiac cycle. In a February 2017 article, a team of veterinary researchers at Hokkaido University in Japan used STE to determine the variations in the extent of strain in the left atrium in the differing MVD stages. "Strain" represents deformation of a myocardial chamber over time. It is based upon the formation of "speckles" -- a series of ultrasonographic components attributable to reflection, scattering, and interference between tissue and ultrasound beams -- that can be tracked over time in 2-D echocardiograms. The researchers found that there were no significant differences in parameters of LA strain between the Stages B1 and B2 groups. However, LA longitudinal strain during atrial contraction and during ventricular systole were significantly lower in Stages C and D than in Stages B1 and B2. They concluded:

"In conclusion, the results of the present study indicate that LA longitudinal strain was significantly lower in dogs in the advanced stages [Stages C and D] of MMVD. LA longitudinal strain during atrial contraction was the best predictor of the presence or history of CHF. LA strain assessed on conventional echocardiography and radiography could add meaningful information to confirm the presence of CHF in the clinical setting. Further studies are needed to determine the clinical implications of these findings for treatment decisions and/or prognosis determination."

In an April 2017 study of 150 dogs in various stages of MVD, including ten cavaliers, Italian investigators concluded that, "Left atrial STE analysis provides useful information on atrial function in the dog, highlighting a progressive decline in atrial function with worsening of MMVD."

In a February 2018 article, Italian and USA researchers examined 96 MVD-affected dogs (7 were cavaliers) using STE to measure left atrial (LA) longitudinal strain and other variables between Stages B1, B2, and C. They report finding that no STE variables differed between Stage B1 and B2 dogs but were lower in Stage C dogs. They concluded that MVD-affected dogs in CHF appear to have lower LA longitudinal strain and strain rate variables compared with dogs in Stage B.

A review of research into STE in detection of left ventricular dysfunction in dogs is this August 2021 article.

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Tissue motion annular displacement (TMAD)

Tissue motion annular displacement of the mitral valve (TMAD) is a refinement of speckle-tracking echocardiography (STE) which measures the mitral valve's annular motion, taking the length of the left atrium (LA) and the left ventricle (LV) into account. It can provide an index of LA and LV function. Studies are being conducted using TMAD to distinguish between MVD-affected dogs in the various stages of severity (B1, B2, C, and D) to complement the more standard methods -- x-rays and more traditional echocardiographic examinations.

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• Lung ultrasound examination (LUS)

Lung ultrasound (LUS) has higher sensitivity than lung auscultation and LUS B-lines from cardiogenic pulmonary edemachest x-rays for many respiratory conditions. In a March 2017 article, a team of Italian researchers used LUS to examine the conditions of dogs in different stages of mitral valve disease (MVD), to distinguish lung patterns leading to congestive heart failure (CHF). They report detecting "B-lines" (also called ultrasound lung rockets) representing interstitial edema. (See image of LUS B-lines at left.) The number and distribution of these B-lines correspond to the presence of extravascular fluid in the lungs and indicate the severity of pulmonary edema (PE) and stage of its progression. Dogs in Stage B1 of MVD had absent or rare B-lines in 14 of 15 cases (93.3%); dogs in Stage B2 had absent or rare B-lines in 16 of 18 cases (88.9%); all dogs in Stage C without radiographic signs of PE, had absent or rare B-lines; dogs in Stage C with radiographic signs of PE, had numerous or confluent B-lines in 18 of 20 cases (90%). They concluded:

"Our findings indicate that LUS has good diagnostic accuracy in identifying cardiogenic PE and might be useful in the staging of dogs with CVHD [chronic valvular heart disease]. Lung ultrasound examination is Point-of-care ultrasounda new, quick, and noninvasive diagnostic tool for the cardiologist, radiologist, or intensive care specialist. It should be considered as complementary to thoracic radiography, and particularly useful when radiographic findings are unclear or in severely dyspneic dogs. In the future, it would be interesting to evaluate the utility of LUS in the chronic management and serial monitoring of dogs with CVHD under treatment."

LUS is also referred to as Point-Of-Care Ultrasound (POCUS). (See photo at right.)

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• Measuring pulmonary hypertension

Pulmonary hypertension -- abnormally high pressures in the pulmonary blood vessels -- is a typical complication of MVD-affected dogs. It normally is measured in humans by cardiac catherization, a complicated invasive procedure which involves inserting a catheter in the right side of the heart. Because of such complications, it rarely is performed in veterinary practices.

Drs. Michele Borgarelli and Jonathan Abbott of the Virginia Tech University's Virginia-Maryland College of Veterinary Medicine are conducting a study comparing pulmonary hypertension by the catheter method with echocardiography. See this article for more information in this on-going study.

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• Dexmedetomidine

Dexmedetomidine often is used to sedate dogs before heart x-rays and echocardiographs. In a January 2016 report, researchers examined the effects of dexmedetomidine on six heart-healthy dogs undergoing chest x-rays and echocardiograms to determine if the sedative caused any changes in the resulting measurements. They found that the x-rays and echos performed after dosing dexmedetomidine resulted in significantly higher measurements of the vertebral heart size and cardiac size, and that moderate to severe mitral regurgitation and mild pulmonary regurgitation occurred in all six dogs. They concluded:

"Findings indicated that dexmedetomidine could cause false-positive diagnoses of valvular regurgitation and cardiomegaly in dogs undergoing thoracic radiography and echocardiography."
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-- cardiac magnetic resonance imaging (cMRI)

Cardiac magnetic resonance imaging (cMRI) is reported to be an accurate technique for quantifying ventricular function, left ventricular (LV) volume and function (including end-diastolic volume, end-systolic volume, stroke volume, and ejection fraction), as well as assessing mitral valve regurgitation and the size of the mitral regurgitant orifice in both humans and dogs. Indeed, cMRI has been described as a "gold standard" for those measurements.

Because of the inconvenience and expense of MRI scanning, and the necessity that the dog be anesthetized, in is seldom used for clinical diagnoses. However, it has been used to verify the accuracy of echocardiographic diagnosing. In a November 2013 article, a team of Korean researchers confirmed the accuracy of contrast echocardiography (CE) compared with unenhanced echocardiography (UE) in measuring LV function. In an October 2015 article, which included cMRIs of cavaliers, UK researchers determined that the echocardiographic measures that correlated most closely with cMRI mitral regurgitant fraction were vena contracta/aortic diameter and E-wave velocity.

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-- computed tomography (CT)

Computed tomography (CT) is an imaging method using digital geometry processing to generate a three-dimensional image of the inside of an object from a large series of two-dimensional x-ray images taken around a single axis of rotation. Multi–detector row computed tomography (MDCT). with its use of a 64-slice scanner, allows 3-D reconstruction of images and enables the cardologist to make measurements in any desired plane.  In studies reported in March 2012, July 2013, and November 2016, MDCT has been found to be an accurate technique for assessing LV volume and function variables, comparable to MRI measurements.

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-- electrocardiography (ECG or EKG)

ElectrocardiogramElectrocardiography (ECG or EKG) is a diagnostic tool that measures and records the heart's electrical activity. Multiple, advanced resting electrocardiographic techniques have been applied to humans to detect cardiac diseases before onset of symptoms or changes in the standard ECG. It is considered the gold standard for detecting arrhythmias.

 In a June 2011 study by Slovenian and Danish researchers, they were able to use advanced ECG to predict the severity of mitral regurgitation in dogs with MVD.  They reported:

"Our results indicate that for a cut-off criteria of MR [mitral regurgitation] 50% jet the five selected ECG parameters could predict the severity of MR caused by MMVD in CKCSs with sinus rhythm with sensitivity 65% (78% with age inclusion) and specificity 98% (92% with age inclusion) (P < 0.05)."

In a September 2016 article which included CKCSs with MVD, researchers found that sinus rhythm is the most common rhythm disturbance in dogs with MVD, compared to supraventricular rhythm in dogs with dilated cardiomyopathy. They also found that the duration of QRS complex (Q-wave; R-wave; and J-point of S-wave)was significantly higher in dilated cardiomyopathy group.

In an August 2017 article, Spanish researchers found that electrocardiographic P wave-related parameters (classical and newly described) had low sensitivity (range=52.3% to 77%; median=60%) and low to moderate specificity (range=47.2% to 82.5%; median 56.3%) for the prediction of left atrial enlargement. Note that newly described P wave-related parameters include P wave area, Macrux index and mean electrical axis, and classical P wave-related parameters are voltage and duration of P wave.

In a September 2019 article, researchers found that there is a gradual increase in the ECG value of intrinsicoid deflection (DI) as the stage of MVD progresses from Stage B1 to B2 to C, associated with left ventricular overload. They concluded that DI measurments can be use to classify MVD-affected dogs.

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-- cardiac catheterization

Elevated left atrial pressure (LAP) is the most common sign of MVD in affected dogs. Cardiac catheterization is the most accurate method of measuring the elevation of LAP. However, catheterization is very invasive and requires anesthesia. In this September 2004 article, echocardiographic estimation of LAP, by calculating the E-peak velocity (E-peak) to Ea-peak ratio (E/Ea ratio) was found to correlate well with the mean LAP in dogs.

Cardiac catherization of the right side of the heart is consdered the "gold standard" for diagnosing pulmonary hypertension (PH) -- increased blood pressure in the lungs' arteries -- because it measures the pulmonary arterial pressure (PAP) directly in the lungs' blood vessels.

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-- natriuretic peptides tests (ANP and BNP)

There has been much research into attempting to diagnose MVD, and more particularly, to diagnose the onset of heart failure (CHF) in dogs, by measuring "cardiac biomarkers", such as plasma concentrations of the natriuretic peptides: atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP).

Natriuretic peptides are hormones manufactured and secreted by areas of the heart. ANP is responsible for the regulation of blood pressure and body fluid homeostasis. BNP  has diuretic, vasodilatory, and anti-remodeling properties which is produced by myocardial cells in response to heart failure. They both can be used as biomarkers specifically to detect cardiac disease and congestive heart failure in dogs (and cats). Heart wall stress in response to volume overload increases the production of natriuretic peptides such as NT-proBNP from cardiomyocytes. Therefore, increased measured quantities of natriuretic peptides can indicate enlargement of the heart due to MVD. 

A test of natriuretic peptides measures the quantity of the natriuretic peptides in the dog's blood. Elevated levels of these natriuretic peptides in the blood may be directly related to heart defects, and natriuretic peptides in the blood become elevated only after the heart has to pump harder to compensate for the disorder. In particular, BNP is secreted by the left ventricle in response to heart wall stretching or stress.

A 2003 study (conducted by Drs. Kristin A. MacDonald, Mark D. Kittleson, Coralie Munro, and Philip Kass of the University of California at Davis) has shown a positive correlation between BNP and heart disease and CHF in dogs. In that study, BNP increased with the progressively increased severity of mitral valve disease and CHF. For every 10-pg/mL increase in BNP, the 2003 study's dogs' mortality rate increased approximately 44% over the four months of the study. In a 2005 study, Drs. William E. Herndon, Justine A. Lee, Kenneth J. Drobatz, and Matthew J. Ryan concluded that "With further investigation, this new BNP assay may someday provide a widely available noninvasive diagnostic test with rapid turnaround time to help diagnose and/or treat heart disease and congestive heart failure in the dog."

However, in earlier studies (1994 and 1997) conducted by Drs. Jens Häggström, Kjerstin Hansson, Clarence Kvart, and others, the researchers have suggested that BNP levels in cavaliers with mitral regurgitation did not rise as dramatically as in humans, and that N-terminal (NT)-proANP (NT-proANP) may better reflect the severity of mitral regurgitation in cavalier King Charles spaniels than NT-proBNP tests.

Four trademarked names for NT-proBNP tests are Canine CardioCare (Veterinary Diagnostics Institute), Canine VetSign CardioSCREEN (Guildhay Ltd.), Cardiopet proBNP (IDEXX Laboratories), and Antech Cardio-BNP (Antech Diagnostics). There have been studies showing the effectiveness of these types of tests for dogs suffering from asymptomatic occult dilated cardiomyopathy (DCM), which is not the same disorder as MVD and is not known to be a genetic problem for cavalier King Charles spaniels.

Natriuretic Peptides Whichever test (NT-proBNP or NT-proANP) is found to be more accurate for detecting MVD, it is believed by some researchers that the test may be useful in assisting examining veterinarians in deciding whether or not detected heart murmurs are innocent or are pathologic in nature. However, in a 2007 study of 54 CKCSs by Drs. Tarnow, Pedersen, Kvart, and others from Denmark and Sweden, they found that "Natriuretic peptides are elevated in cavalier King Charles spaniels with congestive heart failure but not in dogs with clinically inapparent mitral valve disease."

In a May 2008 report by Drs. Mark A. Oyama, Philip R. Fox, John E. Rush, Elizabeth A. Rozanski, and Michael B. Lesser of 119 dogs, they found that "Serum NT-proBNP concentration was significantly higher in dogs with cardiac disease than in control dogs, and a serum NT-proBNP concentration > 445 pmol/L could be used to discriminate dogs with cardiac disease from control dogs with a sensitivity of 83.2% and specificity of 90.0%. In dogs with cardiac disease, serum NT-proBNP concentration was correlated with heart rate, respiratory rate, echocardiographic heart size, and renal function." They concluded that, "For dogs with cardiac disease, serum NT-proBNP concentration could be used to discriminate dogs with and without radiographic evidence of cardiomegaly and dogs with and without congestive heart failure." And that, "Results suggested that serum NT-proBNP concentration may be a useful adjunct clinical test for diagnosing cardiac disease in dogs and assessing the severity of disease in dogs with cardiac disease."

In a May 2009 report from Sweden, the researchers concluded: "Plasma concentrations of the natriuretic peptides measured at re-examination could predict progression in regurgitant jet size."

In an August 2009 report from Japan, the researchers concluded, "These findings could indicate that plasma NT-proBNP concentration was significantly associated with the severity of heart failure due to mitral valve insufficiency in dogs. Further investigation is required to determine factors other than heart failure affecting plasma NT-proBNP concentration."

In a 2012 study of 1,134 dogs, including 37 cavaliers, Stephen J. Ettinger, Giosi Farace, Scott D. Forney, Michelle Frye, and Andrew Beardow concluded that "This biomarker [NT-proBNP] may be a useful tool for staging of cardiac disease and identifying cardiac-related coughing or dyspnea in this species."

In a 2013 study of 36 dogs, none being CKCSs, a team of Japanese researchers concluded: "These results indicated that plasma ANP rose with an increase in the volume overload of the left side of the heart. Plasma ANP discriminated cardiomegaly from non-cardiomegaly caused by asymptomatic MMVD. We conclude, therefore, that plasma ANP concentrations may be a clinically useful tool for early diagnosis of asymptomatic MMVD in dogs."

In an April 2013 report, a team of German veterinary cardiologists studied 352 dogs and found that: "NPs [natriuretic peptides] in canine MMVD are useful to discriminate between asymptomatic dogs and dogs with CHF. Due to a large overlap of NP-concentrations between the groups, NPs do not seem to be useful to differentiate between dogs in stages B1 and B2. Interpretation of NT-proBNP and proANP values should include consideration of sex-specific differences."

In a March 2014 Swedish study of 535 healthy dogs of nine breeds, including 34 cavaliers, researchers found that CKCSs and German shepherds had the highest median ANP concentrations, twice the median concentration in the breed with the lowest concentration, the Doberman Pinscher. Most importantly from that 2014 study, the researchers found that the levels of NT-proBNP concentrations are breed-specific. In other words, there can be no species-wide reference level for NT-proBNP concentrations in healthy dogs.

In a July 2014 report, a Swedish/Finnish/Danish team  examined 78 cavaliers with MVD and found that the risk of CHF increased with NT–proANP concentrations above 1000 picomoles per liter (pmol/l).  In an October 2014 study of 291 dogs, including 38 cavaliers, researchers once again found that plasma NT-proBNP concentrations were higher in dogs in congestive heart failure (CHF) than in dogs with non-cardiac respiratory distress.

In a January 2017 report, researchers focused upon the inherent variability of NTproBNP in all dogs -- both healthy and MVD-affected -- and how those random variations, called biologic variability, affects the accuracy of population-based reference ranges of NTproBNP readings. They measured NTproBNP in healthy dogs and dogs in stages B1, B2, and C of mitral valve disease, to estimate biologic variability and calculate an Index of Individuality (IoI) for each dog. Of the 28 MVD-affected dogs in the study, 14 -- 50% -- were cavalier King Charles spaniels, along with 10 healthy control dogs. They found that MVD-affected dogs had a lower inherent variability of NTproBNP compared to healthy dogs, and that, as a group, MVD-dogs required a change of 58.2% for NTproBNP to be outside the range of inherent biologic variability and indicate a change in disease. They determined that population-based reference ranges for NTproBNP may have limitations. They stated that:

"It is important for veterinarians to have an understanding of how much a biomarker value could change over time due to randomness vs. disease progression in an individual dog. ... Monitoring serial individual changes in NTproBNP values may be clinically relevant in addition to using population-based reference ranges to determine changes in disease status."

In a September 2018 article, a team of USA and UK veterinary cardiologists tested a treatment schedule for MVD-affected dogs in heart failure (CHF) based upon the levels of the NT-proBNP concentration in each dog's bloodstream. The goal of their study was to reduce NT-proBNP because of prior studies showing that such reductions improves outcomes in human CHF patients. Twenty-six dogs were in the study, which included five cavaliers -- the largest number of any breed -- with four examinations over a 21 day period. The dogs were divided into three groups, all three of which were in stable condition based upon routine treatments for CHF (e.g., furosemide, hydrochlorothiazide, spironolactone). Groups were:

Group 1: Baseline NT-proBNP was <1500 pmol/L. No dose adjustments were made to the current treatment.

Group 2: Baseline NT-proBNP was ≥1500 pmol/L. Dogs were eligible for prespecified medical treatment escalation on visit 0 or visit 1 if the serum creatinine concentration was <3.0 mg/dL. If creatinine was ≥3.0 mg/dL, data from the dog would be included in the analysis, but the dog would be ineligible for further treatment escalation.
"Treatment was escalated according to a prespecified plan as follows: if the current furosemide dose was <6 mg/kg/day, this dose was increased by 50%; if the current furosemide dose was ≥6 mg/kg/day, a combination of hydrochlorothiazide (1 mg/kg q24h) and spironolactone (1 mg/kg q24h; Aldactazide, Pfizer, New York) was added; if the current dose of furosemide was ≥6 mg/kg/day and the dog was already receiving hydrochlorothiazide and spironolactone the daily pimobendan dose was increased by 50%-100%."
Group 3: Control Group. Baseline NT-proBNP was ≥1500 pmol/L but received no adjustment in treatment over the 21 day period.

The researchers found that NT-proBNP decreased significantly in group 2, but not in groups 1 or 3. They concluded that the "application of a prespecified treatment escalation algorithm in dogs with recent history and treatment of 1st time CHF secondary to MMVD results in a decrease in plasma NTproBNP concentrations", and that "Use of this treatment escalation algorithm allows effective targeting of treatment for CHF in dogs against an objective criterion."

The Bottom Line on natriuretic peptides: Nevertheless, it appears that veterinary cardiologists and other cardio-specialists should be quite capable of detecting mitral valve prolapse (MVP) murmurs and distinguishing between them and flow murmurs or other innocent varieties of heart murmurs. Since ANP and BNP in the blood becomes elevated only after the heart has to pump harder to compensate for the disorder, the question then is: When does the heart start working so hard that BNP levels start to go up? In the cavalier King Charles spaniel's version of heart defects -- mitral valve disease due to deteriorating valve flaps -- there are no immediate external symptoms. It is not yet clear from research studies thus far, as to whether the heart becomes labored enough to produce increased levels of BNP before auscultation is able to detect the murmurs from minimal backflow of blood leaking through the mitral valve flaps. Advocates of ANP and BNP testing do represent that that studies of ANP and BNP and cardiomyopathy show that ANP and BNP are elevated before the onset of signs and murmur. But it does not yet appear that ANP or BNP testing necessarily is an any earlier warning system for MVD than auscultation.

Bolstering this viewpoint is the comment by Dr. Jennifer L. Garcia in "The NT-proBNP assay: A portent of heart health." in dvm360:

"For conditions such as mitral valve disease, this test may be of limited value because a diagnosis can be readily made by thorough auscultation and documentation of a heart murmur. In these cases, the assay also has limited utility in determining disease severity; thoracic radiography is preferred."

For an added twist, in a June 2016 abstract, Australian researchers have added corin to this list. Corin is a gene on chromosome 4p13-p12 that encodes a serine-type endopeptidase which converts non-functional propeptide NPPA into active atrial natriuretic peptide hormone and processes pro-NPPB, the B-type natriuretic peptide. In the abstract, the concluded that:

"A lack of an increase in corin expression or activation can be postulated to be a possible important pathophysiological mechanism responsible for the natriuretic peptide paradox in dogs with CHF, and warrants further investigation."

One possible uniquely valuable use for natriuretic peptides tests is if the dog is approaching heart failure (HF) without any symptoms. In that case, natriuretic peptides tests, combined with "Left Chambers on Aorta ratio" greater than 4,5, the veterinarian may begin administering ACE inhibitors, pimobendan, and other drugs immediately even though the dog is asymptomatic.  See Dr. Gerard Le Bobinnec's proposal in this report to the 2010 WSAVA Congress. See, also, the 2012 report of the PREDICT Cohort Study, which found that measurements of left heart size (using the "left atrial to aortic root dimension ratio [LA:Ao]") and plasma NT-proBNP concentration independently estimate risk of first-onset of CHF in dogs with MVD. It correctly predicted first-onset of CHF in 72.5% of cases out of 82 dogs, which included cavaliers.

Dr. Oyama has stated that natriuretic peptide tests may also be useful to properly diagnose a dog known to suffer from congestive heart failure and also is in respiratory distress. He said that, “When dogs come into veterinary hospitals in respiratory distress, it’s sometimes difficult to know if they are having a respiratory or heart problem. Such a test could speed effective treatment and also help decide if a dog should be referred to a veterinary cardiologist before undergoing more expensive testing.”

Dr. Adrian Boswood of the Royal Veterinary College has suggested that the NT-proBNP assay may have some value in predicting the future life span of dogs in congestive heart failure. He is participating in an on-going study, called the VetCompass DMVD project, which reportedly aims to identify factors associated with survival of MVD-affected dogs, by evaluating basic clinical measurements and cardiac biomarker levels (NT-pro-BNP and cardiac troponin I).

Finally, the September 2018 study (referenced above) of periodic testing of NT-proBNP levels after the onset of CHF may be useful in regulating the dosages of diuretics. However, in that study, the dogs' blood plasma was tested four times during a three week period, which is not particularly practical for most such patients.

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-- mass spectrometry

Mass SpectrometerMass spectrometry is a technique that identifies the chemical composition of a sample of a compound based on the mass-to-charge ratio of electrically charged particles. A mass spectrometer (right) plots the mass-to-charge (m/z) ratio of compounds in a sample (usually serum or saliva). The sample is vaporized into a gas and then ionized. The ions are focused into an ion beam which passes through a magnetic field which bends the beam, deflecting the ions' components onto a spectrum based upon their weight (mass) and degree of charge.

Two specific types of mass spectrometry are used in diagnosing patterns of peptides -- hormones manufactured and secreted by areas of the heart -- to identify peptide mass, called "peptide barcodes", which can be used as diagnostic tools to recognize certain diseases. These MS techniques are called "matrix assisted laser desorption time of flight mass spectrometry" (MALDI-TOF MS) and "liquid chromatography tandem mass spectrometry" (LC-MS/MS).

In a February 2017 article on a study of twelve cavaliers, an Italian team used MALDI-TOF MS to identify eight serum proteins which were differentially expressed between groups of moderately (M) and severely (S) affected CKCSs with MVD and a control group of healthy cavaliers. These proteins were found to be significantly related to the progression of the disease. See the "serum protein" section of this article for details of this study.

In a December 2020 article, a team of Thai researchers used these two MS methods to distinguish biomarkers between dogs with normal hearts and MVD-affected dogs in the various stages (B and C) of MVD and those with pulmonary hypertension (PH) in addition to MVD. They enrolled 59 dogs -- none of which were cavalier King Charles spaniels -- and divided them into five groups (11 normal dogs; 16 in Stage B2 MVD; 5 in Stage B2 and having PH; 11 in Stage C;, and 16 in Stage C with PH). Among these dogs, six amino acid sequences of peptide candidates were identified as candidate biomarkers which may be involved in the pathogenesis of PH and MVD.

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-- other cardiac biomarkers

Other cardiac biomarkers include:

cardiac troponin I (cTnI), and high-sensitivity cardiac troponin I (hscTnI)
C-reactive protein (CRP)
sodium-calcium exchanger (NCX-1)
aldosterone concentration (UAC)
serum serotonin (serum 5HT)
antidiuretic hormone (ADH)
histamine concentration
enzymes and growth factors
transforming growth factor beta (TGF-β)
Galectin-3 (Gal-3)
vitamin D
serum cystatin-C (Cys-C) and symmetric dimethylarginine (SDMA)
oxidative stress
serum fatty acids
serum leptin and adipokines
anemia 
desmin, vimentin, periostin, caspase-3

serum proteins
serum homocysteine
serum nitrotyrosine
heart-fatty acid binding protein (hFABP)
soluble ST2 (sST2)
adiponectin
serum iron concentration
humanin (HN)

Most of the protein-based biomarkers are identified using plasma proteomics.

---cardiac troponin I (cTnI)

Several studies of cardiac troponin I (cTnI) have shown increases in cTnI concentrations in dogs with poor prognoses, and that cTnI has potential in assessing the prognosis and severity of MVD and enlargement of the heart. See the 2009 study, the January 2010 study, the June 2010 study, and the April 2013 study. In a February 2012 study, high-sensitivity cardiac troponin I (hscTnI), in combination with N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations, has been examined. The researchers concluded that:

"Survival times were shortest in dogs in which both serum hscTnI and NT-proBNP were increased. hscTnI and NT-proBNP increased more rapidly in dogs that died of cardiac disease. Conclusions and Clinical Importance: Serum hscTnI has prognostic value in dogs with DMVD. Measurement of NT-proBNP and hscTnI is prognostically superior to measuring either alone. Serial measurement strategies provide additional prognostic information."

The VetCompass DMVD project is an on-going study which reportedly aims to identify factors associated with survival of MVD-affected dogs, by evaluating basic clinical measurements and cardiac biomarker levels (NT-pro-BNP and cardiac troponin I).

In an April 2017 article, a team of Texas A&M veterinary school investigators applied the concept of biologic variability (BV) testing to concentrations of cardiac troponin I (cTnI) in periodic blood samples of 10 healthy and 28 MVD-affected dogs (including 14 [50%] cavalier King Charles spaniels). They noted that the use of a standard sensitivity cTnI assay was insufficiently sensitive to quantify and study changes in cTnI concentration in both healthy dogs and MVD-affected dogs in their study. They argue that long-term serial measurements of cTnI changes helped predict the MVD end-points of onset of heart failure and death. They suggest that such periodic testing may provide more information for predicting survival time than a single measurement.

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---C-reactive protein (CRP)

In a 2006 study, researchers found that, compared with controls, dogs with chronic valvular disease had higher plasma concentration of C-reactive protein (CRP). In a 2015 report, researchers found a "statistically significant difference" in CRP concentrations between MVD-affected dogs as their MVD progressed from asymptomatic to advanced heart failure. They noted that CRP concentrations were "significantly higher" in the asymptomatic group, and that "Differences in CRP concentrations between clinical stages of MVD suggest a clinically and therapeutically relevant inflammatory component."

However, in a December 2015 report, Swedish and Danish cardiologists studied 188 dogs with varying degrees of MVD, to determine whether CRP concentrations are associated with the severity of MVD, using an automated canine-specific high-sensitivity CRP assay called "Gentian hsCRP". They found that serum CRP concentrations were mildly increased in dogs with congestive heart failure due to MVD, but that the severity of MVD in asymptomatic dogs showed no association with serum CRP concentrations.

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---sodium-calcium exchanger (NCX-1)

Sodium-calcium exchanger (NCX-1) is being examined as an alternative to natriuretic peptides because NCX-1 appears to better differentiate between heart failure and renal failure.  See this 2010 South Korean report.  Also, leptin, a protein produced by fat tissues and associated with canine body fat, was found in an August 2011 UK report to be more highly concentrated in dogs with congestive heart failure.

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---aldosterone concentration (UAC)

In a November 2012 report, researchers found that left ventricular heart enlargement in dogs with MVD is associated with a decrease in the serum concentration of a marker of collagen type III turnover, and an increase in urinary aldosterone concentration (UAC). They also reported that both serum N-terminal procollagen type III concentration and UAC were higher in cavalier King Charles spaniels than in other breeds when other measured variables were controlled for.

However, in an April 2013 study of 50 dogs (including 20 CKCSs), the researchers reported that:

"Cardiac fibrosis and arteriosclerosis in dogs with MMVD are reflected by circulating cTnI [cardiac Troponin-I] concentration, but not by aldosterone concentration or renin activity. Cardiac troponin I could be a valuable biomarker for myocardial fibrosis in dogs with chronic cardiac diseases." (Emphasis added.)

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---serum serotonin (serum 5HT)

In a July 2013 study of 120 dogs, including 92 cavaliers, by an international team of cardiologists, the researchers found that cavaliers had higher concentrations of serum serotonin (serum 5HT) than other breeds not predisposed to mitral valve disease, and that serum 5HT concentrations decreased with increased left atrial enlargement. They concluded that, "the finding of higher serum 5HT concentrations in dogs predisposed to MMVD (CKCS) and dogs with mild MMVD suggests that alterations in 5HT signaling might play a role in progression of early stages of MMVD."

In a 2009 study, some of the same researchers found, "Dogs with DMVD had significantly higher serum 5HT concentrations when compared with large breed control dogs. Healthy CKCS dogs had significantly higher serum 5HT concentrations than other healthy dogs predisposed to DMVD."

In a January 2013 interview with AKC's Canine Health Foundation, board certified cardiologist Dr. Mark Oyama of University of Pennsylvania's veterinary school, said:

"Our research involving serotonin and other pathways involved in the development and progression of disease are ultimately targeted towards discovering the underlying abnormalities that produce mitral valve disease in dogs. If serotonin and other pathways contribute to disease formation blockade of these pathways could result in reduction in disease development and progression."

In a July 2014 report, the international team found that platelet serotonin was elevated in cavaliers compared to other breeds, and that serotonin in left ventricular myocardial and mitral valve leaflet tissue in deceased MVD dogs was elevated compared to dogs which died without cardiac disease. See also this September 2014 report finding serotonin concentration high in cavaliers.

In a September 2016 abstract, Danish and Swedish cardiologists reported their preliminary study of 63 cavaliers and 17 control dogs to determine if 5-Hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite excreted in urine, is associated with MVD severity in the CKCS. They concluded that the preliminary data indicated that urinary 5-HIAA concentrations are dependent on the sex, but not the age of the dog, but that further analyses are necessary to draw final conclusions regarding the possible associations between urinary 5-HIAA concentrations and MVD severity in cavaliers. In a June 2019 article, the same team reported that they examined urinary excretions of serotonin (5-hydroxyindoleacetic acid [5-HIAA]) in 40 cavaliers, 11 without mitral valve disease (MVD) and 29 with MVD prior to heart failure (Stage C) to determine if urine concentrations of 5-HIAA were associated with MVD severity or blood platelet count or circulating serotonin. They concluded that while female cavaliers had higher urine 5-HIAA concentrations than males, 5-HIAA concentrations in CKCSs were not associated with MVD severity or blood platelet count or circulating serotonin.

In a December 2017 article, a team of human and veterinary researchers studied the relationship between serotonin receptors and mitral valve interstitial cells (MVICs) and leaflet remodeling in humans and cavalier King Charles spaniels. Mitral valve specimens from four deceased cavaliers with severe mitral valve prolapse (MVP) and mitral regurgitation and four normal controls showed that serotonin 5HT receptors (5HTRs) signaling contributes to MVP deterioration, in particular, 5HTR2B upregulation. While this was primarily a study of human MVP, it indicates a possible relationship between the upregulation of 5HTR2B in cavaliers and the progression of mitral valve deterioration. It also shows that a 5HTR2B antagonist -- a drug called LY 272015 hydrochloride -- reduces MVICs activation in humans and mice. Since the cavaliers in this study all were deceased, the application of LY 272015 to dogs was not part of this study. LY 272015 is a beta-carboline derivative drug developed by the Eli Lilly company which is known to act as a potent and selective antagonist at the serotonin 5-HT receptor.

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---antidiuretic hormone (ADH)

Antidiuretic hormone (ADH) is produced by the hypothalamus and contributes to regulating blood pressure and blood plasma osmolality. High levels of ADH are believed to play a role in the development of congestive heart failure (CHF) in humans. For humans, an enzyme immunoassay (EIA) kit is used to quantify ADH levels. In a September 2013 study, a team of cardiologists from Oregon State University used EIA kits to compare the ADH concentrations in 6 healthy dogs and 12 with CHF. They researchers concluded that EIA kits can be used to determine ADH concentrations in dogs and that the dogs in CHF had significantly higher ADH concentrations than did the healthy dogs.

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---histamine concentration

In a May 2014 report, Japanese cardiologists found that histamine concentration was higher in the population of dogs with MVD compared with the healthy controls.

---enzymes and growth factors

In an October 2014 study, researchers found that mitral valve and myocardial protein and gene expression of the enzymes matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and transforming growth factor-β (TGF-β) and plasma MMP and TGF-β concentrations appear to play a local role in the development of advanced MMVD.

In a July 2015 thesis, a Swedish veterinary student studied serum activity of matrix metalloproteinase-2, -9 and -14 in 66 dogs, including 49 cavaliers. He concluded that the activity of MMP-14 increases and the activity of MMP-9 decreases when systolic function is impaired; that activity of both enzymes vary during pathogenesis which may implicate that they are involved in different stages of disease progression; and that the study suggests that MMP-2 plays a minor role in dogs with MMVD.

In a March 2016 article, researchers examined the levels of cytokine expression in peripheral blood mononuclear cells (PBMC) of dogs with MVD (none were cavaliers) at different stages and in healthy dogs. They investigated potential relationships between cytokine expression and echocardiographic indices of MVD severity, left ventricular (LV) function and remodelling. For this purpose, IL-102 1, IL-6, IL-8, TGF-β1 and TNF-α peripheral blood mononuclear cells (PBMC) expression was measured. In the dogs with MVD, there were differences in IL-8 and TGF-β1 mRNA concentrations between the ACVIM stages of MVD (Stages B1, B2, and C). No statistically significant differences were detected between groups for IL-1α, IL-1β, IL-6, or TNF-α PBMC expression. IL-8 expression increased with increasing MVD severity and TGF-β1 expression was higher in asymptomatic dogs with echocardiographic signs of heart enlargement (Stage B2) than in all other groups. They concluded that their results could suggest the involvement of these cytokines at different stages of MVD.

In a December 2017 article, Brazilian researchers investigated the concentration of IL-1β, 4, 6, 10, TNF-α and CRP in MVD-affected dogs of ACVIM Stages B1, B2, and C, along with a control group of healthy dogs. The report finding: (1) the serum levels of interleukin 1β increases in MVD-affected dogs, and even higher levels are observed in dogs with MVD symptoms; (2) there is a significant correlation between heart enlargement and congestive heart failure and the circulating levels of IL-1β and IL-4; and (3) the serum levels of IL-6 and the left-ventricular shortening fraction are negatively correlated.

In a January 2020 article, board certified veterinary cardiologist Dr. Mark Oyama and others reviewed the aspects of cardiovascular pathology shared by humans and MVD-affected cavaliers. He focused upon the neurotransmitter serotonin (5HT) and transforming growth factor beta (TGF-β), which he describes as sharing a common ability to activate mitral valve interstitial cells in both dogs -- particularly cavaliers -- and humans. He states: "The dog, and in particular the CKCS breed, represents a model to further study 5HT and TGF-β mechanisms and to test novel therapies." His list includes:

• "One example is the Cavalier King Charles Spaniel (CKCS) breed, in which death due to heart disease comprises over 30% of all causes of death."

• "Beginning at the age of 3 years, the yearly incidence of MMVD in the CKCS is approximately 7% and rises to as high as 15% in subsequent years, such that virtually all dogs exhibit disease by the age of 10 years."

• "CKCS, a breed with extremely high prevalence of MMVD, are reported to have particularly increased serum 5HT levels."

• "5HT in platelet rich plasma was higher in healthy CKCS, as well as both CKCS and mixed breed dogs with MMVD vs. healthy mixed breed controls."

• "Of interest, the CKCS breed is also associated with an inherited thrombocytopenia and giant platelet disorder affecting approximately half of all CKCS dogs."

• "In addition to having macrothrombocytes, the platelet population in CKCS dogs with MMVD also contains at least one flow cytometry scatterplot subpopulation with a higher percentage of surface-bound 5HT-positive expression and activation, but the exact relationship of platelet morphology, ultrastructure, and function to MMVD requires further study."

 In an April 2020 article, a University of Edinburgh team of veterinary researchers led by Dr. Brendan Corcoran examined the mitral valves of 30 euthanized MVD-affected dogs, including 8 cavalier King Charles spaniels (27%) to classify the valves according to MVD severity (Grade 0 - normal -- to Grade 4 - severely affected) and to identify all differentially expressed genes (DEGs) in all four such grades. By transcriptomic profiling they identified a total of 1,002 DEGs associated with a large number of gene families. Depending upon the grade of MVD, they found significant changes in gene expression intensity in especially ACTA2, HTR2B, MMP12, and CDKN2A. The TGFβ1, TNF, IFGN genes were identified as the top up-stream regulators in the diseased valve samples. Of those, they found that TGFβ1 appears to have the strongest associations with the disease. They concluded:

"In conclusion, despite differences in the total number of DEGs identified as canine MMVD pathology progresses over a lifetime, disease initiation, and progression appears to be primarily dependent on changes in TGFβ signaling. This is the first description of the temporal and spatial expression of gene changes associated with naturally occurring myxomatous degeneration in any species. Other signaling pathways likely contribute to disease pathogenesis over time, with some becoming involved only at the stage of advanced disease. The factors that trigger the development of valve myxomatous degeneration are still unknown, but aberrant TGFβ signaling appears to initiate and perpetuate the valve pathology characteristic of this disease in the dog."
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---transforming growth factor beta (TGFβ)

Transforming growth factor beta (TGFβ) is a combination of growth factors which are secreted to support cellular growth in dogs and most all other mammals. The progression of MVD has been found to involve a transition of normal valve cells (qVICs) to an activated myofibroblast type of cell (aVICs), and this transition is dependent on abnormal TGFβ signalling. The mechanisms which initiate and progress MVD development have been found to be due to changes in the TGFβ signalling pathway.

The signalling of TGFβ in cavaliers is suspected to be unique among canines, and theefore studies are on-going to examine this further. As of 2021, the Cavalier Health Fund has been providing financial grants to Dr. Brendan Corcoran at the The Royal (Dick) School of Veterinary Studies to investigate the cause and effect of TGFβ in the CKCS breed.

In an October 2014 study, researchers found that mitral valve and myocardial protein and gene expression of the enzymes matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and transforming growth factor-β (TGF-β) and plasma MMP and TGF-β concentrations appear to play a local role in the development of advanced MMVD.

In a March 2016 article, researchers examined the levels of cytokine expression in peripheral blood mononuclear cells (PBMC) of dogs with MVD (none were cavaliers) at different stages and in healthy dogs. They investigated potential relationships between cytokine expression and echocardiographic indices of MVD severity, left ventricular (LV) function and remodelling. For this purpose, IL-102 1, IL-6, IL-8, TGF-β1 and TNF-α peripheral blood mononuclear cells (PBMC) expression was measured. In the dogs with MVD, there were differences in IL-8 and TGF-β1 mRNA concentrations between the ACVIM stages of MVD (Stages B1, B2, and C). No statistically significant differences were detected between groups for IL-1α, IL-1β, IL-6, or TNF-α PBMC expression. IL-8 expression increased with increasing MVD severity and TGF-β1 expression was higher in asymptomatic dogs with echocardiographic signs of heart enlargement (Stage B2) than in all other groups. They concluded that their results could suggest the involvement of these cytokines at different stages of MVD.

In a January 2020 article, Dr. Mark Oyama and others reviewed the aspects of cardiovascular pathology shared by humans and MVD-affected cavaliers. He focused upon the neurotransmitter serotonin (5HT) and transforming growth factor beta (TGF-β), which he describes as sharing a common ability to activate mitral valve interstitial cells in both dogs -- particularly cavaliers -- and humans. He states: "The dog, and in particular the CKCS breed, represents a model to further study 5HT and TGF-β mechanisms and to test novel therapies." His list includes:

• "One example is the Cavalier King Charles Spaniel (CKCS) breed, in which death due to heart disease comprises over 30% of all causes of death."

• "Beginning at the age of 3 years, the yearly incidence of MMVD in the CKCS is approximately 7% and rises to as high as 15% in subsequent years, such that virtually all dogs exhibit disease by the age of 10 years."

• "CKCS, a breed with extremely high prevalence of MMVD, are reported to have particularly increased serum 5HT levels."

• "5HT in platelet rich plasma was higher in healthy CKCS, as well as both CKCS and mixed breed dogs with MMVD vs. healthy mixed breed controls."

• "Of interest, the CKCS breed is also associated with an inherited thrombocytopenia and giant platelet disorder affecting approximately half of all CKCS dogs."

• "In addition to having macrothrombocytes, the platelet population in CKCS dogs with MMVD also contains at least one flow cytometry scatterplot subpopulation with a higher percentage of surface-bound 5HT-positive expression and activation, but the exact relationship of platelet morphology, ultrastructure, and function to MMVD requires further study."

 In an April 2020 article, a University of Edinburgh team of veterinary researchers led by Dr. Brendan Corcoran examined the mitral valves of 30 euthanized MVD-affected dogs, including 8 cavalier King Charles spaniels (27%) to classify the valves according to MVD severity (Grade 0 - normal -- to Grade 4 - severely affected) and to identify all differentially expressed genes (DEGs) in all four such grades. By transcriptomic profiling they identified a total of 1,002 DEGs associated with a large number of gene families. Depending upon the grade of MVD, they found significant changes in gene expression intensity in especially ACTA2, HTR2B, MMP12, and CDKN2A. The TGFβ1, TNF, IFGN genes were identified as the top up-stream regulators in the diseased valve samples. Of those, they found that TGFβ1 appears to have the strongest associations with the disease. They concluded:

"In conclusion, despite differences in the total number of DEGs identified as canine MMVD pathology progresses over a lifetime, disease initiation, and progression appears to be primarily dependent on changes in TGFβ signaling. This is the first description of the temporal and spatial expression of gene changes associated with naturally occurring myxomatous degeneration in any species. Other signaling pathways likely contribute to disease pathogenesis over time, with some becoming involved only at the stage of advanced disease. The factors that trigger the development of valve myxomatous degeneration are still unknown, but aberrant TGFβ signaling appears to initiate and perpetuate the valve pathology characteristic of this disease in the dog."

---Galectin-3 (Gal-3)

In an April 2015 abstract and a January 2016 article, Thai researchers report finding that MVD-affected dogs have more cardiac fibrosis compared to normal dogs, and that plasma Galectin-3 (Gal-3) concentration was increased in MVD-dogs. They concluded that Gal-3 expression in cardiac muscle was associated with cardiac fibrosis, and that  tissue Gal-3 is a candidate of fibrosis biomarker in MVD, but that further investigation of associations between plasma Gal-3 and myocardial fibrosis is necessary.

In a June 2017 abstract, Brazilian investigators sought to establish the utility of Gal-3, isolated or in association with Type B natriuretic pro-peptide (NTproBNP) and cardiac troponin I (cTnI) to estimate short term prognosis in dogs with heart failure caused by MVD. One hundred thirty nine dogs were distributed among five groups, according to ACVIM Stages. Groups B1, B2, C and D had a second blood sampling at day 60. Measurements were obtained for human Gal-3, NT-proBNP and cTnI. The researchers concluded that the magnitude and variation observed in Gal-3 did not allow for detection of differences between stages of MVD nor were capable of identifying patients in heart failure, compared to the other measured biomarkers, NT-proBNP and cTnI.

In a May 2018 abstract, Henry Ford Hospital researchers report finding that, in dogs in heart failure, increased levels of reactive interstitial fibrosis (RIF) is associated with increased interstitial levels of Gal-3.

---vitamin D

In an August 2015 study, a team of Japanese researchers examined vitamin D concentrations -- specifically serum 25-hydroxyvitamin D (25(OH)D) concentrations -- in 43 MVD-affected dogs, including 4 cavalier King Charles spaniels. They observed that serum 25(OH)D concentration begins to decrease before the onset of heart failure in MVD-affected dogs, and that vitamin D status is associated with the extent of heart enlargement. Previously, in a January 2014 study of serum vitamin D concentration in the bloodstreams of 82 dogs (31 with congestive heart failure [CHF] -- 20 with acquired valve disease (AVD) and 11 with dilated cardiomyopathy (DCM) -- and 51 unaffected control dogs, all over 5 years old), a team of US researchers found that low serum vitamin D concentration was associated with poor outcome in dogs with CHF. They suggested that strategies to improve vitamin D status in some dogs with CHF may prove beneficial without causing toxicity.

---serum cystatin-C (Cys-C) and symmetric dimethylarginine (SDMA)

Dimethylarginines (DMAs) are biological products derived by the methylation process of L-arginine. Symmetric dimethylarginine (SDMA) is used as a circulating biomarker of endothelial cell dysfunction, as is asymmetric dimethylarginine (ADMA). The surfaces of normal valve leaflets are lined with a layer of endothelial cells, aligned in uniform, parallel rows, making up the endothelium which covers a layer of collagen of the myocardium. "Endothelial cells" line the interior of blood vessels and are the layer that is in continuous contact with blood. The endothelium formed a complete and intact covering over the leaflets and chordae tendineae. Endothelial cells also line the interior of blood vessels and are the layer that is in continuous contact with blood and are a specialized category of epithelial cells.

In a September 2016 study by a team of Korean cardiology researchers, they examined serum concentration levels of two kidney function biomarkers -- Cystatin-C or cystatin 3 (Cys-C) and symmetric dimethylarginine (SDMA) -- which appear to play roles in predicting new-onset or deteriorating kidney diseases. Their goal was to evaluate these two renal disorder biomarkers in dogs with mitral valve disease (MVD) at varying degrees of heart failure. They found that serum Cys-C and SDMA concentrations were not correlated to age or body weight, but closely correlated to the severity of heart failure and echocardiographic markers of heart enlargement. The study found progressive elevation in renal markers in dogs with advancing MVD, suggesting that the reduction of glomerular filtration rate (GFR) might be worsened with the progression of cardiac dysfunction. They concluded that their study demonstrated that the glomerular filtration rate (GFR) -- a common complication in advanced stages of heart failure -- was decreased in dogs with MVD in earlier stages of heart failure, based on results from serum Cys-C and SDMA tests, and therefore, earlier intervention for preventing renal injuries even in asymptomatic MVD dogs is necessary for the successful long-term management of heart failure in MVD-dogs.

In an August 2018 article, Italian researchers studied 24 dogs, including 2 cavaliers, to evaluate SMDA in MVD-affected dogs in various stages (B1, B2, C, and D) to assess its reliability as a marker of early renal impairment in dogs affected by mitral valve disease. They report that:

"SDMA can be actually considered a reliable parameter for evaluation of renal function in dogs affected by MMVD, especially in those patients with a non-advanced stage of disease (ACVIM class B2), for which an early diagnosis of the onset of kidney failure is fundamental in order to plan a diuretic therapy. SDMA repeated measurements over time, as recommended by IRIS guidelines, are necessary, because one determination does not allow us to exclude definitely a later onset of the renal impairment and then to be considered diagnostic in order to highlight a possible onset of CRS [cardiorenal syndrome]."

In a September 2021 article, Italian researchers studied 85 MVD-affected dogs, including 9 (9.3%) cavaliers, to measure the plasma concentration of dimethylarginines in the various stages of MVD. They reported finding that "ADMA and SDMA were significantly associated with left atrium to aorta ratio, and creatinine, respectively. Increased plasmatic concentrations of dimethylarginines suggest a possible role as biomarkers of disease severity in dogs with decompensated MMVD."

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---oxidative stress

In a June 2016 abstract, a team of Swedish and Denmark researchers compared levels of markers of oxidative stress in cavaliers with MVD, other MVD-affected breeds, and control group Beagles. They concluded that "Beagles and female dogs appear to have lower plasma concentrations of oxLDL [oxidized low-density lipoprotein]. The results cannot confirm a role of oxidative stress in dogs with MMVD."

---serum fatty acids

In a July 2016 article by a team of Japanese researchers, they studied 30 dogs with various stages of mitral valve disease, including seven cavaliers, to determine whether serum fatty acid concentrations in dogs with MVD differ from those in normal dogs (12 healthy dogs, including 1 CKCS). They found that several fatty acid concentrations were significantly lower in dogs with MVD, and that some of these concentrations and ratios correlated with echocardiographic parameters.

---serum leptin and adipokines

In an August 2016 article,, Korean researchers found that serum leptin concentrations were significantly higher in dogs with MVD than in healthy dogs, and that adiponectin concentrations were significantly lower in dogs with MVD.

---anemia

In an October 2016 article, a team of Taiwan researchers found in 114 MVD-affected dogs that the presence of anemia increased with the progression of MVD and was associated with the severity of heart failure. They stated that anemic dogs in heart failure had shorter median survival times (13 months) than non-anemic dogs in heart failure (28 months), and that anemia was a predictor of mortality.

---desmin, vimentin, periostin, caspase-3

In a December 2016 study by a team of Polish researchers, they examined the cell markers: (a) desmin, a standard cardiomyocyte marker; (b) vimentin, a typical cell marker expressed in mesenchymal cells; (c) periostin, a novel marker for myocardial remodelling; and (d) caspase-3, a marker of cell apoptosis. They compared them in dogs with end-stage dilated cardiomyopathy (DCM) and dogs with MVD and a control group of unaffected dogs. Their research focused upon the enlargement of the left atrium in the diseased dogs. They reported that changes included: (a) irregularity of desmin cross-striation and desmosomes; (b) a higher amount of vimentin-positive cells; (c) a change in the periostin expression pattern from cytoplasmic to extracellular; and (d) a lower expression of caspase-3. The alterations reportedly were more pronounced in the DCM group than in the MVD group. They concluded that, during heart failure, the pattern of desmin, vimentin, periostin and caspase-3 expression alters in the left atrium, regardless of the cause; that the changes are more pronounced in dogs with DCM than in dogs with MVD and similar left atrial enlargement.

---serum proteins

In a February 2017 article on a study of twelve cavaliers, an Italian team reported finding eight serum proteins which were differentially expressed between groups of moderately (M) and severely (S) affected CKCSs with MVD and a control group of healthy cavaliers. These proteins were found to be significantly related to the progression of the disease. In the M group versus healthy dogs complement factor H isoform 2, inhibitor of carbonic anhydrase, hemopexin, dystrobrevin beta isoform X7 and CD5 molecule-like resulted to be down-regulated, whereas fibronectin type-III domain-containing protein 3A isoform X4 was up-regulated. In the S dogs versus healthy group complement factor H isoform 2, calpain-3 isoform X2, dystrobrevin beta isoform X7, CD5 molecule-like and l-2-hydroxyglutarate dehydrogenase resulted to be down-regulated. Complement factor H isoform 2, calpain-3 isoform X2, dystrobrevin beta isoform X7, CD5 molecule-like and hydroxyglutarate dehydrogenase were found to be down-regulated in mild affected group versus healthy dogs. All of these proteins except complement factor H followed a decreasing trend according to the progression of the pathology. They concluded that the differential expression of serum proteins demonstrates the possibility these might be valuable for the detection and monitoring of the disease.

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---serum homocysteine

In an April 2017 article, Korean investigators examined serum homocysteine in 63 dogs to determine if there is any correlation between homocysteine concentrations and the worsening of mitral valve disease. Homocysteine is an essential amino acid metabolite of methionine that is recycled into methionine or converted into cysteine by vitamin B. They found significant correlations between serum homocysteine concentrations and each stage of MVD (Stages B1, B2, C, D). They concluded that the measurement of serum homocysteine concentration may be useful in predicting the severity of MVD in dogs.

---serum nitrotyrosine

In an April 2017 article, Korean investigators examined serum nitrotyrosine in 50 dogs to determine if there is any correlation between nitrotyrosine concentrations and the worsening of mitral valve disease. Nitrotyrosine is an amimo acid product of tyrosine nitration which has been found to be a marker of cell damage and inflammation and appears to be undetected in healthy subjects. They found no significant correlation between serum nitrotyrosine concentrations in control dogs and dogs with mild MVD. However, dogs with moderate MVD had significantly higher serum concentrations of nitrotyrosine than that in the controls, and dogs with severe MVD had significantly lower serum concentrations of nitrotyrosine than that in moderate MVD dogs.

---heart-fatty acid binding protein (hFABP)

In a June 2017 abstract, Ontario Veterinary College researchers studied heart-fatty acid binding protein (hFABP) as a potential marker for MVD and dilated cardiomyopathy (DCM), compared to cardiac Troponin-I (cTnI) in affected dogs and healthy control dogs. They reported that levels showed significantly elevated hFABP with highest levels found in ACVIM Stage C disease regardless of cause, followed by Stage B and controls. cTnI differed in Stage C from both Stage B and controls, but was unable to differentiate between Stage B and controls. cTnI was indistinguishable between MVD-affected dogs and controls. They found that hFABP was the most significant predictor for death, and that the study showed the potential value of hFABP as a cardiac marker to differentiate stages of MVD in dogs.

---soluble ST2 (sST2)

In a June 2017 abstract, Brazilian researchers reported that concentrations of the soluble fraction of ST2 (sST2), a cardiac biomarker, higher than 40 pg/mL indicated higher mortality in dogs with advanced MVD.

---adiponectin

Adiponectin is the most abundant plasma adipokine, and is well known for its role in energy homeostasis and cardiac protection. In a July 2017 article, researchers evaluated adiponectin serum concentrations and myocardial protein expression in MVD-affected dogs in CHF. They reported that serum adiponectin was significantly lower in dogs with CHF and lowest levels in the severest CHF class. Myocardial adiponectin was expressed independent of circulating adiponectin concentrations, suggesting a local regulatory mechanism within the heart.

---serum iron concentration

In an October 2018 article, a team of Italian veterinarians studied the case records of 54 dogs, measuring their serum iron concentration (SIC) and iron-capacity factors. They found that SIC was 18% overall, but that in MVD-dogs in Stage C (congestive heart failure) the SIC was 33%, and in dogs in Stage D (acute decompensated heart failure), the SIC was 100%. They did not find any significant differences in iron values between Stage B and Stage C dogs.

--- humanin (HN)

In a December 2018 article, a team of researchers at Chiang Mai University in Thailand report finding that in a study of 31 dogs (none were cavaliers) grouped in four classes (no MVD, Stage B, Stage C, and Stage D), the levels of humanin (HN), a polypeptide in blood plasma, was lower in dogs diagnosed with mitral valve disease (MVD), and that plasma HN were significantly lower in ACVIM Stages C and D than in healthy dogs. Also, they report finding that plasma NT-proBNP changed significantly only in MVD-affected dogs in Stage D.

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-- quality of life questionnaire

The Functional Evaluation of Cardiac Health Questionnaire is a set of 18 questions for MVD-affected dog owners to answer. It has been developed based on widely accepted clinical signs of heart disease in dogs. (See box below.) The questionnaire consists of 18 questions to be answered by the dog's owner, who grades the severity of symptoms on a scale from 0 to 5, in which 0 = few symptoms and 5 = several symptoms, with higher scores indicating a poorer health-related quality of life. The questionnaire has been shown to be an effective, reliable method for assessing health-related quality of life in dogs with cardiac disease. See this June 2005 article. It also has been found to be valid as an independent measure of evaluating aproaching death due to MVD. See this March 2017 article.

FUNCTIONAL EVALUATION OF CARDIAC HEALTH QUESTIONNAIRE

These questions are included in the Functional Evaluation of Cardiac Health Questionnaire for dogs. Owners are asked to answer the following items to quantify their perception of the degree to which clinical signs of cardiac disease had affected the dog during the preceding 7 days. For each item, the owner grades severity on a scale from 0 to 5, where 0 = not at all, 1 = very little, and 5 = very much. Responses for each of the items are summed to obtain an overall score, with a possible total score ranging from 0 to 85. Because owners are instructed to skip 1 of 2 items (questions 5 and 6) depending on whether they had or had not been instructed to restrict their dogs’ exercise, each owner provides responses for only 17 items.

How much did your dog’s heart disease impact your dog’s comfort or sociability during the last 7 days by:

1. making breathing difficult?
2. making your dog cough?
3. making your dog wheeze when breathing?
4. making your dog generally tired, fatigued or low on energy?

If the dog was on forced exercise restriction, the owner was instructed to skip question 5 and go to question 6. If the dog was not on forced exercise, the owner was instructed to answer question 5 and skip question 6.

5. making recreational pastimes (playing in the yard, playing fetch, etc) difficult?
6. limiting your dog’s favorite activities due to exercise restriction?
7. making your dog sit or lie down to rest during walks?
8. making walking around or climbing stairs difficult?
9. causing fainting or collapsing episodes?
10. making it difficult for your dog to get comfortable?
11. making it difficult for your dog to sleep through the night?
12. making your dog eat less than normal?
13. changing the types of foods your dog is willing to eat?
14. increasing the number of urination accidents in the house?
15. making your dog vomit?
16. limiting your dog’s ability to spend time with the family (can’t get up stairs to join the family, can’t get onto the bed or couch, etc)?
17. making your dog irritable or unwilling to be touched?
18. making your dog less bright and peppy?

(Source: Development and evaluation of a questionnaire for assessing health-related quality of life in dogs with cardiac disease. Lisa M. Freeman, John E. Rush, Andrew E. Farabaugh​‌. J. Am. Vet. Med. Assn. June 2005;226(11):1864–1868.)

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DNA Testing

-- gene identification

DNAIn a 1996 study, Swedish researchers Lennart Swenson, Jens Häggström, and Clarence Kvart, reported that MVD in cavaliers "is a polygenic threshold trait and that sex of the offspring influences threshold levels."

In an April 2020 article, a University of Edinburgh team of veterinary researchers led by Dr. Brendan Corcoran (Greg R. Markby, Vicky E. Macrae, Kim M. Summers) examined the mitral valves of 30 euthanized MVD-affected dogs, including 8 cavalier King Charles spaniels (27%) to classify the valves according to MVD severity (Grade 0 - normal -- to Grade 4 - severely affected) and to identify all differentially expressed genes (DEGs) in all four such grades. By transcriptomic profiling they identified a total of 1,002 DEGs associated with a large number of gene families. Depending upon the grade of MVD, they found significant changes in gene expression intensity in especially ACTA2, HTR2B, MMP12, and CDKN2A. The TGFβ1, TNF, IFGN genes were identified as the top up-stream regulators in the diseased valve samples. Of those, they found that TGFβ1 appears to have the strongest associations with the disease. They concluded:

"In conclusion, despite differences in the total number of DEGs identified as canine MMVD pathology progresses over a lifetime, disease initiation, and progression appears to be primarily dependent on changes in TGFβ signaling. This is the first description of the temporal and spatial expression of gene changes associated with naturally occurring myxomatous degeneration in any species. Other signaling pathways likely contribute to disease pathogenesis over time, with some becoming involved only at the stage of advanced disease. The factors that trigger the development of valve myxomatous degeneration are still unknown, but aberrant TGFβ signaling appears to initiate and perpetuate the valve pathology characteristic of this disease in the dog."

Previously, different researchers had identified different chromosomes as possible regions for genes affecting mitral valve deterioration in MVD-affected dogs. The candidate regions include chromosomes CFA13, CFA14, 15, and 17, and genes COL1A2 (in CFA14)  and CTNNA2 (in 17). See below for details on this research.

A team of veterinarians from Denmark, Sweden, Germany, England, and France reported in September 2011 that they have identified two specific locations on cavaliers' chromosomes CFA13 and CFA14 which are associated the breed's hereditary mitral valve disease. They grouped 139 cavaliers with early-onset MVD and 102 old CKCSs with no or mild signs of MVD as controls. Then they conducted a genome-wide association study to find specific locations associated with development of MVD. They also stated:

"We will initiate studies of the most promising candidate genes in the 2 candidate regions which hopefully will lead us to the mutations affecting the development of mitral valve disease."

However, in November 2011, a team of UK cardiologists and geneticists divided 36 CKCSs into groups of early and late onset MVD and assessed whether the distinction is determined by a small number of genetic factors. They report that they came up dry. They concluded:

"There were no regions of highly discrepant homo/heterozygosity in the two groups. Similarly, there was no evidence for loci associated with mitral valve murmur in a genome-wide association study. This analysis suggests that familial occurrence of mitral valve murmur in the CKCS breed is not due to a single major gene effect, indicating that breeding strategies to eliminate the disease cannot be based on genotype information at this time."

This seems to contradict the much more successful September 2011 report issued by the team of veterinarians from Denmark, Sweden, Germany, England, and France.

In an October 2015 study of Whippets, researchers found evidence that the severity of MVD degeneration is associated with chromosome 15 loci.

In a December 2016 report, a team of Columbian veterinary researchers investigated variations of the COL1A2 gene (within the CFA14 region) in 50 MVD-affected and 80 control Poodles. (The CFA14 region was identified in the September 2011 study, as being associated the CKCS's hereditary mitral valve disease. The Columbian veterinarians found that "the allele T of the rs22372411 variant was over-represented in MMVD patients compared with healthy controls." They concluded:

"Our results show for the first time an association of the rs22372411 COL1A2 gene variant with susceptibility to canine myxomatous mitral valve disease."

In a June 2017 abstract, Cornell University veterinary researchers conducted a genome-wide association study (GWAS) which revealed a strong association signal on Chromosome 17, near the CTNNA2 gene, which codes for alpha-catenin. They then identifying CTNNA2 as a candidate gene, which revealed a 53% decrease in normalized alpha-catenin levels and an 86% decrease in beta-catenin in MVD-affected dogs, when compared to control samples. However, no mutation of that gene was detected. The investigators surmised that a mutation may exist within the non-coding regions controlling CTNNA2 transcription, and they recommended further investigation.

In a December 2017 article, veterinary cardiologists examined the DNA in ten cavalier King Charles spaniels and ten Dachshunds affected with mitral valve disease (MVD), searching for varients of genes known to be analogous to genetic mutations associated with MVD in humans. They reported finding no such variants in any of the canine genes evaluated, and that they could not identify any genetic cause responsible for human MVD in the dogs studied. They concluded that MVD in the CKCS and Dachshund may not share an identical genetic cause with the human MVD.

In a March 2019 abstract, North Carolina State veterinary researchers report testing the involvement of serotonin in the development of mitral valve prolapse (MVP) in dogs. They obtained DNA samples from 51 dogs with MVP and performed whole genome sequencing. They searched for shared genes and/or gene families in the serotonin receptor signaling (SRS) pathway. They report that no single high impact variant or gene or gene family accounted for all of the dogs. They concluded that, although serotonin may play a role in the development of MVP, it may not be the primary genetic cause of the disorder.

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---microRNAs (miRNAs)

MicroRNAs (miRNAs) are regulators of gene expression in heart development and cardiac disorders. MicroRNAs are short, noncoding RNAs that are transcribed from the genome. The biological function of these small RNAs is to negatively regulate gene expression through mRNA degradation or translational inhibition. One microRNA may regulate several target mRNAs and have substantial effects on downstream gene expression networks. The human genome is believed to encode approximately 1,000 microRNAs, and most human protein-coding genes are regulated by these microRNAs. Circulating microRNAs can be detected in the blood, so that they may serve as circulating molecular biomarkers for various cardiac disorders.

In a June 2015 study, researchers examined the role circulating microRNAs may play as biomarkers of mitral valve disease. They examined 18 dogs, divided into three groups of six dogs each: (1) Stage A: normal dogs at risk of heart disease; Stage B1/B2: (2) asymptomatic dogs with MVD and mild to moderate cardiac enlargement; and (3) Stage C/D: dogs with MVD and CHF requiring multiple cardiac medications.  They found that dogs in Stage B1/B2 or C/D had four upregulated miRNAs, including three cfa-let-7/cfa-miR-98 family members, while seven other miRNAs were downregulated, compared to Stage A. Expression of six of the 11 miRNAs also were significantly different between dogs in Stage C/D and those in Stage B1/B2. They observed that the expression changes were greater as disease severity increased. They concluded that their study suggests that there is an opportunity for using some  circulating miRNAs as biomarkers for diagnosis, prognosis or monitoring response to treatment in MVD in dogs.

See also this July 2015 study by substantially the same researchers, in which they examined serum metabolites which they observed were significantly different between healthy and MVD dogs, which they concluded were representing alterations in fat and glucose energy metabolism, oxidative stress, and other pathways. They found that the three metabolites with the greatest single effect were γ-glutamylmethionine, oxidized glutathione, and asymmetric dimethylarginine, representing changes in energy metabolism, antioxidant function, nitric oxide signaling, and extracellular matrix homeostasis pathways. They opined that "Many of the identified alterations may benefit from nutritional or medical management. Our study provides evidence of the growing importance of integrative approaches in multi-omics research in veterinary and nutritional sciences." However, this study was funded by a major dog food manufacturer, and several of the researchers were employed by that manufacturer.

In a July 2017 article, a team of Tufts University investigators reported they had located microRNA (cfa-miR-9, cfa-miR-181c, cfa-miR-495 and cfa-miR-599) expressions which change with the progression of mitral valve disease and development of heart failure. The study consisted of 47 dogs, including 17 cavalier King Charles spaniels, which were divided into three groups based upon their heart conditions. All of the cavaliers in the study were MVD-affected and were in either the ACVIM Stage B (asymptomatic) or Stage C (heart failure) categories. The found:

"The present observations suggest that dysregulation of miR-9 and miR-599 chronologically precedes CHF, suggesting that these miRNA warrant further investigation as putative initiating factors for CHF, while others were found only at the time of CHF (miR-181c and miR-495), which denotes a role in initiation, progression or consequence of CHF. ... The data analysis shows that relative to young normal dogs, dogs with MMVD or dogs with MMVD-CHF, the expression level of cfa-miR-9 is low in older normal dogs. MiR-9 has been shown to have anti-fibrotic effects, and overexpression of miR-9 in neonatal rats inhibits the proliferation of cardiac fibroblasts and collagen production. ... Both of these effects would suggest that miR-9 has protective effects for cardiac remodelling."

"In contrast, cfa-miR-9 expression once again increases with the development of MMVD, which would suggest that MR [mitral regurgitation], volume-overload, cardiac remodelling or haemodynamic effects on other organs (lungs and kidneys) may initiate or propagate higher expression of circulating cfa-miR-9. However, it is not known if the anti-fibrotic effects of miR-9 are sufficient to counter pro-fibrotic stimuli exerted by volume overload and chronic heart failure."

"The data showed that there is high expression of exosomal cfa-miR-181c in dogs with CHF. MiR-181c is encoded in the nucleus and assembled in the cytoplasm of the cardiomyocytes and is then translocated into mitochondria to regulate mitochondrial gene expression. ... [G]iven the significant increase in cfa-miR-181c expression in MMVD-CHF, miR-181c may serve as an important biomarker or therapeutic target in patients at risk for developing CHF."

"Plasma exosomal miR-495, which is repressed with age, increases with MMVD-CHF. This ex-miRNA was upregulated with heart disease, particularly in advanced disease with CHF in defiance of its age-related trend downward. ... Although speculative, cfa-miR-495 may also serve as a potential biomarker to help monitor progression to active CHF in addition to cfa-miR-181c."

"Exosomal miR-599 declines in MMVD compared to age-matched controls. ... An increase in cfa-miR-599 associated with ageing was observed. Studies have shown that this miRNA can inhibit vascular smooth-muscle cell proliferation and production of collagen I, collagen V and proteoglycan by direct targeting of TGFβ2. Interestingly, there is a downregulation of cfa-miR-599 in dogs with MMVD when compared to normal older dogs."

"Based on the present disease model, two miRNA were found, specifically miR-495 and miR-181c, whose rise in expression level coincides with the observation of CHF. The authors acknowledge that dysregulation of these ex-miRNA may not be unique to CHF secondary to MMVD, but rather may be a signature of canine heart failure which is a consequence of other aetiologies."
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-- cell transitions

Deterioration of the mitral valve, which is how MVD "progresses" over time, has been found to be caused by destruction and disorganisation of the valve's extracellular matrix (ECM),  as a result of the valve's interstitial cells transitioning from a normal quiescent  (qVIC) phenotype to an activated myofibroblast (aVIC) phenotype. These aVICs have been found to be persistent in diseased mitral valves, and unlike typical aVICs, these in the mitral valves persist and do not eventually reach the end of a finite life-span and die. The mechanisms which initiate and progress MVD development are due to changes in the TGFβ signalling pathway.

Brendan M. CorcoranIn a February 2004 study, a team of UK researchers led by Dr. Brendan M. Corcoran (right), observed the mitral valves of dogs with deteriorated mitral valves due to MVD. They noticed (a) tissue swelling on the edges of the valve leaflets, chordae tendineae, and the chordal-papillary muscle junction; and (b) the denudation of endothelial cells, primarily along the leaflet edges, exposing the basement membrane or subendothelial valve collagen matrix.

The surfaces of normal valve leaflets are lined with a layer of endothelial cells, aligned in uniform, parallel rows, making up the endothelium which covers a layer of collagen of the myocardium. "Endothelial cells" line the interior of blood vessels and are the layer that is in continuous contact with blood. The normal dogs' mitral valve's endothelial cells appeared orderly in a set pattern that corresponded with the orientation of underlying bundles of collagen. The endothelium formed a complete and intact covering over the leaflets and chordae tendineae.

At the time of that 2004 study, the researchers stated that whether the observed endothelial loss is a consequence or cause of the MVD process remains to be seen. Since then, much has been learned. 

In a March 2015 study, Dr. Corcoran and his research team examined 5,397 differentially expressed canine genes, narrowing down their examination to 591 genes in six to ten biological function clusters -- relevant to inflammation, cell movement, cardiovascular development, extracellular matrix organisation and epithelial-to-mesenchymal (EMT) transition in dogs with mitral valve disease (MVD). They stated:

"Considering the biological relevance to MMVD, the gene families of importance with significant difference between groups included collagens, ADAMTS peptidases, proteoglycans, matrix metalloproteinases (MMPs) and their inhibitors, basement membrane components, cathepsin S, integrins, tight junction cell adhesion proteins, cadherins, other matrix-associated proteins, and members of the serotonin (5-HT)/transforming growth factor -β signalling pathway."

In an August 2015 study published by Dr. Corcoran and the same team of researchers, they examined the mitral valve leaflets of 14 deceased cavaliers which had suffered from MVD, and compared them with the leaflets of 5 unaffected mixed breed dogs. The aim of their study was to investigate the possibility of re-activation -- meaning post-embryotic -- and recruitment of embryotic developmental processes MVD, such as the transition of epithelial cells and endothelial cells to mesenchymal cells.

"Epithelial cells" line the cavities of tissues throughout the body and cover flat surfaces and form glands.  "Endothelial cells" line the interior of blood vessels and are the layer that is in continuous contact with blood and are a specialized category of epithelial cells. "Mesenchymal cells" develop into any types of connective or supporting tissues, smooth muscle, vascular endothelium, and blood cells. "EMT" is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells. Similarly, "EndoMT" is the same process for the transition of endothelial cells to mesenchymal cells. Previous research has shown that EMT and EndoMT contribute to a range of chronic degenerative diseases and cancer metastasis.

Epithelial to Mesenchymal Cell Transition

The Corcoran team found significant differential expression for genes typically associated with EndoMT -- including markers of inflammation (IL6, IL18 and TLR4), basement membrane disarray (NID1, LAMA2 and CTSS), mesenchymal and endothelial cell differentiation (MYH11 and TAGLN) and EndoMT (ACTA2, SNAI1, CTNNB1, HAS2, CDH5, and NOTCH1). In heart valves of MVD-affected dogs, there was increased expression of these genes, with the exception of NOTCH1, and a reduction in CDH5. Apart from down-regulation of NOTCH1 expression, all other changes support a potential contribution of EndoMT and endothelial migration in the development of MVD.

The research findings confirm the study's aim and "strongly suggest involvement of developmental signalling pathways and mechanisms, including EndoMT, in the pathogenesis of canine MMVD." Most significantly, the findings suggest that, instead of MVD being a degenerative condition, MVD may be due to the development of EMT and EndoMT. The researchers point out that this is the first report of involvement of development signalling pathways and endothelial to mesenchymal transition in canine MVD. They also provide information on biological mechanisms that have therapeutic potential for new drug discovery.

In a September 2015 master's thesis by a Colorado State Univ. student, she similarly concluded that "active EndMT in canine degenerative mitral valves could be contributing to the formation of high cellular density myofibroblast transformation which has been postulated to mediate mitral valve degeneration."

TGF-β1 (transforming growth factor beta 1):

Transforming growth factor beta 1 (TGF-β1) is a polypeptide in a family of cytokines. It is a secreted protein that performs certain cellular functions, including control of cell growth, cell proliferation, cell differentiation, and apoptosis. In an August 2008 article, German researchers examined the role of TGF-β1 and reported that in the heart, TGF-β1 is one of the main factors that cause cardiac fibrosis. In that study of the hearts of 40 deceased dogs, consisting of 10 normal hearts, 7 hearts with mild MVD, and 23 hearts with moderate or severe MVD, they found that TGF-β1 expression increased markedly as MVD progressed.

In an August 2019 article, Dr. Corcoran has found that, using mitral valve cells from healthy and MVD-affected dogs, they were able to model heart cell transitions due to MVD by using TGFβ1 to transform normal mitral valve interstitial cells (qVICs) into MVD-diseased activated myofibroblasts (aVICs) and then reverse that transformation by using pan-anti-TGFβ antibodies and the kinase inhibitor SB431542. They also were able to perform that reverse transformation when starting with diseased cells. TGF-β1 is one of a set of multifunctional peptides that controls proliferation, differentiation, and other functions in cells. The researchers noted that:

"This is the first time that an effective reversal of induced- and naturally-occurring disease phenotype has been achieved for MMVD, albeit under cell culture conditions, and has implications for understanding pathogenesis and discovery of novel therapeutic options applicable to MMVD."

 In November 2019, researchers at Tufts' Cummings veterinary school announced an intention to conduct a clinical study in which MVD-affected cavaliers in Stage B2 (murmur and enlargement but not CHF) will be injected with an AAV medium which will contain "transforming growth factor beta receptor 2 (sTGFβR2)", a repressor of TGF-β1, in that it inhibits the action of TGF-β1, most likely by adsorbing TGFβ1 or by acting as a dominant negative receptor.

In a February 2020 article, Dr. Corcoran's team furthered their study of deteriorating cells in MVD-affected cavalier King Charles spaniels. They hypothesised that there is survival of activated myofibroblasts in MVD-affected valves and that this, in part, can be explained by a defect in the activation and progression of apoptotic pathways. They examined the distribution of activated myofibroblasts (valve interstitial cells -- aVICs) to confirm their survival, and then they examined the expression of apoptotic genes by qVICs and aVICs in cell culture, before and after stimulation with doxorubicin, a chemotherapy drug which works by slowing or stopping the growth of certain types of cells. Their data indicated that the ability of aVICs to survive in mitral valves may be due to a heighthened resistence to apoptosis (the programmed death of most cells after a specified life-span).

In an April 2020 article, Dr. Corcoran's team (Greg R. Markby, Vicky E. Macrae, Kim M. Summers) examined the mitral valves of 30 euthanized MVD-affected dogs, including 8 cavalier King Charles spaniels (27%) to classify the valves according to MVD severity (Grade 0 - normal -- to Grade 4 - severely affected) and to identify all differentially expressed genes (DEGs) in all four such grades. By transcriptomic profiling they identified a total of 1,002 DEGs associated with a large number of gene families. Depending upon the grade of MVD, they found significant changes in gene expression intensity in especially ACTA2, HTR2B, MMP12, and CDKN2A. The TGFβ1, TNF, IFGN genes were identified as the top up-stream regulators in the diseased valve samples. Of those, they found that TGFβ1 appears to have the strongest associations with the disease. They concluded:

"In conclusion, despite differences in the total number of DEGs identified as canine MMVD pathology progresses over a lifetime, disease initiation, and progression appears to be primarily dependent on changes in TGFβ signaling. This is the first description of the temporal and spatial expression of gene changes associated with naturally occurring myxomatous degeneration in any species. Other signaling pathways likely contribute to disease pathogenesis over time, with some becoming involved only at the stage of advanced disease. The factors that trigger the development of valve myxomatous degeneration are still unknown, but aberrant TGFβ signaling appears to initiate and perpetuate the valve pathology characteristic of this disease in the dog."

FGF21 (fibroblast growth factor 21):

Fibroblast growth factor 21 (FGF21) is a secreted protein in a class of polypeptide growth factors, that has been found to act as a metabolic regulator and protect cardiac cells against enlargement in mice when injected into them using an adeno-associated virus (AAV)  as the transmitting medium. In November 2019, researchers at Tufts' Cummings veterinary school announced an intention to conduct a clinical study in which MVD-affected cavaliers in Stage B2 (murmur and enlargement but not CHF) will be injected with an AAV medium which will contain FGF21.

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Inflammation

Several inflammatory substances, such as C-reactive protein (CRP), endothelin (ET), interleukins (IL), and tumor necrosis factor alpha (TNF-α) have been found to play roles in the progression of mitral valve disease leading to heart failure in dogs.

C-reactive protein (CRP) is released from hepatic cells after stimulation by cytokines early in the course of the inflammatory process. Increased serum values of CRP have been observed in dogs with MVD in some circumstances. See our C-reactive protein discussion in our Diagnosis section above.

Cytokines are a category of proteins which are secreted by cells and have a specific effects upon their own cell and interactions with other cells as they circulate through the blood system. There are inflammatory cytokines and anti-inflammatory cytokines. Interleukins (IL), including interleukin-1β (IL-1β), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10) are inflammatory cytokines.

In a 2014 Italian doctoral thesis, the researcher suggested that MVD appears to be associated with a chronic state of inflammation, as evidenced by measurements of immunoglobulin antibodies and glycoprotein and complement proteins particularly associated with immune responses to inflammation.

In a March 2016 article, researchers examined the levels of cytokine expression in peripheral blood mononuclear cells (PBMC) of dogs with MVD (none were cavaliers) at different stages and in healthy dogs. They investigated potential relationships between cytokine expression and echocardiographic indices of MVD severity, left ventricular (LV) function and remodelling. For this purpose, IL-102 1, IL-6, IL-8, TGF-β1 and TNF-α peripheral blood mononuclear cells (PBMC) expression was measured. In the dogs with MVD, there were differences in IL-8 and TGF-β1 mRNA concentrations between the ACVIM stages of MVD (Stages B1, B2, and C). No statistically significant differences were detected between groups for IL-1α, IL-1β, IL-6, or TNF-α PBMC expression. IL-8 expression increased with increasing MVD severity and TGF-β1 expression was higher in asymptomatic dogs with echocardiographic signs of heart enlargement (Stage B2) than in all other groups. They concluded that their results could suggest the involvement of these cytokines at different stages of MVD.

In a December 2017 article, Brazilian researchers investigated the concentration of IL-1β, 4, 6, 10, TNF-α and CRP in MVD-affected dogs of ACVIM Stages B1, B2, and C, along with a control group of healthy dogs. The report finding: (1) the serum levels of interleukin 1β increases in MVD-affected dogs, and even higher levels are observed in dogs with MVD symptoms; (2) there is a significant correlation between heart enlargement and congestive heart failure and the circulating levels of IL-1β and IL-4; and (3) the serum levels of IL-6 and the left-ventricular shortening fraction are negatively correlated.

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Stages of MVD

As mitral valve disease (MVD) worsens, cardiologists have categorized the disease in stages. Initially, they used the human heart disease classification scheme devised by the International Small Animal Cardiac Health Council (ISACHC) -- Classes I through IV -- applied mainly to dogs already in heart failure. In 2009, the American College of Veterinary Internal Medicine (ACVIM)  published a Consensus Statement in which the categories were divide into stages, beginning with MVD-affected dogs with only mitral valve murmurs (Stage B1) up to dogs inhaeart failure and for which customary medications no longer were effective (Stage D). In 2019 the ACVIM published a second Consensus Statement in which Stages B1 and B2 were completely revised and no longer make any scientific sense. In a May 2021 article, a team of Italian researchers devised a scoring system for classifying the severity of mitral valve disease (MVD or MMVD) in dogs. Its name, "MINE", is an acronym for "Mitral INsufficiency Echocardiographic score".

ISACHC Classes of Heart Disease

Prior to 2009, the classification system for heart failure most familiar to veterinarians was the published by the  International Small Animal Cardiac Health Council (ISACHC):

Class I describes patients with asymptomatic heart disease (eg, CVHD is present, but no clinical signs are evident even with exercise).
Class II describes patients with heart disease that causes clinical signs only during strenuous exercise.
Class III describes patients with heart disease that causes clinical signs with routine daily activities or mild exercise.
Class IV describes patients with heart disease that causes severe clinical signs even at rest.

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2009 ACVIM Consensus Statement

ACVIMDr. Claude AtkinsIn a very important 2009 "Consensus Statement" published by a panel of ten board certified veterinary cardiologists (C. Atkins [left], J. Bonagura, S. Ettinger, P. Fox, S. Gordon, J. Häggström, R. Hamlin, B. Keene, V. Luis-Fuentes, and R. Stepien) of the American College of Veterinary Internal Medicine (ACVIM), they create a new classification of stages of MVD.

They stated:

"The new system describes 4 basic stages of heart disease and failure:

"Stage A identifies patients at high risk for developing heart disease but that currently have no identifiable structural disorder of the heart (e.g., every Cavalier King Charles Spaniel without a heart murmur)." (So, Stage A means the dog does not have any MVD murmur but that its breed is at high risk for developing MVD.)

ACVIM Cardiac Disease Classification - ©Clarke Atkins"Stage B identifies patients with structural heart disease (e.g., the typical murmur of mitral valve regurgitation is present), but that have never developed clinical signs caused by heart failure. Because of important clinical implications for prognosis and treatment, the panel further subdivided Stage B into Stage B1 and B2.

"Stage B1 refers to asymptomatic patients that have no radiographic or echocardiographic evidence of cardiac remodeling [enlargement] in response to CVHD." (So, Stage B1 means the dog has a murmur but no enlargement of the heart.)

"Stage B2 refers to asymptomatic patients that have hemodynamically significant valve regurgitation, as evidenced by radiographic or echocardiographic findings of left-sided heart enlargement."  (So, Stage B2 means the dog has both a murmur and enlargement of the left side -- atrium and/or ventricle -- of the heart.)

"Stage C denotes patients with past or current clinical signs of heart failure associated with structural heart disease. Because of important treatment differences between dogs with acute heart failure requiring hospital care and those with heart failure that can be treated on an outpatient basis, these issues have been addressed separately by the panel. Some dogs diagnosed with heart failure for the first time may have severe clinical signs requiring aggressive therapy (e.g,, with additional afterload reducers or temporary ventilatory assistance) that more typically would be reserved for those with refractory disease (see Stage D)." (So, Stage C means the dog is or has been in heart failure but drugs are enabling the heart to compensate for that failure.)

"Stage D refers to patients with end-stage disease with clinical signs of heart failure caused by CVHD [MVD]that are refractory to 'standard therapy' (defined later in this document). Such patients require advanced or specialized treatment strategies in order to remain clinically comfortable with their disease. As with Stage C, the panel has distinguished between animals in Stage D that require acute, hospital-based therapy and those that can be managed as outpatients." (So, Stage D means the dog is in heart failure and drugs no longer allow the heart to compensate for that failure.)

The typical progression for MVD-affected cavaliers is to pass from Stage B1 to B2 to C to D. For many other breeds, especially if the onset of MVD is late in life, the progression may stop at Stage B2, with the dog never reaching heart failure. Rarely, a cavalier may by-pass Stage B2 -- the enlargement stage -- and proceed directly from only a murmur in Stage B1 to heart failure in Stage C. This could occur if one or more of the dog's mitral Dr.Andrew Beardowvalve's major chordae tendineae should suddenly rupture before any enlargement takes place. It is even possible for a chord to rupture before a murmur is detected (skipping Stage B1), since degeneration occurs in both the leaflets and the chords of mitral valves.

For an in-depth on-line seminar about the symptoms, diagnosis, progression, stages, and treatment of mitral valve disease, watch Dr. Andrew Beardow (right), with his terrific active graphics, explain MVD.

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2019 ACVIM Consensus Statement

In 2019, the ACVIM issued a new "Consensus Statement" in which it completely changed the definitions of Stage B1 and B2. According to the 2019 definition of Stage B1, the heart either has no enlargement OR either the left atrium (LA) OR the left ventricle (LV) is enlarged, but not both of them, OR, if both of them are enlarged, one of both of them are not enlarged up to the minimum dimensions of the 2019 version of Stage B2.

The 2019 definition of Stage B2 requires that both the left atrium and left ventricle be enlarged by specific minimum dimensions. So, the MVD-affected dog's heart can be enlarged and still be in Stage B1, even if both the LA and LV are enlarged but not large enough to meet those minimum dimensions. And, the MVD-affected dog's heart could normal sized and not enlarged at all, but if its LA and LV meet those minimum dimensions, it will be in Stage B2. This is the result of the 2019 ACVIM Consensus Statement panel assuming (without any scientific evidence to support that assumption) that all breeds of dogs have the same sized hearts when both normal sized and enlarged.

Stage B2: Any MVD-affected dog with these minimum measurements:

• murmur intensity ≥3/6;
• echocardiographic LA:Ao ratio in the right-sided short axis view in early diastole ≥1.6;
• left ventricular internal diameter in diastole, normalized for body weight (LVIDDN) ≥1.7;
• breed-adjusted radiographic vertebral heart size (VHS) > 10.5.

• Ideally, all these criteria should be met before initiating treatment, because treatment represents a lifelong commitment. Of these criteria, echocardiographic evidence of left atrial and ventricular enlargement meeting or exceeding these criteria is considered to be the most reliable way to identify dogs expected to benefit from treatment.

2019 ACVIM Definitions of Stage B1 and Stage B2

This new definition of Stage B2 is the same as that used in the 2016 EPIC Study (which was fully financed by Boehringer Ingelheim, the exclusive patent holder for Vetmedin/pimobendan), with the exception that the VHS > 10.5 was not “breed-adjusted” in the EPIC Study. The 2019 consensus panel unanimously recommends that any Stage B2 dog be treated with pimobendan at a dosage of 0.25-0.3 mg/kg twice a day. No other medication is recommended for Stage B2 by more than half the panel. In the article’s Conflict of Interest Declaration, all ten of the panelists admit that they have been consultants for Vetmedin’s manufacturer, Boehringer Ingelheim, and presumably have been financially rewarded for their services to that company.

Thus far, no species-wide studies of the parameters for determining if a dog’s heart is enlarged have been published which justify applying a single measurement as being the dividing line between a normal-sized left atrium or left ventricle and an enlarged left atrium or left ventricle. Nevertheless, these authors apply three species-wide dividing lines and conclude that if any dog’s heart exceeds them, the dog necessarily has an enlarged heart and should be administered pimobendan for the rest of its life.

The consequence to the MVD-affected dogs of these revisions to the defintions of Stage B1 and B2 is that the dogs with enlarged hearts in Stage B1 are not to be medicated for their MVD, and dogs with normal-sized hearts in Stage B2 are eligible to be medicated.

Numerous veterinary journal articles have concluded that there are significant breed-specific variations in echocardiographic indices measuring left chamber dimensions, when determining whether or not an MMVD-affected dog’s left atrium or left ventricle is, in fact, enlarged. Here are 25 examples (with emphasis added):

(1) Morrison, S.A., et al., Effect of Breed and Body Weight on Echocardiographic Values in Four Breeds of Dogs of Differing Somatotype. J. Vet. Intern. Med. 1992;6:220-224:

“This study demonstrated that breed, in addition to weight, is an important factor in the determination of normal echocardiographic measurements for dogs.

(2) Snyder, P.S., et al., A Comparison of Echocardiographic Indices of the Nonracing, Healthy Greyhound to Reference Values from Other Breeds. Vet. Rad. & Ultra. 1995;36(5):387-392:

“Adult nonracing greyhounds were shown to have increased left ventricular cavity dimensions, systolic time intervals and wall thicknesses as compared to mongrels and various other dog breeds. ... Our finding that greyhounds have cardiac dimensions that are apparently larger than other dogs of similar weight is supported by earlier gross anatomic studies of greyhounds.”
“In summary, normal nonexercised adult greyhounds have increased left ventricular cavity dimensions, systolic time intervals and left ventricular and septal wall thicknesses that differ markedly from reported normal echocardiographic values derived from mixed breed and other dogs. ... Despite correction of the data for body weight or surface area, the differences remained, suggesting that breed and body conformation may need to be considered in addition to heart rate when interpreting echocardiographic studies in the dog. Nonetheless, caution should be employed in utilizing generic reference ECHO values in the evaluation of echocardiographic studies in greyhounds.”

(3) P.K. Della Torre, et al., Echocardiographic measurements in Greyhounds, Whippets and Italian Greyhounds -- dogs with a similar conformation but different size. Austr. Vet. J. 2000;78(1):49-55:

“The results from this study, taken together with previous reports, suggest Greyhounds, Whippets and Italian other breeds of comparable body size. This possibly reflects selection for athletic performance. This study adds further weight to the notion that breed variation precludes the determination of an effective reference range for echocardiographic measurements widely applicable to all purebred and crossbred dogs.

(4) O’Leary, C.A., et al., Echocardiographic parameters in 14 healthy English Bull Terriers. Austr. Vet. J 2003;81(9):535-542:

“In this study, the prediction interval for LA:Ao calculated from 2D long axis measurements in English Bull Terriers was 1.3 to 2.1.”

The dogs in this study had increased LA diameter, LV wall thickness and AoV, and decreased aortic root diameter compared with other breeds of similar body size. In addition, FS% was lower than in dogs of comparable size, and more similar to the values reported from giant breeds.”

(5) Muzzi, R.A.L., et al., Echocardiographic indices in normal German shepherd dogs. J. Vet. Sci. 2006;7(2):193-198:

“Adult German shepherd dogs were shown to have larger left ventricular dimensions and wall thicknesses than other small breeds of dogs. These differences suggest that the breed and body conformation in addition to the heart rate may need to be considered when interpreting echocardiographic studies in dogs. Caution should be taken in extending these generic reference echocardiographic values to an evaluation of echo studies.”

(6) Kayar, A., et al., M-Mode Echocardiographic Parameters and Indices in The Normal German Shepherd Dog. Vet. Rad. & Ultra. 2006;47(5):482–486:

“Although some normal echocardiographic values for dogs have been published, there is variation based on breeds, body size, and somatotype. Indeed, echocardiographic reference ranges derived from some dog breeds may be misleading for others.”

(7) Bavegems, V., et al. Echocardiographic Reference Values in Whippets. Vet. Rad. & Ultra. 2007;48(3):230-238:

“We confirm that whippets have a larger LVD, a thicker IVS and LVW, and a lower FS than expected for dogs of comparable body weight. The clinician should be aware of these specific differences in whippets to avoid misdiagnosis of cardiac dilation, hypertrophy, and/or myocardial failure in these dogs.”

(8) Vörös, K., et al., M-Mode and Two-Dimensional Echocardiographic Reference Values for Three Hungarian Dog Breeds: Hungarian Vizsla, Mudi and Hungarian Greyhound. Acta Vet. Hungarica. 2009;57(2):217-227:

Breed has been demonstrated to be an important factor, influencing intracardiac parameters in addition to body weight in dogs. Therefore, the need for normal breed-specific reference ranges has been emphasised for comparison of pathological changes caused by cardiac disorders.”

(9) Jacobson, J.H., et al., An echocardiographic study of healthy Border Collies with normal reference ranges for the breed. J. Vet. Cardiol. 2013;15(1):123-130:

“There are differences in some echocardiographic parameters between healthy Border Collies and the general dog population, and the echocardiographic reference ranges provided in this study should be used as breed specific reference values for Border Collies.”

“Although echocardiographic values for the general dog population have been published, it is now known that there can be variation based on breed, body size, somatotype and body surface area. Echocardiographic reference ranges derived from some dog breeds may be misleading for others, limiting their clinical usefulness.”

“There are over 37 papers investigating breed specific and generic echocardiographic parameters. These studies add support to the belief that breed variation precludes the determination of a single reference range for echocardiographic measurements that may be widely applied to all purebred and crossbred dogs.

(10) M. Höllmer, et al. Left atrial volume and phasic function in clinically healthy dogs of 12 different breeds. Vet. J. September 2013; doi: 10.1016/j.tvjl.2013.05.045:

We provided breed-specific reference ranges for 12 breeds and clinical reference ranges for use in all dogs based on BW. ... These values of LA volume might provide a better basis for assessing LA size than linear LA dimensions when examining dogs with heart disease, since small increases in linear dimensions can reflect significant increases in LA volume due to the asymmetrical nature of LA dilatation. Since body size is a major determinant of LA size, LA volume should be indexed to a measure of body size to allow meaningful comparison.”

“Even when the effects of body size were taken into account, these data showed significant breed differences for LA volume. Thus, LA volume measurements in dogs of the same weight can differ slightly among breeds. It would be ideal to establish breed-specific reference values due to the differences in type of breed, size and conformation of the thorax.

(11) Gugjoo, M.B., et al., Reference values of M-mode echocardiographic parameters and indices in conscious Labrador Retriever dogs. Iranian J. Vet. Res. 2014;15(4):341-346:

The echocardiographic indices show significant breed variations and it is important to know the normal echocardiographic values for each dog breed considering the influence of body weight on the established echocardiographic values.”

(12) Misbach, C., et al. Echocardiography and conventional Doppler examination in clinically healthy adult Cavalier King Charles Spaniels: Effect of body weight, age, and gender, and establishment of reference intervals. J. Vet. Cardiol. 2014;16(2):91–100:

“Due to the large variations in size and conformation within the canine population, significant breed and body weight (BW) effects on echocardiographic variables have been demonstrated, mainly for left ventricular (LV) M-mode measurements. Body weight independent differences among breeds have also been reported. For these reasons, the breed must be considered when establishing echocardiographic RI [reference intervals] in the dog.

“In conclusion, although predictive RI assessed according to Cornell’s formula seem to be acceptable for CKCS dogs, the present results suggest that establishing specific RI for echocardiographic and Doppler variables in this breed is relevant.

(13) Limm, C.K., et al., Two-dimensional left atrium–to–aorta ratios and left ventricular M-mode transthoracic echocardiographic measurements in clinically normal adult Dachshunds. AJVR 2016;77(4):374-382:

The mean LA:Ao for the clinically normal Dachshunds of the present study was markedly different from the mean LA:Ao for clinically normal CKCSs in another study, even though the body weights for the Dachshunds (range, 5.0 to 12.6 kg) and CKCSs (5.5 to 11.9 kg) were similar. The LA:Ao as determined by the diameter method was < 1.67 for all the Dachshunds of the present study and < 1.28 for all the CKCSs of that other study.”

(14) Duler, L., Interreader agreement of radiographic left atrial enlargement in dogs and comparison to echocardiographic left atrial assessment. J. Vet. Cardiol. August 2018; doi: 10.1016/j.jvc.2018.07.004:

Our results also suggest that there are limitations to using a single linear dimension (LA:Ao) to assess LA size. The LA is a complex cardiac structure that can enlarge in multiple planes, so single measurement may not accurately reflect actual LAE. This is supported by the stronger agreement of radiographic LAE with LAV, rather than LA:Ao. Owing to the eccentric manner in which atrial enlargement occurs, large differences in overall LA size may be misrepresented by a small range of LA:Ao values. Enlargement of the LA primarily in the dorsal-ventral orientation may not be apparent in the single plane LA:Ao measurement, while enlargement in multiple directions is incorporated into the LAV value by tracing the LA border. In addition, dividing by the aortic dimension is an attempt to index LA size to a cardiac structure that theoretically does not change much in disease states. However, the size of the aorta may vary throughout the cardiac cycle [15]. While LA:Ao is less time consuming than volumetric measurements, this study and other recent veterinary studies emphasize the limitations of the LA:Ao measurement.”

(15) Garncarz, M, et al., Reference intervals for transthoracic echocardiographic measurements in adult Dachshunds. Polish J. Vet. Sci. 2018;21(4):779-788:

In recent years many breed specific echocardiographic parameters have been published for canines showing significant differences between these measurements in different dog breeds. This underlines the necessity to prepare reference values for specific breeds.”

“It appears that the different size heart in the Dachshunds could simply be a characteristic of the breed, possibly resulting from a smaller body size compared to other dog breeds, a different chest conformation, or even the influence of systemic blood pressure. ... To minimize the chance of erroneously accepting an enlarged left ventricle as normal, Dachshund specific values should be used. This is especially important when classifying disease stage in Dachshunds with chronic mitral valve disease according to the most recent guidelines (Atkins et al. 2009) as this disease readily leads to chamber enlargement, including the left atrium and left ventricle.”

(16) Visser, L.C., et al, Echocardiographic quantitation of left heart size and function in 122 healthy dogs: A prospective study proposing reference intervals and assessing repeatability. J. Vet. Intern. Med. 2019; doi: 10.1111/jvim.15562:

“Unlike in human medicine, recommended standards for quantitation of cardiac chamber size and function by echocardiography in dogs do not currently exist.”

Currently, no accepted standard exists on how to determine RIs [reference intervals] (ie, clinical cutoffs to help distinguish normal from abnormal) for echocardiography data sets in healthy dogs.

Thus, common approaches for indexing linear measurement to body size have included breed-specific reference values ...”.

(17) Rishniw, M., Two-dimensional echocardiographic left-atrial-to-aortic ratio in healthy adult dogs: a re-examination of reference intervals. J. Vet. Cardiol. November 2019;doi: 10.1016/j.jvc.2019.11.001:

“Twenty-eight dogs [12%] had LA:AoMAX (RPSA) >1.6, and seven dogs [3%] had LA:AoMAX (RPSA) >1.7. ... In our current study, approximately 10% of apparently healthy dogs exceeded this [LA:Ao = 1.6] limit. ... Our finding that LA:AoMAX, obtained from the right parasternal short-axis view, might exceed 1.6 in approximately 10% of dogs has clinical implications. ... We have shown that previously published upper reference limits for LA:AoMAX might be slightly low and that LA:Ao obtained at different time-points or from different views are not interchangeable.”

(18) Stack, J.P., et al., Reference Intervals and Echocardiographic Findings in Leonberger Dogs. J. Vet. Cardiol. 2020; doi: 10.1016/j.jvc.2020.03.006:

“Currently, the normal echocardiographic variables of Leonbergers are unknown. Although general canine reference ranges have been published, the large number of studies evaluating breed-specific data supports the notion that the general reference ranges have limitations due to the marked phenotypic variations across canines.”

(19) Gerhard Wess, et al., Echocardiographic reference intervals for volumetric measurements of the left ventricle using the Simpson's method of discs in 1331 dogs. J. Vet. Intern. Med. March 2021; doi: 10.1111/jvim.16089:

“Veterinary cardiologists face the problem of dealing with many different breeds and therefore a wide range of different body and BWs [body weights]. ... The optimal situation would be to have breed-specific RIs, generated from a large healthy population.”

(20) Dutton, E., et al., Echocardiographic reference intervals in healthy UK Deerhounds and prevalence of preclinical dilated cardiomyopathy: a prospective, longitudinal study. J. Vet. Cardiol. April 2021; doi: 10.1016/j.jvc.2021.04.001:

Healthy Deerhounds have higher LVDd, LVDs and EDVI compared with other breeds. This study provides ECHO RIs [reference intervals] for Deerhounds; sex or BW [body weight] RIs should be used when screening.”

(21) Tommaso Vezzosi, et al. Reference intervals for transthoracic echocardiography in the American Staffordshire Terrier. J. Vet. Med. Sci. April 2021; doi: 10.1292/jvms.20-0622:

“Regarding echocardiographic variables, the mean LVIDDn in our AST population was significantly higher than values reported in a range of canine breeds. ... Regarding the LA/Ao, the upper reference limit in our AST population was 1.75, with 6/57 (10%) dogs with a LA/Ao >1.6. ... The LA/Ao is the most widely used echocardiographic index to evaluate left atrial dimension in dogs, and several studies have used the upper reference limit of 1.6 to define left atrial enlargement. However, our results are in line with a study demonstrating that in around 10% of dogs, in particular in Boxers and Beagles, a small aortic root is present, which leads to an increase in the LA/Ao up to an upper reference limit of 1.73.”

These breed-specific echocardiographic features should be taken into consideration for an accurate echocardiographic interpretation and screening in the AST.

(22) Patata, V., et al., Echocardiographic parameters in 50 healthy English Bulldog: Preliminary Reference Intervals. J. Vet. Cardiol. May 2021; doi: 10.1016/j.jvc.2021.04.010:

“In our sample of EB [English bulldogs], the LA:Ao ratio in the short axis plane exceeded the previous upper reference limit of <1.6 in a significant number of dogs (12%). ... Thus, the use of breed-specific echocardiographic reference intervals is ideal for appropriate structural and functional assessment. ... Additionally, breed-specific reference intervals offer the possibility to develop better echocardiographic screening programs in the EB. ... Further studies comparing indexed cardiac dimensions and geometry among canine breeds with different thoracic somatotype may be useful.”

(23) Oktawia Szpinda, et al. Impact of selected individual dog traits on echocardiographic parameters obtained in 1-dimensional (M-mode) and 2-dimensional (2D) imaging. Canadian J. Vet. Res. April 2021;85(2):112-118:

“It is important to establish echocardiographic values for individual dog breeds, not only for primary measurements such as left ventricular dimension or left atrial dimension, but also for secondary measurements. ...

“Due to the wide variety of dog breeds and inhomogeneous research groups, echocardiographic measurements should be established individually for each breed based on a population study. This will allow for a more accurate interpretation of the results obtained in the echocardiographic examination and lead to earlier diagnosis of heart disease. ...

“The great variety of dog breeds means that echocardiographic findings should be individually interpreted rather than establishing reference ranges for each breed in population studies. This will allow for a more accurate interpretation of the results obtained in the echocardiographic examination and consequently lead to earlier diagnosis of changes in myocardial morphology.”

(24) Murat Vurucu, et al. An echocardiographic study of breed-specific reference ranges in healthy French Bulldogs. Vet. Radiol. Unltrasound. May 2021; doi: 10.1111/vru.12997:

Reference values obtained from breed-specific echocardiographic studies have been reported to have a significant difference compared to the general population of healthy different dog breeds. Therefore, breed-specific echocardiographic reference ranges may be more helpful in avoiding the misinterpretation of echocardiographic findings. During an evaluation without considering the breed-specific echocardiographic reference values, a normal heart structure and/or measurement could end up being falsely interpreted as either large or small or increased or decreased when compared to the general non-breed-specific reference ranges. These misinterpretations could lead to a misdiagnosis or an underdiagnosis of an underlying cardiac problem resulting in unnecessary/wrong treatment and/or no treatment.

“An echocardiographic evaluation of French Bulldogs based on general or different dog breed population reference ranges may result in misdiagnosis (such as an early phase of dilated cardiomyopathy or heart failure) because this breed has a different chest structure, cardiac silhouette, and left ventricular internal dimensions compared to other breeds. ... Normal heart sizes and shapes show substantial variation based on dog breed. Breed-specific reference ranges should be taken into consideration when evaluating the heart.

(25) Liva Vatne, et al. The effects of activity, body weight, sex and age on echocardiographic values in English setter dogs.  J. Vet. Cardiol. August 2021; doi: 10.1016/j.jvc.2021.08.003:

“Our study provides transthoracic echocardiographic values for English setter dogs, showing that they have larger hearts than many other breeds and fall outside of generic reference intervals for dogs. ... Breed specific reference intervals improve echocardiographic interpretation and thereby reduce misdiagnoses. ... The study provides breed specific transthoracic echocardiographic values for English setter dogs, thereby contributing to improve diagnostic assessment of cardiac health in this breed.”

Our Blog: "Should arbitrary reference intervals in research studies also be used to diagnose individual MVD patients?"

Our Blog: "Why do so many ACVIM cardiologists insist upon being Stuck On Stupid?"

Our Blog: "ACVIM’s 2019 definition of Stage B2 heart enlargement in MVD-affected dogs ignorantly assumes that one size fits all"

Mitral INsufficiency Echocardiographic score (MINE)

 In a May 2021 article, a team of Italian researchers devised a scoring system for classifying the severity of mitral valve disease (MVD or MMVD) in dogs. Its name, "MINE", is an acronym for "Mitral INsufficiency Echocardiographic score". MINE score consists of four echocardiographic measurements -- (1) the left atrium-to-aorta ratio (LA/Ao); (2) the left ventricular end-diastolic diameter normalized for body weight (LVIDDn); (3) the left ventricular fractional shortening (FS); and (4) the E-wave transmitral peak velocity (E-vel) -- that have been associated with survival in MVD-affected dogs. The authors "arbitrarily selected" minimum and maximum species-wide cutoffs for each of those MINE Tables 1 & 2four echo measurements by the severity of the class -- scores 1, 2, 3, and 4 -- based upon their own clinical experiences. (See Table 1.) They then totaled each dog's scores for the four echo measurements to arrive at a "severity classification" of:

• Mild (total score 4-5)
• Moderate (total score 6-7)
• Severe (total score 8-12),
• Late Stage (total score 13-14).

(See Table 2.) Based upon the dogs in the study, they calculated median survival times for each of their proposed severity classes, as follows:

• Mild: 2344 days (6.42 years)
• Moderate: 1882 days (5.16 years)
• Severe: 623 days (1.71 years)
• Late Stage: 157 days (o.43 years)

They found that a MINE score above 8 (the lowest total score for the "severe" classification) was predictive of MVD being the cause of the dog's death. They concluded:

"In conclusion, we have proposed the MINE score, which is an easy-to-use echocardiographic classification of severity of MMVD, proven to be clinically effective since it is associated with survival. This classification provides prognostic information and could be useful for an objective echocardiographic assessment of MMVD. The MINE score could also be useful in identifying asymptomatic dogs with higher risk of cardiac death."
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Progression & Prognosis

CavalierHealth.org Copyright © 2004 Blenheim CompanyThe progression of mitral valve disease can be rapid or slow. In most breeds, MVD barely progresses beyond a murmur or mild enlargement for most dogs -- up to 70% to 80% of them. The typical MVD-affected cavalier King Charles spaniel is not so fortunate. In most CKCSs, the disease shows a gradual progression in the loudness of the murmur and to more serious symptoms, in as little as two years after first detecting the murmur. But, some cavaliers develop a mild murmur without any more serious symptoms for many years. During this period, the dog's heart is doing its best to compensate for the affects of the blood backflowing through the valve. However, as veterinary cardiologist Dr. Stephen Ettinger has observed about the dog's efforts to compensate for those deliterious affects:

"A common characteristic of all compensatory responses is that the short-term effects are helpful, but the long-term effects are deleterious."

If the progression is slow enough, the dogs may die of other causes before their hearts reach failure. This is the usual pattern of MVD in most other breeds affected with it. Reportedly, up to 80% of small breed dogs which develop MVD murmurs, and even a mild degree of heart enlargement, will not reach Stage C -- congestive heart failure (CHF). But cavaliers are a breed apart in that regard, because the onset of MVD is so early in the CKCS and so pervasive. Therefore, most all cavaliers which develop heart enlargement will reach CHF.

In one particular case, the progression of MVD to heart failure is not Stage B1 and then Stage B2 and finally Stage C. An MVD-affected dog could have a mild mitral valve murmur and no enlargement at  all, and then suddenly, that dog could develop heart failure and enter Stage C because one or more chordae snap or deteriorate.

Once the dog reaches the stage of congestive heart failure (CHF),  the average time until death reportedly is 9 months and typically is expected to be between 6 and 14 months. The median survival period for dogs once they develop severe CHF due to MVD is approximately 7 months, with 75% of the dogs dead by one year. For dogs with less severe CHF, the median survival period is one year, with 75% of the dogs dead by 21 months. However, the CKCS has a more accelerated version of MVD, and they typically progress more rapidly to heart failure.

However, in an April 2018 report, a team of researchers at Tufts University's Cummings vet school examined the records of 54 MVD-affected dogs (including 9 cavalier King Charles spaniels) in advanced heart failure (AHF). Their definition of AHF was the recurrence of heart failure signs despite treatment with initial doses of pimobendan, ACE-inhibitor, and furosemide. At the diagnosis of AHF, they found that for most of the 54 dogs, doses of pimobendan, furosemide, ACE-inhibitor, and spironolactone were increased, with new medications added in most dogs. They found that the median survival time after diagnosis of AHF was 281 days (range, 3-885 days), and that dogs receiving a furosemide dose >6.70 mg/kg/day had significantly longer median survival times (402 days [range, 3-885 days] versus 129 days [range 9-853 days]). They concluded that dogs with AHF can have relatively long survival times, and that "a higher furosemide dose was significantly associated with longer survival time."

Risk factors associated with progression of MVD include:

• breed: CKCS is 20 times more prone to have-mitral valve disease than other breeds.
• age
• gender
• grade of heart murmur
• degree of mitral valve regurgitation
• extent of mitral valve prolapse
• severity of mitral valve lesions
• degree of left atrial enlargement
• rupture of chordae tendinae
• pulmonary hypertension
• increased concentration of natriuretic peptides.

Drugs may help to minimize the symptoms of MVD-affected dogs in Stage C, but eventually the drugs may be unable to control them, and they progress to Stage D. Severe symptoms in some cavaliers will appear more quickly, although previously having been stable.

A method which cavalier owners can use to determine if and when their dog reaches the stage of heart failure is to count the dog's breaths per minute while sleeping. Researchers found that healthy adult dogs generally have a mean sleeping respiratory rate of less than 30 breaths per minute and rarely exceed that rate at any time. Some cardiologists recommend that their patient's owners periodically count their dog's respiratory rate, and when the average rate starts to creep up to the high twenties, to make an appointment for the dog to be re-examined by the cardiologist to see if the dog is approaching or has reached the stage of heart failure. See our section on Respiratory Rates for more information.

Studies are being conducted into possibly slowing the progression of MVD. These studies, discussed in greater depth below at Drugs to Slow the Progression of MVD, involve the testing of medications.

For an in-depth on-line seminar about the symptoms, diagnosis, progression, and treatment of mitral valve disease, watch Dr. Andrew Beardow, with his terrific active graphics, explain MVD.

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left atrial enlargement 

Outline of enlarged left atriumEnlargement of the left atrium (LA) results when some of the blood already pumped from the LA through the mitral valve into the left ventricle, reverses direction and backflows through the mitral valve (mitral regurgitation -- MR) back into the LA again. As more blood flows into the LA from both directions, this volume overload increases stress on the atrium wall, which in turn drains the heart of its main sources of energy -- adenosine triphosphate (ATP) and oxygen. The left atrium necessarily begins to enlarge by stretching, called dilation. It is classified as Stage B2 in the list of ACVIM stages of MVD discussed above. (The x-ray at the right shows severe enlargement of the left atrium of a dog's heart, outlined in red.)

ATP is essential for the heart to function properly. It is an energy-carrying molecule found in all cells of the body, including in particular, the dog's heart.  When energy is needed by the cell, it is converted from storage molecules into ATP. ATP then delivers energy to places within the cell where energy-consuming activities are taking place. When the LA is stressed and over-worked, as it is during volume overload due to mitral valve regurgitation, the process of maintaining necessary levels of the supply of ATP do not meet the demand, and the walls of the LA weaken due to the stress of the volume overload, causing them to stretch and enlarge.

Left atrial enlargement is one of the most reliable predictors of risk factors. In a June 2017 abstract report, the risk of death with a left atrium/aortic root ratio greater than 1.7 was over two times that of dogs with smaller atrial dimensions. In an April 2010 research article, Swedish cardiologists reported finding that cavaliers' left heart chambers increased in size rapidly only during the last year before the onset of heart failure.

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left ventricle enlargement

The left ventricle (LV) is the main pumping chamber of the heart. As MVD progresses, the LV may also enlarge. Comparison of Left VentricleBut unlike the enlargement of the walls of the left atrium, which stretch and thin, the LV walls thicken to increase the force of its contraction, to compensate for the lessened quantity of blood the LV is intended to pump though the arteries to the body. This thickening process is called myocardial hypertrophy. The enlarged LV is more rounded than a flatter, normal sized LV.  It is classified as Stage B2 in the list of ACVIM stages of MVD discussed above. (At the left here are a pair of computer-designed models of a normal sized LV on the left and an enlarged LV on the right. Note that the healthy LV is flatter [elliptical], and the enlarged LV is wider and rounded [globular]). (Image from Ljungvall, et al. 20111.)

This enlargement process also saps the LV walls of its energy source, ATP, and the LV also loses the flexibility it needs to act as a pumping device.

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congestive heart failure

Heart failure (HF) has been discussed elsewhere in this article. It is classified as Stage C in the list of ACVIM stages of MVD discussed above. To summarize, HF is the stage of MVD at which HF is a point at which the MVD-affected dog's heart no longer is able to compensate by itself (meaning, without medication) for the debilitating efffects of MVD on the heart's ability to pump adequate quantities of blood throughout the entire body. It is the end result, short of death, of the progression of MVD in the cavalier King Charles spaniel.

"Congestive heart failure" (CHF) refers to the leakage (effusion) of white blood cells through the walls of the capillaries (also called diapedesis) to the surrounding tissues, in this case into the air sacs (alveoli) of the lungs, as a result of increased pressure in the left atrium which then increases pulmonary and venous pressures. The result of this process is called pulmonary edema (oedema).

While CHF is an actual event occuring within the heart and the blood system, it is not detected directly, but instead by outward signs and x-rays.

The first observable indication that the dog is experiencing CHF is an increase in the dog's breaths per minute, called its respiratory rate (RR). When the RR while the dog is at rest (RRR) or preferably while sound asleep (SRR) consistently reaches or exceeds 30 breaths per minute, the dog probably is in heart failure. This is discussed in more detail here.

In a March 2020 article, an international team of cardiologists studied 135 MVD-affected dogs, including 62 cavaliers, as they approached and entered CHF. They found:

"Dogs with MMVD in ACVIM stage B2 experience increases in HR [heart rate], RR [clinical respiratory rate], RRR [at-home resting respiratory rate], and VHS [heaert size], and decreases in BW [body weight] and RT [rectal temperature] as they progress into CHF. The change in VHS is characterized by a gradual increase over time, whereas the other variables change within the last few months before CHF. The variables with highest absolute change and rate of change were RR and RRR. This finding reinforces the value of RR and RRR as indicators of impending or incipient CHF. If RR and RRR are routinely and frequently measured in dogs with stage B2 MMVD, it may be possible for the onset of CHF to be detected earlier and therefore for it to be managed sooner and more effectively."

The other observable indication of CHF is fluid in the lungs. X-rays are the best diagnostic device for detecting fluid in the dog's lungs. This is discussed in more detail here. Other typical outward signs of HF or CHF include tiredness, difficulty exercising, fainting (syncope), or collapse (presyncope).

The most important significance of detecting heart failure in the MVD-affected cavalier is that it needs to be treated with a diuretic immediately and most likely for the rest of its life.

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atrial fibrillation

Atrial fibrillation (AF) is an abnormally rapid and uneven heartbeat. It is attributed to the effects of left artial enlargement (LAE) due to MVD. Not all MVD-affected dogs with LAE develop AF, but most will once they reach heart failure (CHF).

Veterinarians refer to abnormally fast heartbeats as supraventricular tachycardia, and to uneven heartbeats as arrhythmias. So, AF is both a supraventricular tachycardia and an arrhythmia.

AF requires treatment of its own, including digoxin (Lanoxin, Digitek, Digox, Lanoxicaps, Cardoxin), diltiazem, and lidocaine (lignocaine, Xylocaine). In addition, obesity is one factor associated with AF. In an October 2020 article, researchers examined the veterinary records of 2,194 dogs diagnosed with mitral valve disease (MVD), including only 51 (2.3%) cavaliers. Their objective was to estimate the prevalence of AF in MVD-affected dogs. Only 59 (2.7%) of all of these MVD-affected dogs were diagnosed with AF. They concluded that AF is not commonly associated in MVD-affected dogs, but that left atrial enlargement, increased body weight, decreased fractional shortening (below 40%), and heart failure are risk factors for MVD-affected dogs to develop AF.

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chordae tendineae rupture

Mitral Valve Cross-Section  Copyright © Cleveland ClinicChordae tendineae rupture (CTR) is a special case -- the exception to the general rule when it comes to predicting the typical progression of MVD. The chordae tendineae are the tendons which control the opening and closing movements of the mitral valve leaflets. They are shaped much like the chords of a parachute. Some of these chords are small and a few are quite large. The largest are called "first-order" or major chordae, and the smaller ones are "second-order" or "third-order" or minor chordae.

 As the MVD progresses, these chordae deteriorate in the same manner as the leaflets of the valve. In some cases, one or more of them shred or rupture, and if the ruptured chorda is a large one, or if several of the smaller ones tear apart, the valve leaflet to which the chords had been attached will "flail" or flap as it opens and closes, allowing blood to backflow through the valve at a far more rapid rate than before the rupture.

Thus far, CTR has not been predictable or directly related to the deteriorated condition of the valve flaps. Once a major chorda ruptures, severe signs may appear almost instantly, including cardiogenic shock -- the sudden lack of blood being delivered to the body.

In a 2007 study of 706 MVD-affected dogs, CTR was found to occur in 114 (16.1%) of the dogs, most all of which already had severe mitral regurgitation. While the rupture of chords may quickly send a Stage B2 dog into Stage C -- heart failure -- it does not necessarily mean sudden death for the dog. In that 2007 study, the median survival time for the 114 dogs was 425 days (range 5–1,324 days).

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pulmonary hypertension

Pulmonary hypertension (pulmonary arterial hypertension -- PH or PAH) is the name given to increased blood pressure in the pulmonary (lungs) arteries. While PH can have various underlying causes, the most common one is a complication of mitral valve disease, usually in Stage C.

PH is higher diastolic or systolic pulmonary arterial pressure than normal pressure. Normal pulmonary arterial pressure is 10-15 mmHg, and PH is defined as a sustained pressure greater than 25 to 30 mmHg. Pressure at or above 48 mmHg suggests that the PH is irreversible. In a February 2020 ACVIM Consensus Statement on PH, the authors recommend defining PH in dogs as having a tricuspid regurgitation pressure gradient cutoff of >46 mmHg (TRV >3.4 m/s).

PH is suspected in MVD-affected dogs if the dogs display symptoms of heart failure, including syncope during exertion, respiratory distress while at rest or after exercise, and ascites (fluid in the abdomen or abdominal effusion).

The form of PH most often resulting from MVD is called "post-capillary PH" (as opposed to pre-capillary PH), which is due to backward transmission of the increased filling pressures in the left atrium into the pulmonary circulation. This high pressure may lead to increased right ventricular pressure and right atrial chamber enlargement, leading to possible right side heart failure.

In a March 2015 study of 212 dogs, including 30 cavaliers, diagnosed with either Stage B2 or Stage C MVD, the researchers found that 39% of the dogs had PH, and that PH was more commonly found in Stage C. They concluded that the presence of moderate to severe PH predicted a shorter survival time in dogs with MVD.

In a June 2019 article, researchers sought to determine if MVD-affected cavalier King Charles spaniels (CKCS) are more likely to develop pulmonary hypertension (PH) than MVD-affected dogs of other breeds. Ninety-four CKCSs were compared with 93 other dogs (= 187 dogs) in a variety of stages of MVD, some with PH and some without. They compared several different measurements of MVD, including the ACVIM stages (Stage B2, C, and D), and echo variables of left-atrium-to-aortic ratio (LA/Ao), E wave velocity (E vel) and isovolumic relaxation time (E/IVRT) and found that all of them were significant in the development of PH. However, instead of finding that cavaliers were uniquely disposed to PH, they concluded that for all breeds, the worsening of MVD, from ACVIM stage B2 to C to D, was the predominant determinant of PH development. However, 59.4% of the Stage B2 CKCSs and 38.3% of the Stage B2 non-CKCSs had PH, indicating that the onset of PH can precede the onset of congestive heart failure (CHF). As additional findings, they confirmed that CKCSs are more likely to experience cardiac death than the other breeds, and that PH is associated with greater likelihood of reaching CHF and cardiac death. ("Associated with" means that they cannot confirm that PH is the cause of CHF or death.) They stated that, "Further studies are needed to determine the causative mechanism for PH development in CKCS with MMVD."

In that February 2020 article, the ACVIM has issued a Consensus Statement of guidelines for the diagnosis, classification, treatment, and monitoring of pulmonary hypertension (PH) in dogs. They group the PH into six categories, of which Group 2 is PH secondary to left-sided heart disesase, meaning MVD. At the outset for Group 2 PH-affected dogs, they warn that "a PDE5i (e.g. sildenafil, Viagra, Revatio) should be administered only to dogs free of acute or decompensated LHF (cardiogenic pulmonary edema." In other words, if the MVD-affected dog is in Stage C (heart failure) and still has fluid in its lungs, treating with Viagra is not appropriate. They add that PDE5i drugs may be considered if the dog has exertional syncope due to its MVD, and it has failed to respond to other treatments, specifically pimobendan.

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left atrial tear and defects

Defects and/or rupture (tear) of the wall of the left atrium, usually the rear (caudal) wall, is considered a consequence of severe MVD. The left atrium's caudal wall is the location where regurtitant jets of blood commonly are directed when they backflow through the mitral valve, causing a trauma to that region of the wall. See these reported cases: August 2010; December 2012; August 2015; October 2016.

As a result of the rupture, fluid may collect in the space surrounding the heart, called the pericardial sac or pericardium. This accumulation of fluid may compress the heart, leading to a decrease in the heart's output of pumping blood and obstructive shock. Emergency treatment is necessary, which may include medication with atropine, to treat the resulting low heart rate, and dobutamine, a cardiac stimulator. In the event that medication is not successful, a procedure called pericardiocentesis may be performed to remove the fluid from the pericardial sac. See this November 2021 reported case.

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right-sided heart failure

The form of congestive heart failure discussed here in connection with MVD affects the left side of the heart, the left atrium and the left ventricle and the mitral valve between them. The right side of the heart consists of an atrium and ventricle separated by the tricuspid valve, which controls the flow of blood from the right atrium into the right ventricle.

In some cases of MVD, as they progress towards CHF, with pulmonary hypertension, the tricuspid valve also begins to leak, causing blood to backflow from the right ventricle into the right atrium. This can result in right-sided heart failure, in which the fluid build-up takes place in the cavity of the abdomen as well as organs below the heart, including the stomach, liver, and gastrointestinal tract. This is called ascites (or abdominal effusion). The dog with right-sided heart failure also likely will have jugular puslsation when their pulses are examined. See our discussion on this page about removal of retained fluids in the abdomen (abdominocentesis) resulting from right-sided heart failure.

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sudden death

MVD-affected dogs may die suddenly and without much or any preliminary indications, due to any of these causes listed above: atrial fibrillation, chordae tendineae rupture, atrial tear (rupture).

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Treatment before medication

It is unrealistic to try to cure canine mitral valve disease. "Management" is a word frequently used by veterinary cardiologists to describe the conventional means of treating MVD. It involves medications, supplements, and diets intended to compensate for the progression and symptoms of MVD, especially once the disease reaches heart failure (HF). The veterinarian tries to eliminate or reduce signs of fluid accumulation and congestion, and to maintain adequate cardiac output in order to provide needed blood flow. The degree of treatment will depend upon the stage of the disease. Early MVD is not treated in the same way as advanced MVD. The particular management treatments are discussed below: Stage B1 (mild), Stage B2 (moderate), Stage C (severe), or Stage D (end stage). 

For an in-depth on-line seminar about the symptoms, diagnosis, progression, and treatment of mitral valve disease, watch Dr. Andrew Beardow, with his terrific active graphics, explain MVD.

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-- dietary treatment

Cavalier eating from bowlGeneral nutrition is very important as the MVD progresses throught Stages B, C, and D. Dietary treatment varies, depending upon the stage (B1, B2, C, D) of the MVD. For dogs with any heart enlargement (Stages B1 if one chamber is enlarged and B2), the panel of cardiologists authoring the ACVIM’s 2019 Consensus Statement on diagnosing and treating MVD recommends "mild dietary sodium restriction and provision of a highly palatable diet with adequate protein and calories for maintaining optimal body condition."

Dogs in Stages C (heart failure) and D may suffer severe weight loss, called progressive cardiac cachexia, and they should be fed any protein-rich palliative food to maintain muscle mass. See this January 2012 article about cardiac cachexia and the importance of maintaining body weight as a preventative measure.

In the ACVIM’s 2019 Consensus Statement, the panel of cardiologists recommends maintaining an adequate calorie intake to minimize weight loss that often occurs in CHF. Specifically, they advice a maintenance calorie intake in Stages C and D of approximately 60 kcal/kg of body weight. They suggest warming food, mixing wet food with dry food, and offering a variety of foods, to encourage the affected dogs to eat. They also recommend "modestly" restricting sodium (table salt) intake. Specifically, they state:

"Modestly restrict sodium intake, taking into consideration sodium from all dietary sources (including dog food, treats, table food, and foods used to administer medications) and avoid any processed or other salted foods."

UK cardiologist Simon Swift noted at a 2010 symposium that:

"Interestingly, asymptomatic dogs fed a 'heart diet' had a reduction in heart size. The 'heart diet' included decrease sodium, increased levels of arginine, carnitine and taurine as well as supplementation with omega 3 fatty acids. Whether this translates into a delay before heart failure develops remains to be proven."

The Heart Diet was reported in a 2006 article by Drs. Lisa M. Freeman (board certified veterinary nutritionist) and John E. Rush (board certified veterinary cardiologist), and by Peter J. Markwell (senior veterinary nutritionist at a UK dog food company). They fed "a moderately reduced sodium diet enriched with antioxidants, n-3 fatty acids, taurine, carnitine, and arginine" for four weeks to fourteen dogs, including cavaliers, with asymptomatic mitral valve disease. Another fifteen asymptomatic dogs, including cavaliers, were fed a placebo. They found that the dogs on the heart diet had measurable reductions in heart size, including the left-atrial dimension and left-ventricular internal dimension.

A downside of this 2006 study was that the food fed in both diets consisted of "commercial, extruded, dry dog foods", i.e., kibble. Another downside is that the study was funded by Mr. Markwell's employer, a kibble manufacturer.

In a January 2017 article, Dutch Dr. Anton C. Beynen reviewed sodium restricted diets for MVD-affected dogs and concluded:

"There is no evidence that sodium restriction improves clinical signs in canine cardiac disease. Worse still, there are good reasons for contraindication."

In a November 2016 article by a team of French cardiologists and specialists, they reported on the use of a palatable high-energy complementary feed composed of high-energy ingredients (glucose syrup, soybean oil and cod liver oil), hydrolyzed animal proteins, vitamins and oligo-elements, called Nutri-Plus Gel, in five case studies.

Case Report 4 was of a female 13-year-old cavalier King Charles spaniel in Stage C2 (advanced heart failure) of mitral valve disease, which had lost 1.5 lbs. in the previous month and now weighed 11.5 lbs. She exhibited signs of fatigue, lack of appetite, and diarrhea. Her MVD treatment had been the standard four medicines for cavaliers in heart failure (diuretic, pimobendan, ACE-inhibitor, and spironolactone). They reported:

"Nutri-Plus Gel was also prescribed to stimulate appetite, limit the already considerable loss in body weight (10% of the initial weight in one month), and facilitate treatment compliance (six drugs in all, requiring eleven oral doses). During the follow-up visit one week later, the owner reported that the digestive and cardiac symptoms had disappeared (stage C1). One month later, a gain in weight was noted (200 g [0.44 lb.]). Two years after this episode, the dog was in good general condition and no change in the medical treatment was proposed, as the symptoms had not returned. As the animal’s weight is now stable, Nutri-Plus Gel is recommended solely on demand, during phases of hyporexia (infrequent to date, according to the owner)."

See a list of suggested heart-healthy supplements here.

Two studies reportedly are being conducted to find medications directed at the pathology of mitral valve disease and which may slow the progression of MVD. 

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-- supplements

--- In General

A good multi-vitamin, like VetriScience Canine Plus MultiVitamin, which provides vitamins C, D, and E.

Fish oils for Omega 3s.

Vetri-Science Cell Advance 880 Immune Health Antioxidant Support.

A cardiac-specific combination supplement, like Canine Cardiac Support by Standard Process. Alternatives would be Bio-Cardio by Thorne Veterinary Products or Vetri-Cardio Canine Chews.

D-Ribose: (Natural supplements which may help to strengthen and energize the heart of a dog with severe MVD include D-Ribose, also known as alpha-D-ribofuranoside, for MVD-affected dogs in Stage B2 or Stage C. See details here. Doses are of 1/4 to 1/2 teaspoon with meals, twice daily.

Vitamins and food supplements such as these may be prescribed for all stages of mitral valve disease. Holistic supplements should be taken only if prescribed by a licensed veterinarian who also is holistically trained. Search webpages for finding holistic veterinarians  in the United States and Canada are located here, and in the United Kingdom, here.

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--- CoQ10

Coenzyme Q10 (CoQ10) has been reported to be of benefit and is recommended as a nutraceutical in human heart failure (CHF) patients. In a 2000 experimental study, the antioxidant CoQ10 reportedly had some limited success in treating dogs in heart failure. It aided the left ventricle in properly relaxing and filling with blood properly. However, in a September 2018 article, Thai veterinary cardiologists tested 13 dogs in congestive heart failure (CHF) due to mitral valve disease (MVD) with coenzyme Q10 (CoQ10) over a four-week period. The dose was 100/mg twice a day for both small (Group I) and large dogs (Group II). They report finding that:

• CoQ10 caused a reduction of cardiac troponin I (cTnI) level in 71% of the dogs.
• Systolic function -- fractional shortening (FS) and ejection fraction (EF) -- increased significantly in small dogs after CoQ10 supplementation.
• Other echocardiographic parameters were not altered in either group.
• CoQ10 did not alter sympathovagal balance in MMVD dogs.
• Supplementation dose of CoQ10 should be based on the body weight.

In a June 2020 abstract, Slovenian researchers tested daily doses of water-soluable CoQ10 supplementation in 19 MVD-affected dogs in heart failure (CHF) for two weeks, and compared them to 12 healthy dogs. They divided the MVD-dogs in three groups and dosed 100 mg, 200 mg, or placebo divided into two doses each day. One week after the last dose, the CoQ10 concentrations had decreased, but in the 200 mg group, it remained significately higher. They concluded that:

"A daily dose of 200 mg resulted in at least a 3-fold increase of plasma CoQ10 concentration in all patients and might be used in supplementation studies in canine CHF patients."

In a September 2020 article, a team of Danish investigators conducted a 3-week study of 18 cavalier King Charles spaniels (CKCS) diagnosed with mitral valve disease (MVD) in either Stage B2 or Stage C, to determine the pharmacokinetics* of repeated oral dosing of the ubiquinone form of CoQ10 and to evaluate echocardiographic parameters, circulating cardiac biomarkers, and quality of life (QoL) after treatment. The dose was 100 mg given orally twice a day in a placebo-controlled trial. They found that a 3-week period of treatment with CoQ10 did not significantly improve echocardiographic indices of MVD severity, circulating cardiac biomarkers, or owner perceived QoL, compared to the placebo. The concluded:

"In conclusion, we show that a gelatin capsule formulation of solubilized Q10 is well tolerated in CKCS with MMVD and is absorbed into the circulation without adverse reactions. There were, however, inter-individual variations in the plasma concentrations with this formulation of Q10 similarly to findings in humans. A dosage of 200 mg/day for three weeks of Q10 does not appear to change the clinical severity of MMVD or QoL in CKCS. The estimated T1/2 of 2.95 days may suggest that every other day treatment in dogs may su ce to keep circulating concentrations of Q10 ≥ 2.0 µg/mL in dogs. The variation in Q10 plasma concentrations observed among the CKCS suggests initiation of studies investigating the physiological factors determining intestinal absorption of Q10, including dosing and feeding regimens. ...Ultimately, investigation of long-term use of Q10 in dogs with MMVD and heart diseases of other etiologies are therefore relevant — preferably with dosing tailored in accordance with laboratory testing of Q10 plasma concentrations."

* Pharmacokinetics is the study of the movement of drugs in the body, including the processes of absorption, distribution, localization in tissues, biotransformation, and excretion.

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   --- D-ribose

D-RiboseD-ribose as a nutritional supplement provides needed added energy to the heart muscle and walls. It is a natural sugar which the canine body produces on its own but which can be depleted when the stressful forces of MVD begin to drain the heart of its ability to compensate for the affects of mitral valve regurgitation. The dog's heart and skeletal muscles can only make enough D-ribose to manage their day-to-day needs when those cells are not under stress. When dogs are in heart failure or are approaching it, the heart cells cannot make enough D-ribose.

D-ribose is a primary component of adenosine triphosphate (ATP), an energy-carrying molecule found in the cells of all living things. ATP is the means of transforming the energy from the breakdown of food molecules into the energy consumed by all cells of the body, including in particular, the dog's heart. ATP is essential for the heart to function properly. D-ribose is the only compound used by the dog's body to replenish diminished ATP energy stores.

When the MVD-affected left atrium (LA) and left ventricle (LV) of the heart are stressed and over-worked, as they are during volume overload due to mitral valve regurgitation, the heart consumes greater quantities of ATP. At that point, the process of the heart maintaining necessary levels of ATP does not meet the demand, and the walls of the LA and LV weaken due to the stress of the volume overload, causing them to stretch and enlarge. The dog’s natural replenishment of necessary levels of ATP can take a considerable amount of time in the hearts of dogs affected with MVD. D-ribose, when taken as a nutritional supplement, bypasses the slow conversion steps needed to recreate ATP and rapidly replenishes the supply of ATP which the heart needs to offset the stresses of mitral regurgitation.

D-ribose is available on-line and at health food stores. All holistic supplements should be taken only if advised to do so by an holistically trained, licensed veterinarian. Search engine webpages for finding holistic veterinarians in the United States and Canada are located here, and in the United Kingdom, here.

D-Ribose Dosage Chart

See these articles for more information:

February 1989: "No significant ATP recovery occurred after 24 hr in the control dogs, but in the ribose-treated animals, ATP levels rebounded to 85% of control by 24 hr. Total myocardial adenine nucleotide content and energy charge also recovered in the ribose group but not in the control animals. The ribose infusion, therefore, significantly enhanced the recovery of energy levels in the postischemic myocardium in the intact animals."

Summer 2004: "Patients with congestive heart failure often experience fatigue despite intensive pharmacological therapy. Ribose can aid the recovery of ATP levels and, hence, diastolic function. Clinical trials have shown that ribose supplementation improves ischemic threshold and enhances diastolic function in congestive heart failure."

July 2007: "We then turned our attention to ribose. Ribose is made in your body in a slow, laborious process and cannot be found in food. ... Not having ribose would be like trying to build a fire without kindling--nothing would happen. ... I am now recommending ribose for ... heart problem patients ... . In fact, one patient in our study had atrial fibrillation that resolved with ribose, and most practitioners using it are finding it to be simply outstanding for their cardiac patients in general."

June 2015: " Previous studies have demonstrated that diastolic function is energy dependent and supplemental D-ribose has shown to improve diastolic dysfunction. This study investigated what role D-ribose might play in congestive heart failure patients with preserved systolic function and diastolic dysfunction. ... Results: An improvement in their tissue Doppler velocity (E′), which was maintained at 9 weeks, was demonstrated in 64% of the patients."

June 2016: "Myxomatous mitral valve disease (MMVD) is the most common cause of mitral valve regurgitation (MVR) in small animals, with a prevalence of approximately 30% in small breed dogs over the age of 10 years. The time course of the disease influences the clinical symptoms. If MVR occurs slowly, there is time for compensation and the animal may be asymptomatic; if MVR develops acutely, the clinical signs can be very severe. With MVR there is a decrease in stroke volume because part of the outflow of the left ventricle (LV) is directed back to the left atrium (LA). The regurgitant fraction causes volume overload of the LA and LV, according to Laplace’s law. Volume overload increases wall stress, which in turn requires greater adenosine triphosphate (ATP) and O2 consumption. As a compensatory mechanism, myocardial hypertrophy occurs. The chronic volume overload of the LA can lead to dilation of the atrium, with increased pressure and pulmonary congestion, resulting in pulmonary oedema and congestive heart failure (CHF). Possible complications of MMVD are right-sided CHF, due to direct involvement of the tricuspid valve or as a consequence of pulmonary hypertension (PH), and arrhythmias, such as atrial fibrillation (AF), due to atrial enlargement."

May 2017: "D-ribose is a carbohydrate (sugar) that is important for the body’s cellular metabolism through the production of a substance known as ATP (adenosine trisphosphate). Patients suffering from severe heart disease, especially heart diseases such as dilated cardiomyopathy, may have severely depleted stores of ATP within heart muscle tissue. A small study in humans with congestive heart failure suggested that supplementation with ribose may improve heart muscle function."

January 2018: " Mitochondria are important organelles referred to as cellular powerhouses for their unique properties of cellularenergy production. With many pathologic conditions and aging, mitochondrial function declines, and there is a reduction in the production of adenosine triphosphate. The energy carrying molecule generated by cellular respiration and by pentose phosphate pathway, an alternative pathway of glucose metabolism. D-ribose is a naturally occurring monosaccharide found in the cells and particularly in the mitochondria is essential in energy production. Without sufficient energy, cells cannot maintain integrity and function. Supplemental D-ribose has been shown to improve cellular processes when there is mitochondrial dysfunction. When individuals take supplemental D-ribose, it can bypass part of the pentose pathway to produce D-ribose-5-phosphate for the production of energy. In this article, we review how energy is produced by cellular respiration, the pentose pathway, and the use of supplemental D-ribose."

March 2018: "Cardiovascular disease still remains the leading cause of deaths worldwide. ... All cells require adequate adenosine triphosphate (ATP) levels to maintain their integrity and function. ... D-ribose, a naturally occurring pentose carbohydrate, has been shown to increase cellular energy levels and improve function following ischemia in pre-clinical studies and have demonstrated potential benefits in clinical evaluations. This review paper presents an overview of ischemic cardiovascular disease and the potential role that D-ribose could play in improving myocardial energy levels and function in the area of ischemic cardiovascular diseases."

Our Blog: "D-ribose can boost the energy in MVD-affected hearts"

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    --- salvia shou wu

Salvia Shou Wu is a proprietary combination of herbs (Salvia root, polygonum, crataegus, peony (red), astragalus root, achyranthes, loranthus, tangkuei, dalbergia, licorice) by Seven Forests, which is designed to enhance blood circulation, dispense stagnant blood, and nourish the blood. Holistic veterinarians recommend this product for dogs with enlarged hearts or in heart failure, due to MVD, at the rate of 1/4 tablet twice daily with food, for dogs the size of cavaliers.

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--- taurine

If cavalier owners choose to ignore the advice to consult with an holistic veterinarian before giving their dogs supplements, they nevertheless should be aware of falsehoods about certain supplements, such as taurine. Research studies have shown that MVD-affected dogs tend to have higher plasma taurine concentrations than unaffected dogs. In a 1995 study (by George A. Kramer, Mark D. Kittleson, Philip R. Fox, Julia Lewis, and Paul D. Pion), for example, "[P]lasma taurine concentrations were highest in dogs with AVD [acquired valvular disease, e.g, MVD] ... We conclude that plasma taurine concentrations may be increased in dogs with AVD." In a 2002 presentation, Dr. Bruce Keene stated: "Taurine supplementation is indicated whenever plasma or whole blood taurine concentrations are found to be low. ... [S]upplementation is generally only recommended after discovery of deficiency." See, also, Dr.  Rebecca E. Gompf's 2005 article on nutritional therapies.

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-- stem cells

Research in cardiac stem cell therapy is in early stages and is on-going. Researchers are dealing with issues such as the ever-pumping heart washing out stem cells which have been inserted into it.

In a 2008 pre-med research paper, the author suggests that injecting bone marrow stromal cells into the heart of a cavalier King Charles spaniel may stimulate stem cells to regenerate heart muscle and repair damage to the valve tissues. See also this February 2012 article.

Preventative Vitamins and Supplements?

No medications or food supplements are known to prevent the onset of MVD. However, some supplements may defer the time of onset (although there is no scientific proof that they do so), including:

Vitamin C (300 to 400 mg. daily)

Vitamin E -- Tocopherol (100 I.U. daily)

CoQ10 (100 mg. twice daily, for small dogs)

Fish oils high in Omega 3 (about 400 mg. daily). as in canned sardines

Antiox-Ultra 5000 by Sogeval Laboratories (a nice all-in-one blend of antioxidants in a chewable tablet.)

 In a 2014 report, veterinary researchers at North Carolina State University have successfully figured out a way to magnetize cardiac stem cells so that they are directed to the hearts of rats and remain there to perform therapeutic effects. The team has attached metalic nanoparticles from an FDA-approved drug, Feraheme, to cardiac stem cells and used a magnetic field to keep the cells in the heart. The process has resulted in a three-fold increase in cell retention in the rats' hearts.

Beginning in 2016, a research team at Tufts' University's Cummings veterinary school, led by Dr. Andrew Dr. Vicky YangHoffman and veterinary cardiologist Dr. Vicky Yang (right), has been conducting a study of ten MVD-affected dogs in congestive heart failure (determined by fluid in the lungs), which are being injected with mesenchymal stem cell (MSC) treatments to determine, first, if the therapy is safe for the dogs, and, second, will result in improved cardiac function, as determined by echocardiography, cardiac biomarkers, and quality of life.  The study is titled, "Allogeneic Umbilical Cord Tissue (Wharton Jelly) Derived Mesenchymal Stem Cell Therapy for Chronic Valvular Disease and Associated Congestive Heart Failure".

Dr. Philip Richard VullietDr. Philip Richard Vulliet (left), veterinary medical director at ReGena-Vet Laboratories and professor at UC Davis, is investigating the potential of injecting adult bone marrow stem cells in MVD-affected dogs, including cavalier King Charles spaniels, with the goal of slowing the progression of MVD and even shrinking the size of the enlarged hearts. The lab currently is experimenting with Doberman Pinschers affected with dilated cardiomyopathy. His contact information is: ReGena-Vet Laboratories, LLC, 2079 Anderson Rd., Suite B, Davis, CA, 95616, Tel: 530-902-9006, Fax: 530-756-0459, email info@regenavetlabs.com or regenavetlabs@gmail.com, website regenavet.com

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-- growth differentiation factor 11 (GDF11)

A protein called "growth differentiation factor 11" (GDF11) has been found to have a restorative effect in the hearts of aged mice. In a May 2013 study, the protein was injected into the blood systems of mice with hearts enlarged due to cardiac hypertrophy, for 30 days. At the end of the treatment. their hearts were significantly smaller than those in the control group. The researchers found that the treated mice' heart cells had shrank significantly.

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-- new DNA injections

Researchers at the Wyss Institute and Harvard Medical School announced in July 2017 that they are developing a novel cardio-protective gene therapy to stop the progression of heart failure in dogs. As part of the technical development, the Wyss Institute is planning to launch a study in MVD-affected dogs. According to the developers, new DNA segments are to be injected into the MVD-affected dogs with cardiac enlargement (Stage C), which lead to the production of a "beneficial" protein intended to suppress fibrotic processes and halt the build-up of scar tissue in the heart. See this linked article for more information. 

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 -- inflammation

MVD appears to be associated with a chronic state of inflammation, as evidenced by measurements of immunoglobulin antibodies and glycoprotein and complement proteins particularly associated with immune responses to inflammation. Therefore, among the treatments to consider would be methods of reducing inflammation by diets and supplements.

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-- physical exercise

Treadmill ScarlettThere is very little published research regarding the advisability of physically exercising MVD-affected dogs, by such things as walks, treadmill running (right), or training for events such as agility. In an October 2018 article, a team of Thai veterinary researchers tested six Beagles with Stage B1 mitral valve disease (mitral regurgitation but no heart enlargement), to determine the effects of "submaximal endurance training" by treadmill running and 6-minute walks, over a period of eight weeks. They report finding that the exercise:

• significantly improved the physical capacity of the dogs,
• did not affect cardiac function, and
• significantly reduced serum creatine.

They concluded that, "supervised or moderate regular exercise that is within the individual physical capacity should be performed in subclinical MMVD dogs and dogs with low routine physical activity, in order to preserve or improve physical capacity and quality of life." This study was limited to fairly sedentary MVD-affected dogs in Stage B1. It did not test dogs in Stage B2 or in Stage C.

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MedicationsMedications for MVD

The major means of treating mitral valve disease in dogs is called "maintenance" and consists of medicating the dog with drugs. The severity of the dog's MVD determines whether any drugs should be administered and what quanitities. Since the ACVIM's 2009 Consensus Statement was published, the severity of MVD has been divided into "stages" -- B1, B2, C, D -- what follows are discussions of which medications typically are prescribed for each stage of MVD.

-- Stage B1 -- murmur & no enlargement

ACVIM Stage B1A cavalier with early mitral valve disease has a mild murmur (usually at Grade 1 or 2 out of 6) but the heart is not enlarged and the dog is symptom-free (asymptomatic). This dog would be at Stage B1 of the ACVIM's 2009 Consensus Statement, although a dog with even a higher grade murmur (Grade 3 or 4) could meet the Stage B1 definition, as long as it is symptom-less and has no heart enlargement.  Cardiologists refer to this as the pre-clinical stage. At this stage, there is no need for treatment, but heart size should be monitored by x-rays every 6 to 12 months. Overweight dogs should be put on a weight-reducing diet. Low salt diets have been suggested, to help reduce water retention. It would be prudent to avoid extreme exertion.

  The participating cardiologists in the ACVIM's 2009 Consensus Statement unanimously declined to recommend any drug or dietary therapy for Stage B1 dogs. Nevertheless, studies of drugs have been conducted on dogs in Stage B1, and what follows is a discussion of the reports of those studies:

In a 2013 presentation titled "Medical Therapy of Congestive Heart Failure: The Essentials", Dr. Matthew W. Miller, board certified veterinary cardiologist, concisely summarized the current treatment protocol for cavaliers not yet in heart failure (Stage C):

"Treatment of the asymptomatic dog with a murmur caused by endocardiosis is not currently recommended unless there is evidence of impending heart failure (dramatic cardiomegaly and pulmonary venous distension). Scandinavian studies in the CKCS dog have failed to reveal any benefit in asymptomatic dogs; results from a North American study suggest a possible benefit, but were by no means conclusive."
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--- supplements

Vitamins and food supplements such as these listed above may be prescribed for all stages of mitral valve disease. Holistic supplements should be taken only if prescribed by a licensed veterinarian who also is holistically trained. Search webpages for finding holistic veterinarians  in the United States and Canada are located here, and in the United Kingdom, here.

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--- ACE-inhibitors in Stage B1

CavalierHealth.org Copyright © 2004 Blenheim CompanyAngiotensin converting enzyme inhibitors (ACE-inhibitors or ACE-I) in humans have been found to widen blood vessels by relaxing the smooth muscle cells in the vessels' walls (vasodilation), counteract fluid retention, and blunt heart enlargement due to MVD. However, in dogs with Stage B1 MVD (or Stage B2), and particularly in cavaliers, the results have been more mixed and much less favorable. In fact, the most recent studies have concluded that ACE-inhibitors are worthless, even in cases of heart failure (Stage C).

Since the ACVIM Consensus Statement does not recommend any drugs for Stage B1 dogs, there should be no reason to prescribe an ACE-inhibitor to a cavalier in Stage B1 of MVD.

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--- alpha & beta blockers in Stage B1

As noted, the ACVIM Consensus Statement does not recommend any drugs for Stage B1 dogs. Nevertheless, other drugs being used by some veterinary cardiologists are carvedilol (Coreg), and bisoprolol, both non-selective beta-and alpha-blockers with anti-oxidant effects -- also known as beta- (β-) adrenergic receptor antagonists (BARA) -- which reduce the heart's rate and the force of its contraction, thereby reducing the work of the heart. Carvedilol and bisoprolol also cause the arteries to relax and the blood pressure to drop. A few cardiologists have begun to administer low doses of carvedilol and Bisoprolol early in the disease process, in hopes of causing MVD to progress at a slower rate than dogs not taking the medication. In a 2009 study, it has been suggested that BARA have the potential to slow the progression of the mitral valve's degeneration by interfering with the serotonin signaling pathway -- a possible major factor in MVD progression -- and by reducing the "wear and tear" of the valve by reducing the pressure differences between the left ventricle and atrium.

To learn more about alpha and beta blockers, go to our discussion of them in our Treatment - Stage B2 section.

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--- pimobendan in Stage B1

As noted above, the members of the ACVIM panel who participated in its 2009 Consensus Statement unanimously refused to recommend prescribing pimobendan to Stage B1 dogs.

Pimobendan (Vetmedin, Cardisure, Safeheart, Pimocard, Pimotab, Zelys), has been prescribed for MVD-affected dogs in heart failure (Stage C) and, in some cases, dogs with left-side heart enlargement (Stage B2). It should not be prescribed for cavaliers in Stage B1. In a September 2016 article, an international team of veterinary cardiologists published the EPIC Study report, which tested the dosing of pimobendan on MVD-affected dogs in Stage B2 (discussed below). They do not recommend prescribing pimobendan for dogs in Stage B1. Also, harmful side effects have been noted from early use of this drug. See the "A Few Words About Pimobendan" box below for details. The US Food & Drug Administration (FDA) has approved the administration of pimobendan only for MVD-affected dogs in heart failure (Stage C) and not for dogs in either Stage B1 or B2.

To learn more about pimobendan, go to our discussion of it in our Treatment - Stage B2 section.

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--- sildenafil (Viagra, Revatio) in Stage B1

Sildenafil (Viagra, Revatio) (a/k/a sildenifil) is a selective phosphodiesterase-5 inhibitor that has been demonstrated to delay ventricular enlargement in humans and experimental animals. In MVD-affected dogs, this drug has been prescribed for MVD-affected dogs already in heart failure (Stage C) if pulmonary hypertension is also detected. Pulmonary arterial hypertension, as a complication of mitral valve disease, is higher diastolic or systolic pulmonary arterial pressure than normal pressure. This high pressure may lead to increased right ventricular pressure and right atrial chamber enlargement, leading to possible right side heart failure.

In a March 2017 report of a 180-day study of 30 MVD-affected dogs (none were cavalier King Charles spaniels) in Stage B1 or Stage B2 (non-symptomatic), a team of Thailand investigators treated half of the group with sildenafil (Viagra, Revatio) (a/k/a sildenifil) versus a control group. They found:

• The stroke volume (the volume of blood pumped from the left ventricle per beat) at day 30 was significantly higher in the sildenafil group
• The LA/Ao (left atrial-to-aortic ratio) and the MR jet area were significantly lower beginning at day 30, day 90, and day 180.
• The 2D-LA (2-dimentional left atrium size) was significantly lower at day 90 when compared with control group.
• The differences of NTproBNP (a natriuretic peptides test biomarker in cardiac disease) from baseline were significantly lower when compared with control group at the same timepoint, day 90 and day 180. (Click here for details about natriuretic peptides tests.)

They concluded:

"In conclusion, this study suggested that long-term treatment with sildenafil prevented aggravation of disease progression as suggested by several echocardiographic indices (i.e. SV, LA/Ao, MR jet area, 2D-LA) and reduced NTproBNP level at the indicated timepoints in dogs with asymptomatic mitral valve degeneration."

To learn more about sildenafil, go our discussion of it in our Treatment - Stage B2 section.

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-- Stage B2 -- enlarged heart

ACVIM B2The next stage in the progression of MVD is indicated (usually) by a louder murmur and by  enlargement of the heart on x-rays or echo scan. At this stage, reducing exercise will help to reduce the heart's workload. This is a Stage B2 dog, according to the 2009 ACVIM Consensus Statement. Stage B2 encompasses all variations of enlargement -- mild, moderate, and severe -- and enlargement due to either or both the heart's left atrium and the left ventricle.

A majority of the participating cardiologists in the ACVIM's 2009 Consensus Statement declined to recommend any drug or dietary therapy for Stage B2 dogs, apart from an ACE-inhibitor. Nevertheless, some cardiologists begin prescribing other medications at this stage, and studies of drugs have been conducted on dogs in Stage B2. What follows is a discussion of the reports of those studies.

--- pimobendan in Stage B2

Since 2009, the only drug which has been found by peer-reviewed veterinary studies to be effective in treating MVD-affected dogs in Stage B2 is pimobendan (Vetmedin, Cardisure, Safeheart, Pimocard, Pimotab, Zelys). However, the US Food & Drug Administration (FDA) has approved the administration of pimobendan only for MVD-affected dogs in heart failure (Stage C) and not for dogs in Stage B2.

Pimobendan works in two separate ways. First, it relaxes and widens the blood vessels, allowing more more blood to flow from the heart in the proper direction, thereby reducing the congestion of blood in the heart and reducing the blood pressure. This is called vasodilating.  Second, it strengthens the heart muscle, enabling it to pump more efficiently. This is called an inotropic effect, and it works on the heart muscle's contractility. 

Technically speaking, pimobendan is a benzimidazole pyridazinone derivative and is classified as an inodilator (a calcium sensitizer and phosphodiesterase-III inhibitor and a positive inotrope) and arteriovenous dilator, which reportedly has a potent, positive affect upon the force with which the heart muscle contracts, and also mildly eases the resistance in the circulatory system by dilating blood vessels.

Pimobendan typically is prescribed at the dosage rate of 0.2 to 0.3 mg/kg every 12 hours on an empty stomach. The Vetmedin website recommends giving it an hour before meals. A recent meal reportedly significantly decreases absorption.

The 2016 EPIC Study report:

In a November 2016 article (the EPIC Study), an international team of veterinary cardiologists report that the administration of pimobendan to MVD-affected dogs with echocardiographic and radiographic evidence of specific minimum degrees of heart enlargement results in prolonging the pre-heart failure period by approximately 15 months over non-treatment (a placebo), which represents a substantial clinical benefit. (Note that this study was entirely funded by the manufacturer of pimobendan.)

To be included in the study, a dog had to be 6 years of age or older, have a mitral valve murmur of at least Grade 3 of 6, have echocardiographic evidence of advanced MVD consisting of characteristic valvular lesions of the mitral valve, regurgitation through the mitral valve (MR) on the color Doppler echocardiogram, and have specific minimum degrees of echocardiographic evidence of left atrial (LA/Ao] ≥ 1.6) and left ventricular (LVIDDN ≥ 1.7) dilation, plus radiographic evidence of a vertebral heart size  (VHS) > 10.5. The researchers warn that:

"... it should be borne in mind when interpreting these results that all dogs included in the analyses also met the echocardiographic inclusion criteria and these results therefore might not be generalizable to all dogs with a VHS > 10.5 in the absence of concurrent echocardiographic measurements and a confirmed diagnosis of MMVD."

Therefore, to apply the results of this study to future treatment of MVD-affected dogs, an x-ray of the heart, showing a VHS over 10.5, is not sufficient by itself, and that the two echo measurements must also be confirmed. In addition, none of the participating dogs were being treated with any other cardiac medication. This raises the question as to the advisability of prescribing ACE-inhibitors prior to or while treating Stage B2 dogs with pimobendan.

Of 354 dogs in the EPIC Study, 161 (45.5%) were cavaliers. Of those 354 dogs, 178 of the dogs were treated with pimobendan (approximately 81 CKCSs), and 180 received the placebo (about 80 cavaliers). Of those 178 dogs treated with pimobendan, 59 (33.1%) reached congestive heart failure (CHF), 15 (8.4%) died of cardiac-related deaths during the treatment. The authors explained that:

"Although a greater number of dogs in the pimobendan group experienced spontaneous cardiac death (12 versus 5), the proportion of dogs in each group experiencing this event was not significantly different."

They concluded:

"Chronic oral administration of pimobendan to dogs with echocardiographic and radiographic evidence of cardiomegaly secondary to MMVD, in the absence of concurrent cardiovascular medication, results in the prolongation of the preclinical period, and is safe and well tolerated. The median time to the onset of CHF or cardiac-related death was prolonged by approximately 15 months, and the risk of a dog experiencing this event was reduced by approximately one-third; the majority of the benefit observed was attributable to delaying the onset of CHF. This substantial degree of prolongation of the preclinical period is f clinical relevance and is of importance to veterinarians and owners of dogs affected by this common disease."

So, the bottom line for starting pimobendan in Stage B2, according to this EPIC Study, is:

(1) The dog must be in Stage B2 of mitral valve disease; AND
(2) Have a murmur of at least Grade 3; AND
(3) The dog must NOT be on any other cardiac medication; AND
(4) An echocardiogram must be conducted and show valvular lesions of the mitral valve, regurgitation through the mitral valve (MR) on the color Doppler echocardiogram, and have echocardiographic evidence of left atrial and left ventricular dilation (defined as a left atrial-to-aortic root ratio [LA/Ao] equal to or greater than 1.6 and body weight normalized left ventricular internal diameter in diastole [LVIDDN] equal to or greater than 1.7); AND
(5) X-rays showing evidence of enlargement with a vertebral heart size (VHS) greater than 10.5.

This essentially means that once the MVD-affected dog develops a Grade 3 murmur and an x-ray showing enlargement, the owner should have a board certified veterinary cardiologist perform the echo exam. However, published research, confirmed by admissions made by two of the EPIC Study's lead investigators, has demonstrated that the EPIC Study's minimum measurements of enlargement really are within the range of normal sized hearts for cavaliers, meaning those in Stage B1. WARNING: Therefore, the EPIC Study's parameters should be ignored, and CKCSs' cardiologists should determine whether or not the Stage B dog really does have enlargement, rather than just a large normal size heart. This can be done by comparing baseline x-rays with current ones, or baseline echocardiogram measurements with current ones and/or comparing the shape of the cavalier's heart with the known shape of a normal heart, on x-rays.

Critical analysis of the EPIC Study:

Notwithstanding the recommendations of the EPIC Study, several cardiologists warn against starting pimobendan if the amount of enlargement of the left atrium is only mild, meaning that the degree of mitral regurgitation (MR) likewise is mild. They recommend waiting until the amount of MR is at least moderate to severe before prescribing pimobendan to dogs in Stage B2. Their reasoning is two-fold. First, the data from the EPIC Study indicates that study's dogs with only mild MR did not benefit any more from the administration of pimobendan than did the dogs with greater degrees of MR. Second, these cardiologists point out that the condition of many dogs with only mild MR will never reach heart failure (Stage C), and therefore there would be no point in starting those dogs on pimobendan to begin with. Pimobendan is an expensive drug, and it would be financially unfair to expect owners of dogs which may never reach Stage C to start dosing that pill twice daily for the rest of those dogs' lives.

Another advantage of waiting to see if the degree of enlargement of the heart reaches moderate to severe is that more than one echocardiogram would be performed before confirming the extent of the enlargement. A disadvantage of a single echocardiogram is that, while enables the operator to measure the dimensions of the left atrium and left ventricle, it does not, by itself, determine whether either of those chambers are enlarged. If two or more echos are performed over a period of several months, then the operator can confirm by comparing measurements whether the heart indeed has enlarged, as well as how rapidly that enlargement is taking place.

Our Blog: "The EPIC Study’s three heart “enlargement” parameters are arbitrary and unsupported by their cited authorities!"

2019 ACVIM Consensus Statement:

A majority of the ACVIM panel who participated in its 2009 Consensus Statement did not recommend prescribing pimobendan to Stage B2 dogs, but that was prior to the 2016 EPIC Study. The U.S. Food and Drug Administration’s (FDA) 2007 report approving the use of pimobendan for dogs also contains the warning that the drug not be prescribed by dogs which are not in heart failure. On each container of Vetmedin is the warning that “Vetmedin should not be given in cases ... where an augmentation of cardiac output is inappropriate for functional or anatomical reasons. Warnings: Only for use in dogs with clinical evidence of heart failure. However, research reports are conflicting, and harmful side effects have been noted from early use of this drug. See the "A Few Words About Pimobendan" box below for details.

The 2009 Consensus Statement was revised in an April 2019 ACVIM Consensus Statement, to take into account the results of the 2016 EPIC Study. The main changes have been to re-define Stage B1 and Stage B2. In short, the new Stage B1 is determined by whether echocardiographic measurements of either the dog's left atrium or left ventricle is less than the EPIC Study's species-wide cut-off dimension. If one of those measurements, say of the left atrium (LA), is equal to or above that cut-off measurement (which is LA/Ao = 1.6), but the other measurement, of the left ventricle (LV), is less than the species-wide LV cut-off measurement (LVIDDN = 1.7), then by this 2019 definition of Stage B1, the dog's heart is not deemed to be enlarged, and therefore administering pimobendan would not be appropriate. The 2019 ACVIM definition of Stage B2 is the corollary of the new Stage B1. In other words, an MVD-affected dog's heart is not deemed to be enlarged unless both its LA and its LV dimensions are equal to or greater than those two EPIC Study species-wide cut-off dimensions. This revision of Stages B1 and B2 and reliance upon both the LA and LV dimensions exceeding the EPIC Study's arbitrary mininum measurements could also result is a dog with both an enlarged LA and LV not being placed in Stage B2 because, even though its chambers are enlarged, neither of them are large enough to meet the species-wide minimum measurments of the new definitions.  (See this chart.)

2019 ACVIM Definitions of Stage B1 and Stage B2

Unfortunately, these 2019 re-definitions of Stages B1 and B2 are patently nonsensical, and we expect they will be ignored by many cardiologists when categorizing left sided heart enlargement for prescribing pimobendan. For example, we expect that cardiologists will continue to categorize an enlarged LA or an enlarged LV as being Stage B2 regardless of whether or not the other left-side chamber is or is not enlarged, continuing to rely upon the 2009 ACVIM definitions of Stages B1 and B2. Nevertheless, in one published study following the issuance of the 2019 ACVIM Consensus Statement, a team of cardiologists actually treated dogs in their study with enlarged LVs but normal LAs as not being in Stage B2.

Interestingly, neither in the EPIC Study nor anywhere else have researchers been able to determine why pimobendan appears to prolong the time before MVD-affected dogs reach heart failure. Some have speculated that the drug improves blood flow through the heart  -- its vasodilating effects. Others surmise that it keeps the mitral valve leaflets tighter and thereby reduces mitral regurgitation.

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--- amlodipine in Stage B2

Amlodipine besylate (Amodip, Norvasc) is a long acting vasodilator. Unlike pimobendan, it does not also have inotropic effects but as a vasodilator, it is much more potent than pimobendan and also considerably less expensive. Amlodipine acts by calcium channel blockage. It decreases resistance to the forward flow of blood, which results in a decrease in the back flow of blood from the left ventricle through the mitral valve into the left atrium (mitral regurgitation), and thereby decreases pressure in the left atrium. High doses of amlodipine are necessary for it to be effective, up to 1 mg/kg/day. Blood pressure checks before starting this drug, and over the course of administrating it (as doses may need to be increased), are necessary.

In a June 2003 study of sixteen  dogs in Stage C with moderate to severe mitral regurgitation (MR), treatment with amlodipine reduced systolic blood pressure (9.6% decrease) and severity of MR (15.1% decrease in regurgitant fraction) and the dimension of the left ventricle (3.5% decrease in LV end-diastolic dimension). However, no significant change of the echographic LA/Ao-ratio was detectable in that study. The investigators concluded that the drug can be used simultaneously with standard cardiac therapy, which would include ACE-inhibitor, Lasix, spironolactone, and digoxin in Stage C. Amlodipine reportedly may cause gingival hyperplasia with chronic administration in dogs, with a reported incidence of 8.5%.

In a May 2017 report of a study involving 21 MVD-affected dogs in Stage C, a team of Brazilian researchers compared the treatment of CHF dogs with either pimobendan or amlodipine. They found no statistically significant differences in measurements of systolic blood pressure, or electrocardiographic parameters, or diastolic function using echocardiographic parameters. They concluded that neither pimobendan nor amlodipine appears to be superior to the other. Because of those results, the invesigators speculated that the clinical benefits of pimobendan in Stage C of MVD may be due to its vasodilating properties rather than its inotropic effects. 

See this September 2015 Plumb's overview for more details.

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--- sildenafil (Viagra, Revatio) in Stage B2

Sildenafil (Viagra, Revatio) (a/k/a sildenifil) is a selective phosphodiesterase-5 inhibitor that has been demonstrated to delay ventricular enlargement in humans and experimental animals. In MVD-affected dogs, this drug has been prescribed for MVD-affected dogs already in heart failure if pulmonary hypertension is also detected. Pulmonary arterial hypertension (PH or PAH), as a complication of mitral valve disease, is higher diastolic or systolic pulmonary arterial pressure than normal pressure. This high pressure may lead to increased right ventricular pressure and right atrial chamber enlargement, leading to possible right side heart failure.

In a March 2017 report of a 180-day study of 30 MVD-affected dogs (none were cavalier King Charles spaniels) in Stage B1 or Stage B2 (non-symptomatic), a team of Thailand investigators treated half of the group with sildenafil (Viagra, Revatio) (a/k/a sildenifil) versus a control group. They found:

• The stroke volume (the volume of blood pumped from the left ventricle per beat) at day 30 was significantly higher in the sildenafil group
• The LA/Ao (left atrial-to-aortic ratio) and the MR jet area were significantly lower beginning at day 30, day 90, and day 180.
• The 2D-LA (2-dimentional left atrium size) was significantly lower at day 90 when compared with control group.
• The differences of NTproBNP (a natriuretic peptides test biomarker in cardiac disease) from baseline were significantly lower when compared with control group at the same timepoint, day 90 and day 180. (Click here for details about natriuretic peptides tests.)

They concluded:

"In conclusion, this study suggested that long-term treatment with sildenafil prevented aggravation of disease progression as suggested by several echocardiographic indices (i.e. SV, LA/Ao, MR jet area, 2D-LA) and reduced NTproBNP level at the indicated timepoints in dogs with asymptomatic mitral valve degeneration."

In a July 2017 article, the same group of Thai researchers compared sildenafil (Viagra, Revatio) to enalapril (an ACE-inhibitor) in their effectiveness in increasing heart rate variability (HRV) in MVD-affected dogs in ACVIM Stage B (pre-heart failure). Thirty-four MVD-affected dogs and thirteen healthy dogs participated, divided into groups of control, sildenafil, and enalapril. At the outset, they noted that MVD degeneration causes an imbalance of sympathovagal* activity, which results in poor cardiac outcomes. The results showed that MVD-affected dogs had significant higher heart rates (HR), systemic blood pressures, and significant decreased HRV than the healthy control dogs. After treatment with sildenafil for 90 days, both time- and frequency-domain parameters were significantly increased when compared with control and enalapril groups. This study demonstrated that sildenafil improves HRV in Stage B dogs, and that enalapril did not. They concluded that this result suggests that sildenafil should be used in MVD-affected dogs to restore the sympathovagal balance.

* Changes in the dog's heart rate are tied to changes in cardiac output. Heart rate variability (HRV) reflects variations in the time periods between heart beats. Generally, a low HRV indicates that the dog is under stress, which may be due to exercise, psychological events, or other internal or external events. A higher HRV usually means that the dog has a strong ability to tolerate stress or is strongly recovering from prior accumulated stress. A reduction in HRV in MVD-affected dogs reflects a "sympathovagal imbalance", which has been identified as a risk factor for sudden cardiac death. "Sympathovagal" refers to an interaction between the dog's sympathetic nervous system and its vagus nerve. HRVs reflect the output of the heart as regulated by the sympathetic nervous system.

Alternative drugs to sildenafil include tadalafil (Cialis), bosentan (Tracleer), and varenafil (Levitra). For more information about treating pulmonary hypertension in MVD-affected dogs, go to our discussion under medications for Stage C.

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--- diuretics in Stage B2

Diuretics are intended to treat fluid buildup in the lungs, which is pulmonary edema, a symptom of left-sided congestive heart failure Stage C). Stage B2 does not include signs such as fluid retention. Furthermore, we know of no published veterinary research supporting administering diuretics to MVD-affected dogs in Stage B2. As board certified veterinary cardiologist Dr. Janet Olson states in her December 2016 article about diuretics, "Therefore, it is necessary to take thoracic radiographs to confirm the presence of pulmonary edema prior to starting lasix." 

Nevertheless, some cardiologists hypothesize that administering a diuretic to a Stage B2 dog with severe mitral regurgitation may delay the onset of heart failure. See this article, "Should MVD-Affected Dogs Start Furosemide Treatment Before Congestive Heart Failure?", on our Blog webpage.

To learn more about diuretics, go to our discussion of them in our Treatment - Stage C section

Our Blog: "Should MVD-Affected Dogs Start Furosemide Treatment Before Congestive Heart Failure?"

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--- ACE-inhibitors in Stage B2

ACE-inhibitors  -- enalapril maleate (Enacard, Vasotec, Prilenal, Envas), benazepril hydrochloride (Lotensin, Fortekor, Banacep Vet, Benefortin, Benazecare, VetACE, Prilben, Nelio), imidapril (Tanatril), ramipril (Altace, Tritace, Vasotop), captopril (Capoten), fosinopril, lisinopril (Zestril, Prinivil), quinapril (Accupril), alacepril, temocapril (Acecol),  and zofenopril -- may also be prescribed by some cardiologists. ACE-inhibitors (ACE-I) are intended to block the angiotensin converting enzyme, which is necessary to produce a substance that causes blood vessels to tighten. So, ACE-I serve to relax the blood vessels, thereby lowering the blood pressure and increasing the supply of blood and oxygen to the heart. However, studies have shown only a low concentration of angiotensin II receptors in dogs' affected mitral valves. Therefore, the 2009 ACVIM Consensus Statement has not endorsed ACE-I therapy of MVD dogs at Stage B2 MVD. Further, ACE-inhibitors have not been approved for veterinary medicine for MVD dogs in Stage B2 by regulating authorities. However, oddly enough, a majority of the ten members of the 2009 ACVIM Consensus Statement panel did recommend starting an ACE-inhibitor at Stage B2 (although their reasoning was not included in the Consensus Statement).

The 2009 Consensus Statement was revised by the 2019 Consensus Statement.  Among the changes are that ACE-I therapy still has not been approved, but this time the split between the ten cardiologists participating in the report is 5 for and 5 against.

An additional reason for not prescribing ACE-inhibitors prior to heart failure is a 2002 Scandinavian study (the "Scandinavian Veterinary Enalapril Prevention [SVEP] Trial") of 229 asymptomatic cavalier King Charles spaniels with mild MVD murmurs, which has has shown that ACE-inhibitors had no significant affect upon the time from the initiation of ACE-I therapy to the point of heart failure (HF).  The authors stated:

"[T]his study failed to show any preventive effect of enalapril for developing CHF. ... Indeed, the finding in this study, ie, that enalapril did not prevent CHF regardless of whether the dogs had cardiomegaly or not at the time of initiation of therapy, speaks against the possibility that ACE inhibition prevents progression of dilatation. Accordingly, the practice of starting ACE inhibitor treatment in dogs with MVD as soon as cardiomegaly is evident, as is commonly recommended and used in clinical practice, is not supported by the present study. ... In conclusion, long-term treatment with ACE inhibition in asymptomatic dogs with MVD does not delay the onset of CHF regardless of whether cardiomegaly is present at initiation of therapy or not. " (Emphasis added.)

A 2007 study (the "VETPROOF Trial"), sponsored by an ACE-inhibitor manufacturer and involving 124 dogs of several breeds (including only 10 cavaliers), showed that enalapril given to dogs with only mild MVD murmurs and some enlargement of the heart but which otherwise are symptomless, "modestly delayed" the onset of HF.  (Also, see below for discussion of ACE-inhibitors' adverse side effects.)  Further, in a 2013 study by Thai graduate students, of twenty dogs (none CKCS) in Stage B2, they found that ramipril did not affect cardiac chamber size, mitral regurgitation severity and systolic function assessed by echocardiography in 91-day period of treatment.

This chart, prepared by veterinary cardiologist Dr. Niek Beijerink, compares the results of the two ACE-inhibitor studies. The 2002 SVEP study of only cavaliers is summarized on the left, and the 2007 VETPROOF study is on the right. He concluded from these results that no ACE-inhibitors should be given prior to heart failure -- Stage C (see below). Other researcher-cardiologists, including Drs. Mark Oyama and Adrian Boswood, have reached the same conclusion that ACE-Is at Stage B2 is not appropriate. In a 2012 presentation, Dr. Oyama stated that not giving an ACE-inhibitor to Stage B2 cavalier King Charles spaniels was "a slam dunk" decision, in view of the SVEP trial of 229 cavaliers, noted above.

Niek Beijerink's ACE-Inhibitor Studies Comparison.

Benazepril likewise has been found to not postpone the onset of CHF in cavaliers. In this July 2008 article, this drug had no beneficial effect on CKCSs with Stage B MVD. It did not delay the onset of heart failure in the cavaliers in that study.*

* Interestingly, the findings in the June 2008 article also did not demonstrate any differences in the time to onset of CHF in any other dogs in the study, although oddly, the report's conclusion seems to contradict that express finding. The finding is: "No differences in the time to onset of CHF were found between the BNZ [benazepril] and UT groups in the whole study population or in the OB [other breed] and CKC [Cavalier King Charles spaniels] populations." The contradictory conclusion is: "BNZ had beneficial effects in asymptomatic dogs other than CKC and KC [King Charles spaniels] affected by MVD with moderate-to-severe MR." So, go figure.

In an October 2017 article, researchers reported that a polymorphism of an ACE gene, intron 16, is most commonly found in the CKCS and that MVD-affected dogs with that mutation tend to have significantly lower ACE activity. In a December 2017 article, the same team of researchers studied 73 cavalier King Charles spaniels and reported finding that:

"The CKCS appears to have a high prevalence of the ACE variant. Dogs with the ACE variant had lower levels of ACE activity even in more advanced mitral valve disease than dogs without the variant."

They concluded that the impact of their finding "on the need for ACE-I in dogs with the polymorphism and heart disease deserves further study."

In a July 2021 article, this same team identified studied the gene for the ACE enzyme -- canine chromosome 9:11507816:G > A -- in 497 dogs of 54 breeds, including 13 cavaliers, to determine the prevalance of a variant of that gene which prevents ACE-inhibitors from suppressing the RAAS and instead allows aldosterone breakthrough. The ACE gene variant was found in 32 of the 54 breeds. The variant was greatest five breeds, including the CKCS with a prevalence of 85%. The other four breeds were the Irish wolfhound (95%), Dachshunds (90%), great Danes (84%), and bull mastiffs (58%).

Nevertheless, Dr. John Bongura reported in 2010 that out of 100 board certified veterinary cardiologists surveyed, nearly 70% indicated that an ACE-inhibitor was warranted for dogs in Stage B2, notwithstanding the lack of any research reports supporting their conclusions.

ACE Inhibitors -- More Pluses Or Minuses?

In studies, ACE-inhibitor enalapril has improved survival by more than 100%, and reduced pulmonary edema and improved quality of life scores, for dogs in congestive heart failure (CHF). Studies also found that exercise capacity was also improved in dogs with experimental mitral regurgitation. Benazepril also has been shown to improve survival, and imidapril was shown to be equal to enalapril in survival studies of dogs in heart failure due to mitral regurgitation.

However, ACE-inhibitors may have serious side effects. They can cause severe renal insufficiency, and the kidneys should be monitored carefully when using these drugs. A baseline renal panel should be conducted before treatment is initiated and again five to ten days later. Adverse reactions to the drug typically occur within three to five days of therapy initiation.

Benazepril (Lotensin, Fortekor, Benefortin, VetACE) is reported to be slightly less harsh on the kidneys than is enalapril maleate (Enacard, Vasotec) or ramipril (Altace, Tritace, Vasotop). Also, ACE-inhibitors traditionally are used for the treatment of high blood pressure. However, not all veterinary cardiologists check a cavalier's blood pressure before prescribing the drug. Unless the dog's blood pressure is high, the use of an ACE-inhibiting drug could dangerously lower its blood pressure.

The use of ACE inhibitors combined with extreme salt (sodium) restriction may contribute to renal dysfunction by activating the renin-angiotensin aldosterone system (RAAS). Therefore, some cardiologists recommend only moderate salt restricted diets when prescribing ACE inhibitors.

Other side effects include the accumulation of toxins which can damage the liver, anorexia or loss of appetite, vomiting, azotemia -- elevation of blood urea nitrogen (BUN) -- and the development of a dry cough due to the accumulation of bradykinin. Since a dry, hacking cough is a frequent symptom of progressing MVD, this side effect of the drug could be confused with the worsening of the disease.

In a February 2020 article, Dr. Mark Rishniw carefully dissected all five drug-company-funded studies of the ACE-inhibitor enalapril (the IMPROVE, COVE, LIVE, SVEP, and VETPROOF studies) to determine whether the drug would delay the onset of cardiac death in MVD-affected dogs in heart failure (CHF) or would delay the onset of CHF in pre-clinical MVD-affected dogs (i.e., in Stages B1 or B2). While the conclusions of some of the studies were muddled by drug-company interference, Dr. Rishniw's analysis of the underlying data showed that ACE-inhibitors have not been scientifically shown to delay the onset of either CHF or cardiac death due to MVD. He goes on to determine that:

"In retrospect, it became clear that the veterinary community was hoodwinked into believing that ACE-I were the medical cure for CHF dogs because of corporate marketing decisions."
"So, what does all this mean? My interpretation of all this literature suggests that ACE-I have no place in managing mitral valve disease, whether in dogs with CHF or dogs with subclinical disease."

 Notwithstanding the lack of effectiveness of ACE-inhibitors in delaying the onset of CHF, alacepril may be effective in reducing or eliminating the cardiac-related cough in Stage B2 dogs. In an August 2018 article, a team of Japanese researchers tested the angiotensin-converting enzyme inhibitor (ACE-inhibitor) alacepril on 36 dogs, including four cavalier King Charles spaniels, which were in Stage B2 of mitral valve disease (having an MVD-murmur and an enlarged heart but prior to heart failure) and all displaying an MVD-related cough. They primarily were testing the cough-suppression efficacy of alacepril over a period of four weeks. They report finding that alacepril resolved or lessened the cough in 20 (55.6%) of the dogs and had no cough-suppressant effect upon the remaining 16 (44.4%). They also found that alacepril reduced LVIDDN in the effective group in the present study, noting that LVIDDN is known as an indicator of left ventricle enlargement in dogs. These invsetigators observe that alacepril is among a sub-group of ACE-inhibitors (including captopril and zofenopril) which contain sulfhydryl, which may confer properties additional to ACE inhibition, which may explain the cough-suppressant qualities.

Studies currently are planned to determine if aldosterone receptor blockers (AFBs) including Losartan potassium (Cozaar), telmisartan (Micardis), valsartan (Diovan), sacubitril/valsartan (Entresto), and direct renin inhibitors (DRIs) including aliskiren (Tekturna, Rasilez), will significantly lower the incidence of ABT than will treatment with ACE-inhibitors.

In an August 2018 article, a team of Auburn University researchers examined the effectiveness of an aldosterone receptor blocker, sacubitril/valsartan (S/V), in 7 dogs diagnosed with mitral valve disease (MVD), compared to 6 MVD-affected dogs in the placebo group. They report finding that S/V is effective at lowering the urine concentration of aldosterone and that it was safe, with no deleterious effects on BUN, creatinine, and electrolyte concentrations, or systolic arterial pressure.

A baseline renal panel should be conducted before treatment is initiated and again three to five days later. Adverse reactions to the drug typically occur within three to five days of therapy initiation.

--- natural alternatives to ACE-inhibitors

A natural supplement as an alternative to ACE-inhibitors is a combination of active fish petides, including LKPNM, from the bonito fish (Sarda orientalis), such as Vasotensin, manufactured by Metagenics, Inc., and PeptACE by Natural Factors.  Holistic supplements should be taken only if prescribed by a licensed veterinarian who also is holistically trained in TCM. Search webpages for finding holistic veterinarians  in the United States and Canada are located here, and in the United Kingdom, here.

Other Chinese herbal alternatives include Salvia Shou Wu, a Seven Forests patented supplement which consists of Salvia extract, and several other herbs and flowers.  Salvia Shou Wu encourages blood circulation.

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--- spironolactone, aldosterone antagonist in Stage B2

Spironolactone (Aldactone, Prilactone, CaroSpir), a synthetic 17-lactone drug, is a mild diuretic. However, there are no published studies of the efficacy of spironolactone as a diuretic in dogs.  It also is an aldosterone antagonist (or mineralocorticoid receptor blocker -- MRB). Aldosterone is a hormone in the mineralocorticoids group. Its function is to regulate blood pressure and sodium potassium levels. High levels of this hormone may have harmful effects in the heart, including as mechanism of cardiac remodeling, meaning enlargement.

There are no peer-reviewed veterinary studies recommending beginning spironolactone in Stage B2. In a July 2017 article by a team of UK investigators, they report the inconclusive results of a pilot study of 25 dogs (13 treated with spironolactone and 12 with placebo). All of the dogs were MVD-affected and in Stage B2. None of them were being treated with any other drugs. Just about the only thing the study results confirm is their statement that the drug's "efficacy in preclinical MMVD is unknown."

However, spironolactone, which is known as a potassium-sparing diuretic because, unlike some other diuretics, it does not cause the loss of potassium -- reportedly may lead to excessively high, life-threatening levels of potassium in the dog's blood, particularly when combined with ACE inhibitors. Some veterinary cardiologists recommend that potassium levels be carefully monitored when using spironolactone in combination with ACE inhibitors by drawing blood at regular intervals until it is evident that the potassium level is or is not going to be a problem.

In a 2013 study of the possible increased risk of adverse events for dogs taking spironolactone in addition to conventional therapies, the researchers concluded that dogs with heart failure receiving spironolactone in addition to conventional treatment are not at a higher risk for any adverse events, death caused by cardiac disease, renal disease, or both, hyperkalemia, or azotemia. The study was funded by the manufacturer of Prilactone. See also this May 2016 review of the use of spironolactone as a diuretic.

Cardalis is a tablet which combines spironolactone with the ACE-inhibitor benazepril. Aldactazide is a combination of spironolactone and hydrochlorothiazide,  which inhibits the activity of the hormone aldosterone.

The Delay StudyThe DELAY Study: In 2010, a team of Italian cardiologists, led by Dr. Michele Borgarelli (now at VA-MD Regional College of Veterinary Medicine in Virginia, USA), began the DELAY Study to determine if giving combined doses of  spironolactone and benazepril can delay the onset of symptoms of heart failure in dogs with MVD. The results of the study were reported in a January 2020 article, and they were mixed. A total of 183 dogs participated, including 34 cavaliers (19%), the highest number of purebreds. Mixed breeds totaled 72 (40%). The dogs were divided into a treatment group (87 dogs) and control group (92 dogs) which received a placebo and no medication. At the end of the study, 42 dogs in the treatment group and 33 in the control group remained (most of the drop-outs opting to switch treatment to pimobendan). Of those, the median time to reaching heart failiure in the treatment group was 902 days, and the median time in the placebo group was 1,139 days, a difference of 237 days, roughly 8 months. However, the treatment group's heart measurements showed that treatment could reduce -- and in some cases even reverse -- heart enlargement and reduce NT-proBNP. They concluded:

"This study failed to demonstrate a prolongation of the asymptomatic phase of the disease in this population of dogs. Nevertheless, the treatment appears effective in reducing or even reverse cardiac remodeling as indicated by various cardiac imaging parameters and NT-proBNP concentrations. Chronic administration of combined spironolactone and benazepril treatment in dogs with pre-clinical MMVD and cardiac enlargement is safe and well tolerated. The significant effect of this treatment on secondary end-points could be of clinical relevance and merits further study."

To read more about spironolactone, go to our discussion of it in our Treatment - Stage C section.

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--- angiotensin receptor blockers (ARBs) in Stage B2

Angiotensin receptor blockers (ARBs) are drugs intended to block activation of the renin-angiotensis-aldosterone system (RAAS) due to RAAS' known contribution to the development of CHF in MVD-affected dogs. ARBs include

• telmisartan (Micardis)
• sacubitril/valsartan (Entresto)
• valsartan (Diovan)

 Studies currently are underway or planned to determine if some of these ARBs will significantly lower the incidence of ABT than will treatment with ACE-inhibitors.

Telmisartan (Micardis): In an October 2018 article, Japanese researchers reported that the ARB telmisartan did not suppress RAAS activation in five healthy laboratory beagles.

In a December 2020 article, University of Pennsylvania researchers compared the effectiveness of angiotensin converting enzyme inhibitors (ACE-I) -- enalapril and benazepril -- with the angiotensin receptor blocker (ARB) telmisartan in offsetting the activatation of the renin-angiotensin-aldosterone-system (RAAS) in the kidneys of dogs in Stage B2 of mitral valve disease. Eight MVD-affected dogs were included in the study, all diagnosed with Stage B2 of MVD, including two cavalier King Charles spaniels (25%). They report finding that telmisartan treatment resulted in higher activity of favorable angiotensin peptide (AP) concentrations, as compared to ACE-I treatment. They concluded that:

"Treatment with ARBs, such as telmisartan, or combined ARB and ACE2 [angiotensin converting enzyme 2] treatment represents a potential treatment strategy for dogs with DMVD and warrants additional preclinical study."

Sacubitril/valsartan (Entresto): In an August 2018 article, a team of Auburn University researchers examined the effectiveness of a combination of an aldosterone receptor blocker and a neprilysin (NEP) blocker, sacubitril/valsartan (S/V), in 7 dogs diagnosed with mitral valve disease (MVD), compared to 6 MVD-affected dogs in the placebo group. They report finding that S/V is effective at lowering the urine concentration of aldosterone and that it was safe, with no deleterious effects on BUN, creatinine, and electrolyte concentrations, or systolic arterial pressure.

In a July 2021 article, Thai investigators compared sacubitril/valsartan (Entresto) with the ACE-inhibitor ramipril in treating dogs diagnosed with Stage C (heart failure) due to MVD, along with both pimobendan and the diuretic furosemide. Twenty-one dogs -- none being cavaliers -- were divided into the S/V group (11 dogs) and the ramipril group (10 dogs) for four weeks. The investigators report that short-term administration of SV in dogs with MVD stage C resulted in a greater extent of reverse myocardial remodeling of both the left atrium and the left ventricle than in the ramipril group, as indicated by several echocardiographic parameters. They concluded:

"The current study suggested that the short-term effects of SV can reverse myocardial remodeling, as inferred from several echocardiographic indices (i.e., the reduction in LA/Ao, LVIDDN, EDVI and ESVI) in dogs with MMVD stage C. These findings would support the use of SV in clinically symptomatic heart failure in dogs."

However, they warn of a few limitations: (a) a very small sample size, with a much larger sample size needed to confirm the findings; (b) the study was for a very short term -- four weeks -- and a longer term study should be conducted; (c) the results thus far "do not suggest that ACEi should be replaced with S/V in dogs with MMVD stage C."

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--- alpha & beta blockers in Stage B2

Carvedilol (Coreg), and bisoprolol, also are being prescribed for Stage B2 MVD by some cardiologists. They are non-selective beta-and alpha-blockers with anti-oxidant effects -- also known as beta- (β-) adrenergic receptor antagonists (BARA) -- which reduce the heart's rate and the force of its contraction, thereby reducing the work of the heart. Also, in a 2009 study, it has been suggested that BARA have the potential to slow the progression of the mitral valve's degeneration by interfering with the serotonin signaling pathway -- a possible major factor in MVD progression -- and by reducing the "wear and tear" of the valve by reducing the pressure differences between the left ventricle and atrium. In a 2012 report, researchers studied the effect of carvedilol in treating cavaliers with Stage B2 MVD and found no adverse effects and median survival of 48.5 months. See also this January 2015 report regarding Carvedilol's effect upon hypertension.

Phenoxybenzamine ( Dibenzyline) is another alpha-blocker, with vasodilator properties.

A less expensive alternative beta-blocker is atenolol (Tenormin, Tenoretic). However, atenolol lacks the vasodilatory and antioxidant properties of carvedilol. Other beta blockers include metoprolol (Lopressor, Toprol).

Nicorandil (Ikorel, Angedil, Dancor, Nikoran-PCA, Aprior, Nitorubin, Sigmart), is an alternative to beta-blockers and/or calcium antagonists. It is a potassium channel activator with arterial vasodilator and venodilating properties. It increases blood flow through the heart, improves the heart's blood and oxygen supplies, and reduces its workload. Nicorandil is not available in the United States. See this January 2011 article on nicorandil.

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--- D-Ribose in Stage B2

Read about D-Ribose here as a supplement to strengthen the heart muscle and otherwise energize MVD-affected dogs with enlarged left atriums and/or left ventricles.

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--- other drugs for treating Stage B2

Ivabradine is a selective sinus node If Channel (funny channel) inhibitor which may be used to lower and maintain heart rate without affecting cardiac function. In a November 2017 abstract, researchers report finding that ivabradine lowers the heart rate in dogs, with no clinical discernable side effect, and therefore is safe to use in dogs with mitral regurgitation.

In a May 2018 study of seven laboratory Beagles with naturally-occuring asymptomatic MVD (ACVIM Stage B), the researchers reported that a single oral dose of ivabradine for dogs with asymptomatic MVD reduced both the dogs' heart rate (HR) and the hearts' consumption of oxygen (MVO2) without significantly affecting blood pressure. They concluded that ivabradine may be promising for management of an elevated HR in asymptomatic MVD-affected dogs. In a September 2018 article, the same team of Thai veterinary researchers conducted a long term (3 months) study of oral doses of ivabradine in four MVD-affected Beagles with heart enlargement (Stage B2). They evaluated the dogs'heart rate (HR), blood pressure (BP), myocardial oxygen consumption (MVO2), and heart rate variability (HRV). They report finding that "the results revealed that chronic administration of ivabradine significantly decreased HR, BP, and RPP without adverse effects. All indices of time- and frequency- domain of HRV at M3 were significantly increased when compared with baseline values)." They conclude that "The findings of this study imply that long-term treatment with ivabradine at a dose of 1.0 mg/kg twice daily in dogs with asymptomatic DMVD stage B2 decreased the HR, BP, MVO2 and improves HRV. This makes ivabradine potentially promising for management of elevated HR and impaired HRV in asymptomatic dogs with DMVD stage B2."

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--- Bronchial dilators for coughing

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MVD-affected dogs with an enlarged left atrium may develop a periodic, odd-sounding cough which cardiologists often describe as a "cardiac cough".

Some cardiologists may prescribe a bronchial dilator (bronchodilator), such as a methylxanthine, for example, aminophylline, millophyline, oxtriphylline, theophylline* (Corvental, Apo-Theo-LA, Theo-Dur), or terbutaline (Brethine, Bricanyl) which are human grade prescription medications which relax and open air passages in the lungs, making breathing easier.** A narcotic, hydrocodone bitartrate with homatropine MBr or guaifenesin  (Hycodan, Hydromet, Tussigon, Mycodone), or butorphanol tartrate (Torbutrol, Stadol, Torbugesic)  may be prescribed to suppress the coughing by affecting the brain's cough centers.

* Theophylline is a PDE inhibitor which should not be given concurrently with pimobendan, which is another PDE inhibitor, unless the combination of those two drugs is carefully balanced.
** Fluoroquinolone antibiotics should not be given concurrently with any methylxanthines.

The cough could be due to a combination of factors, which include the enlarged left atrium of the heart pressing against and compressing the left mainstem bronchus, but more likely to airway disorders independent of any relationship with the heart. It may even cause the trachea to collapse*.

* Trachea collapse also may be due to Brachycephalic airway obstruction syndrome (BAOS).

In a March 2012 article, USA researchers found no association between left atrial enlargement (LAE) and bronchial collapse in MVD-affected dogs with moderate-to-severe LAE and chronic coughing, but they did find that airway inflammation is common in dogs with airway collapse.

In a January 2019 article, a pair of experts concluded that a cough in the absence of rapid and labored breathing would indicate that it is due mainly to a respiratory disease rather than a cardiac disease. Coughing is a hallmark sign of bronchitis. Dogs with severe pulmonary edema can cough but coughing is much more common with primary lung disease. By severe pulmonary edema, they mean that the fluid has completely filled the lungs and also has started to fill the upper airway passages, as well.   (The x-ray below shows the heart's enlarged left atrium impinging upon the left main bronchus.).

One of the most common -- and potentially dangerous -- misjudgements some veterinarians tend to make is to assume that such a cough indicates the onset of CHF and the need for immediate treatment with a diuretic. Cardiologist Dr. Michele Borgarelli has warned:

"It should be stressed that cough is a general clinical sign of respiratory disease and its presence in a dog with a murmur is not an indicator for starting treatment for CHF."

 

--- avoid vaccines

Vaccine WarningVaccine manufacturers provide warnings on their products' data sheets and labels, advising that only healthy dogs should be vaccinated. (Click on the thumb-nail image at right to view a typical warning on a rabies vaccine data sheet.)

Some veterinarians recommend that dogs with advanced mitral valve disease not be vaccinated with the usual serums, including rabies, because of possible adverse reactions which might accelerate damage to the dogs' hearts. In such cases, the veterinarians will write letters to the county licensing authorities which require periodic vaccinations, and in many instances, the counties will accept the veterinarians' letters and excuse the dogs from having to be vaccinated.

For example, Dr. Larry Glickman, veterinary immunologist at Purdue University's veterinary school, wrote regarding cavaliers:

“Our ongoing studies of dogs show that following routine vaccination, there is a significant rise in the level of antibodies dogs produce against their own tissues. Some of these antibodies have been shown to target the thyroid gland, connective tissue such as that found in the valves of the heart, red blood cells, DNA, etc. I do believe that the heart conditions in Cavalier King Charles Spaniels could be the end result of repeated immunisations by vaccines containing tissue culture contaminants that cause a progressive immune response directed at connective tissue in the heart valves. The clinical manifestations would be more pronounced in dogs that have a genetic predisposition [although] the findings should be generally applicable to all dogs regardless of their breed.”
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-- Stage C -- heart failure

AVCIM Stage CSevere MVD normally involves a murmur that has become much louder. However, the murmur can become more difficult to hear, if the heart's deterioration has been sudden. So a Grade 6 murmur later could be downgraded to a Grade 5, but that would not mean an improvement in the dog's condition. Also, the dog likely will have some "clinical signs" of heart failure, such as difficulty breathing while at rest, and may not be able to tolerate even minimal exercise. This is a Stage C dog, according to the 2009 ACVIM Consensus Statement. Most MVD-affected dogs at Stage C are in congestive heart failure (CHF), a common term used by cardiologists to describe dogs with pulmonary congestion and edema.

Cardiologists categorize "clinical signs" of heart failure as either "congestive", meaning the production of fluids which may enter the pulmonary vein and the lungs, or "low output", meaning that the heart is not pumping adequately to energize the dog's body. Here is a chart from Dr. Beardow's presentation showing the two classifications of clinical signs:

Clinical Signs of Heart Failure from MVD

A method which cavalier owners can use to determine if and when their dog reaches the stage of  heart failure is to count the dog's breaths per minute while sleeping. See our section above on Respiratory Rates for details. In an October 2012 study, researchers found that healthy adult dogs generally have a mean sleeping respiratory rate (SRR) of less than 30 breaths per minute (BPM) and rarely exceed that rate at any time. Some cardiologists recommend that their patient's owners periodically count their dog's respiratory rate, and when the average rate starts to creep up to the high twenties, to make an appointment for the dog to be re-examined by the cardiologist to see if the dog is approaching or has reached the stage of heart failure.

The Lasix Trial: If and when the MVD-affected dog's respiratory rate reaches or exceeds 30 BPM, that by iteself deos not confirm that the dog is in CHF. A technique some cardiologists may use to be certain the signs indicate heart failure is to perform the Lasix Trial. The dog will be administered a dose of the loop diuretic Lasix (furosemide). If the dog's sleeping respiratory rate lowers because of the Lasix dose, that will confirm that the dog has reached CHF and needs diuretic medication. If the SRR does not reduce after the Lasix trial, then the dog is not in CHF and probably is suffering from chronic bronchitis or some other respiratory disorder.

Dogs in HF with clinical signs mild enough for home therapy are classified as in Stage Cc ("c" for "chronic"). Pressure in the left atrium can be relieved by diuretics* and drugs which lower the pressure in the veins, called venodilators. Diuretics should be given by injection in severe cases. ACE-inhibitors also have venodilating effects.

* See diuretics above. In a 2012 report, researchers compared doses of torsemide and furosemide in treating dogs with stable heart failure (Stage C). They found that "torsemide is equivalent to furosemide at controlling clinical signs of CHF in dogs and is likely to achieve greater diuresis vs. furosemide."

Dogs with severe signs of HF -- Stage Ca ("a" for "acute") -- require hospitalization for stabilization.

Stage C typically is treated with medications to manage the heart failure by alleviating the congestion, improve the cardiac output, remove the fluids from the lungs, and maintain normal blood pressure and heart rhythm. In summary, the aim of medications at Stage C is to bring the dog out of heart failure and keep the dog out of heart failure as long as possible. Eventually, initial doses of medications for Stage C dogs may not keep the dog out of heart failure, and at that point, increases in dosages and the addition or substitution of other medications may be expected.

Some cardiologists sub-categorize Stage C -- mild, moderate, and advanced -- based upon the dosages of drugs necessary to maintain normal sleeping respiration (consistently below 30 breaths per minute).

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--- diuretics in Stage C

Diuretic treatment will be necessary at Stage C, usually in a tablet form. Since a dog with moderate MVD begins to retain fluid and salt, drugs which prevent fluid retention, or which increase fluid elimination, may be used. There are four classes of diuretics commonly prescribed: (a) loop diuretics, (b) aldosterone receptor antagonists, (c) thiazide diuretics, and (d) direct renin inhibitors. Each of them affect the kidneys to remove fluids and increase urine production, thereby eliminating fluids in the lungs and also decreasing blood volume and reducing blood pressure. Side effects would be that the dog is thirstier than normal, and, of course, increased urination.

MVD-affected dogs on high doses or combinations of diuretics should have their electrolytes and renal function monitored periodically.

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Loop diuretics:

Loop diuretics* include:

furosemide (such as Lasix, Diuride, Frudix, Frusemide, Flusapex, Salix, Puresis, Libeo)
torasemide (Torsemide, Demadex, UpCard)
Bumetanide

*Loop diuretics are pyridine-3-sulfonurea drugs that act on the thick portion of the nephron’s ascending loop of Henle (the part of a kidney tubule that forms a long loop in the medulla of the kidney, from which water and salts are resorbed into the blood), where they inhibit the sodium–potassium–chloride (Na+–K+–2Cl–) cotransporter, leaving sodium (and other ions) to be lost, with water, in the urine.

In an April 2018 report, a team of researchers at Tufts University's Cummings vet school examined the records of 54 MVD-affected dogs (including 9 cavaliers) in "advanced heart failure" (AHF). Their definition of AHF was the recurrence of heart failure signs despite treatment with initial doses of pimobendan, ACE-inhibitor, and furosemide. At the diagnosis of AHF, they found that for most of the 54 dogs, doses of pimobendan, furosemide, ACE-inhibitor, and spironolactone were increased, with new medications added in most dogs. They found that the median survival time after diagnosis of AHF was 281 days (range, 3-885 days), and that dogs receiving a furosemide dose >6.70 mg/kg/day had significantly longer median survival times (402 days [range, 3-885 days] versus 129 days [range 9-853 days]). They concluded that dogs with AHF can have relatively long survival times, and that "a higher furosemide dose was significantly associated with longer survival time."

Loop diuretics, including furosemide, can severely affect the kidneys by activating the renin-angiotensin aldosterone system (RAAS)*, since reduction in the total circulating blood volume results in activation of RAAS. Loop diuretics also can adversely affect the liver and other bodily functions, and so a baseline of the kidneys and liver should be evaluated before starting furosemide and should be monitored three to five days later (since adverse reactions to the drug typically occur within three to five days of therapy initiation) and every three months thereafter. See this December 2016 article for details about administering loop diuretics to dogs with MVD.

* When the RAAS is activated, it causes the kidneys to over-work by retaining more water and sodium and excreting more potassium. As a result of this process, the overall volume of blood increases, meaning that more blood is pumped through narrowed arteries, which also increases the blood pressure.

In a 2009 study report which did not include CKCSs, veterinary cardiologists observed a three-fold increase in RAAS activity using furosemide.  Their conclusion was that "furosemide is not recommended for chronic use in the absence of concurrent therapy to blunt RAAS activity, such as ACE-I, aldosterone receptor blockers, or angiotensin II type I receptor blockers." A subsequent similar study in 2011 concluded:

"These results in clinically normal dogs suggested that furosemide, administered with or without pimobendan, should be accompanied by RAAS-suppressive treatment."

In a July 2015 study, the researchers determined that doses lower than those identified to activate the circulating RAAS were not effective in treating the disorder.

Torasemide  (Isemid, Torsemide, Demadex, UpCard), another loop diuretic, is more effective than furosemide due to its relatively consistent absorption and longer half-life. This typically results in torsemide having a longer duration and slower urinary excretion rate than does furosemide. Torasemide often is substituted for furosemide once furosemide seems to be losing its effectiveness (furosemide resistance). In a 2012 report, researchers compared doses of torasemide and furosemide in treating dogs with stable congestive heart failure (Stage C). They found that "torsemide is equivalent to furosemide at controlling clinical signs of CHF in dogs and is likely to achieve greater diuresis vs. furosemide." Torasemide is approximately 10- to 20-times as potent as furosemide in dogs, depending upon the frequency of the dosages -- 10-times stronger if given once daily and 20-times if given twice. (See this October 2015 article and this November 2019 article.) Therefore, the starting dosage is approximately 1/20 that of the furosemide dose. A possible side effect of torasemide is syncope. It also  only requires a single dose per day for most dogs in Stage C. 

In a November 2019 article, Colorado State Univ. researchers tested 6 healthy Beagles to compare the effects of the diuretics torsemide and furosemide upon activation of the kidney renin-angiotensin-aldosterone system (RAAS). Chronic RAAS activation is known to promote sodium and water retention, vasoconstriction, heart enlargement, and renal remodeling. The goal of the study was to compare the magnitude of RAAS activation between these two loop diuretics, administered at approximately equipotent dosages. Since torsemide has been found to be 20 times more potent than furosemide, the equipotent dosage of torsemide was 1/20th that of furosemide. The researchers report finding that, over a 10-day period, the diuretics behaved similarly, including the extent of increase in RAAS activity. There also was no significant difference in the extent of potassium excretion, although furosemide caused less than did torsemide. They also confirmed that torsemide given twice daily had a potency factor close to 20 times that of furosemide.

In an October 2017 article on the TEST Study, researchers sponsored by UpCard's manufacturer found that over a short-term of 84 to 91 days, torasemide resulted in a two-fold reduction over furosemide in the risk of reaching the cardiac endpoint (either a cardiac-associated death or worsening of the degree of CHF). They concluded by warning:

"However, given its potent diuretic effects, the lowest effective dosage should always be determined and, as recommended by the ACVIM consensus guidelines, dogs under such diuretic treatment should be closely monitored for renal and electrolyte abnormalities. Further studies are now required to explore the potential beneficial antifibrotic effect of torasemide on dogs with CHF, and its potential benefit over furosemide on long-term survival."

In an August 2020 article, a team of employees of Ceva Santé Animale, manufacturer of torasemide, along with PennVet cardiologist Mark A. Oyama, compared the diuretic to furosemide in a study of 319 MVD-affected dogs diagnosed with new onset congestive heart failure (CHF), including 52 (16.3%) cavalier King Charles spaniels. Their study, titled CARPODIEM, had the aim to evaluate the efficacy and safety of torasemide compared to furosemide in treating CHF. They report finding that torasemide was superior to furosemide in that it required only once-daily dosing, resulting in increased owner compliance, and also that torasemide had less than half the risk of cardiac death or euthanasia or worsening of CHF than did furosemide. They emphasized that monitoring of the dogs' reactions, hydration status, renal function, and serum electrolyte concentrations should be performed when using any diuretic.

See also this November 2017 article on the efficacy of long-term use of torasemide.

Bumetanide, another loop diuretic, is 25 to 50 times more potent than furosemide. Otherwise, it performs in the same manner as furosemide. Proper dosages for treating pulmonary edema (fluid in the lungs) of dogs have not been published.

Medications approved to treat humans with congestive heart failure, such as the aquaretic (vasopressin receptor anatagonist = vaptans), (tolvaptan),  are being empirically considered as alternatives to diuretics such as furosemide.

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Spironolactone:

Spironolactone is a synthetic 17-lactone drug, a mild, potassium-sparing diuretic. However, there are no published studies of the efficacy of spironolactone as a diuretic in dogs in CHF.* Therefore, it should not be substituted for furosemide or any other diruetic in dogs in CHF. It will not sustain control of the fluid retention in CHF. Spironolactone is no more sparing on the kidneys than furosemide, except to the extent that it is a less effective diuretic than furosemide.  

* See this May 2016 review of the use of spironolactone as a diuretic.

There is a lot of conflicting research information about Spironolactone (Aldactone, Prilactone, CaroSpir).

While it is known as a potassium-sparing diuretic, it is not needed as such since most dogs receiving furosemide do not become potassium-depleted, especially if the furosemide is coupled with an ACE-inhibitor or aldosterone receptor blocker (AFB). In a 2010 European study, sponsored by the manufacturer of  Prilactone, the investigators reported that spironolactone, when added to conventional cardiac therapy (such as an ACE-inhibitor, plus furosemide and digoxin if needed ) was found to decrease the risk of reaching the primary endpoint (ie, cardiac-related death, euthanasia, or severe worsening) in dogs with moderate to severe mitral regurgitation caused by MVD. However, in a 2010 Letter to Editor, Drs. Mark Kittleson and John Bonagura disagreed with the authors of the 2010 European study's conclusion that a survival benefit of spironolactone in canine MR was proven, stating that there was confusion as to "which dogs if any did benefit from spironolactone" along with other criticisms, including the extent of sponsor control over the study. *

*See also a 2011 report indicating that spironolactone did not extend survival times of dogs with advanced heart failure.

See mineralocorticoid receptor antagonists (below) for more information about using spironolactone in the treatment of Stage C MVD-affected dogs.

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Thiazide diuretics:

Thiazide diuretics inlude:

• hydrochlorothiazide (Dyazide, Thiuretic, Esidrix, Hydrodiuril, Microzide)
• co-amilozide or amiloride / hydrochlorothiazide (Moduretic, Moduret),
a combination of amiloride and hydrochlorothiazide.

A thiazide diuretic is typically administered in combination with a loop diuretic (e.g., furosemide) if the loop diuretic alone does not adequately control fluid retention.

In a July 2021 article, a team of Japanese cardiologists studied the effects of adding hydrochlorothiazide (HTCZ) in treating 14 dogs in heart failure due to mitral valve disease (MVD) which no longer were responding to treatment with high doses of the loop diuretic torsemide. One of the 14 dogs was a cavalier. After dual treatment with the two diuretics, the echocardiographic data showed significant improvement. However, blood urea nitrogen and creatinine levels increased, and potassium levels decreased, indicating a decline in renal function following HTCZ administration. They concluded that their study suggested that the administration of HTCZ in combination with loop diuretics may improve cardiac function during advanced heart failure in MVD-affected dogs. However, as the combination of HTCZ and loop diuretics can deteriorate renal function, they advised that caution should be exercised prior to making recommendations regarding its use, and renal function should be monitored.

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Direct renin inhibitors (DRIs):

Direct renin inhibitors (DRIs) include:

• carperitide
• NPA7
• aliskiren (Tekturna, Rasilez)
.

Carperitide, an alpha-human atrial natriuretic peptide, is a human drug which is known to reduce pressure in the left atrial and left ventricle chambers of the human heart.  In an August 2013 report, a team of Japanese veterinary heart surgeons compared dosing lab dogs with carperitide and furosemide. The team reported that both drugs similarly reduced left atrial pressure. They found that carperitide had less adverse effects than furosemide because it did not activate the renin–angiotensin–aldosterone system (RAAS). They concluded that additional studies are warranted in clinical patients with degenerative MVD and congestive heart failure.

In a June 2017 abstract, Japanese cardiologists tested MVD-affected dogs which also had pulmonary edema, using carperitide. Factors such as atrial natriuretic peptide (ANP), N-terminal pro b-type natriuretic peptide (NT-proBNP), and aldosterone levels, were measured before and after administration of the drug. In addition, chest radiography, echocardiography, and blood pressure measurements were performed depending on the specific cases. Seven of the 9 dogs showed improvements post-treatment, although 2 cases did not show any improvement. ANP levels increased post-treatment in all cases. NT-proBNP levels increased in 4 cases and decreased in 5 cases. Aldosterone level increased only in one case. In addition, the left atrial aortic root ratio (LA/Ao), E-wave, vertebral heart size (VHS), and blood pressure decreased. They observed a decrease in NT-proBNP levels in all cases that were treated for more than 7 hours. In addition, the ventricular muscle stretch was reduced by the decrease in left atrial pressure following the administration of the carperitide, which lasted for more than 7 hours. Finally, the decrease in aldosterone levels was thought to be due to the inhibitory effects of carperitide on the renin-angiotensin-aldosterone system. They concluded that carperitide administration may be effective since pulmonary edema improved and aldosterone was suppressed.

 In a May 2017 abstract, Mayo Clinic researchers reported on the success of their engineered designer natriuretic peptide "NPA7" as co-therapy with diuretics (furosemide) in treating ten dogs in acute decompensated heart failure (ADHF). They noted that furosemide (FURO) alone lacks vasodilatory actions, impairs kidney function, and activatesd the renin-angiotensin-aldosterone system (RAAS). They found NPA7 to decrease vascular resistance, reduce pulmonary capillary pressure, increase renal blood flow, increase urinary flow and sodium excretion. They concluded:

"In conclusion, in experimental ADHF, NPA7 is a vasodilatory therapeutic with cardiac unloading, diuretic and natriuretic actions. FURO is more diuretic, but is associated with significant renal impairment, vasoconstriction and RAAS-activation. In addition, pre-treatment with NPA7 enhances natriuresis and diuresis while preserving kidney function. Priming with NPA7 may therefore represent a novel renoprotective strategy for treatment of ADHF. Importantly, this study underscores the need for future studies assessing the impact of timing of diuretics on treatment effects of novel therapies in patients with ADHF."
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Natural alternative diuretics in Stage C

Natural diuretics include urea (AC Carbamide) by Standard Process, and Wu Ling San by Mayway and Alisma by Seven Forests, and Zhen Wu Tang, all being traditional Chinese herbal medicines (TCM). 

 Holistic supplements should be taken only if prescribed by a licensed veterinarian who also is holistically trained in TCM. Search webpages for finding holistic veterinarians  in the United States and Canada are located here, and in the United Kingdom, here.

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--- pimobendan in Stage C

In advanced heart failure, the heart muscle may become weakened so that it does not contract properly. This is known as “systolic dysfunction”, which occurs when the heart muscle does not contract with enough force to pump enough oxygen-rich blood throughout the body. It also is referred to as “diminished contractility”. During an echocardiogram, the cardiologist is able to calculate the “ejection fraction” and the “fractional shortening” percentage (FS%), which measure how well the heart pumps with each beat. That ejection fraction and/or the FS% determine whether there is systolic dysfunction.  

Reducing pressure in the arteries can make it easier for the heart to pump. Pimobendan (Vetmedin, Cardisure, Safeheart, Pimocard, Pimotab, Zelys) works in two separate ways. First, it relaxes and widens the blood vessels, allowing more more blood to flow from the heart in the proper direction, thereby reducing the congestion of blood in the heart and reducing the blood pressure. This is called vasodilating.  Second, it strengthens the heart muscle, enabling it to pump more efficiently. This is called an inotropic effect, and it works on the heart muscle's contractility. 

Pimobendan typically is prescribed at the dosage rate of 0.2 to 0.3 mg/kg every 12 hours on an empty stomach. The Vetmedin website recommends giving it an hour before meals. A recent meal reportedly significantly decreases absorption.

Technically speaking, pimobendan is a benzimidazole pyridazinone derivative and is classified as an inodilator drug with both an inotropic effect (meaning that it modifies the force or speed of contraction of muscles) and as an arteriolardilator (meaning that it widens blood vessels, allowing blood to flow more easily), promoting increased cardiac output, reduction both in preload and afterload and increased myocardial contractility without increases in myocardial oxygen and energy consumptions.  See the "A Few Words About Pimobendan" box below for more details.

In a July 2015 opinion, the European Medicines Agency's Committee for Medicinal Products for Veterinary Use has recommended granting marketing authorization for Fortekor Plus, a combination of benazepril and pimobendan. The committee warns that the combination "should only be used in patients whose clinical signs are successfully controlled by administration of the same doses of the individual components (pimobendan and benazepril hydrochloride) given concurrently."

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--- amlodipine in Stage C

Amlodipine besylate (Amodip, Norvasc) is a long acting vasodilator. Unlike pimobendan, it does not also have inotropic effects but as a vasodilator, it is more potent than pimobendan. Amlodipine acts by calcium channel blockage and therefore also is referred to as a calcium channel blocker (CCB). It decreases resistance to the forward flow of blood, which results in a decrease in the back flow of blood from the left ventricle through the mitral valve into the left atrium (mitral regurgitation), and thereby decreases pressure in the left atrium. High doses of amlodipine are necessary for it to be effective, up to 1 mg/kg/day. Blood pressure checks before starting this drug, and over the course of administrating it (as doses may need to be increased), are necessary.

In a June 2003 study of sixteen  dogs in Stage C with moderate to severe mitral regurgitation (MR), treatment with amlodipine reduced systolic blood pressure (9.6% decrease) and severity of MR (15.1% decrease in regurgitant fraction) and the dimension of the left ventricle (3.5% decrease in LV end-diastolic dimension). However, no significant change of the echographic LA/Ao-ratio was detectable in that study. The investigators concluded that the drug can be used simultaneously with standard cardiac therapy, which would include ACE-inhibitor, Lasix, spironolactone, and digoxin in Stage C. Amlodipine reportedly may cause gingival hyperplasia with chronic administration in dogs, with a reported incidence of 8.5%.

See, also, this 2012 comparative study of amlodipine versus benazepril. In a 2011 study, the Canadian researchers concluded that:

"Combining furosemide, ACEI, pimobendan, spironolactone, and amlodipine may result in long survival times in dogs with MR [mitral regurgitation] and CHF."

 However, combined use of CCBs and ACE-inhibitors is controversial because of concerns for systemic hypotension and worsening renal function.  Also, overdoses of CCBs can cause serious adverse effects on the cardiovascular system. See this September 2015 report specifically on amlodipine.

In a May 2017 report of a study involving 21 MVD-affected dogs in Stage C, a team of Brazilian researchers compared the treatment of CHF dogs with either pimobendan or amlodipine. They found no statistically significant differences in measurements of systolic blood pressure, or electrocardiographic parameters, or diastolic function using echocardiographic parameters. They concluded that neither pimobendan nor amlodipine appears to be superior to the other. Because of those results, the invesigators speculated that the clinical benefits of pimobendan in Stage C of MVD may be due to its vasodilating properties rather than its inotropic effects.

See this September 2015 Plumb's overview for more details.

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--- isosorbide dinitrate (ISDN) & arteriolardilators

Isosorbide dinitrate (ISDN) is a cavernous artery vasodilator which leads to a reduction in preload and cardiac oxygen consumption. ISDN causes a decrease in arterial pressure and reduction in afterload. In a September 2013 article involving experimentally induced MVD in six lab Beagles, the investigators report that ISDN significantly reduced left atrial pressure (LAP). The efficacy of ISDN currently is being studied by Dr. Dennis Trafny at Animal Medical Center in New York. See this article.

Sodium nitroprusside (Nitropress, Sodium Niroprusside) is an intravenous drug used to control high blood pressure in CHF dogs. It is a smooth muscle relaxant which causes vasodilation of the arteries and veins. It requires almost constant, close attention to the blood pressure levels.

Other arteriolardilators include milrinone (Primacor), hydrazaline (Apresoline), levosimendan (Simdax), and SCH00013.

In a November 2019 article, Michigan State University veterinarian reported the safe use of intravenous nitroglycerin (IV-NTG) in treating three MVD-affected chihuahuas in heart failure (CHF) -- Stage C -- to reduce preload pressure on the left ventricle and improve blood flow. They elected to use IV-NTG due to the severity of the dogs' CHF conditions and lower cost of IV-NTG compared to nitroprusside, an extremely expensive drug. They report that these are the first reported cases of using IV-NTC on veterinary patients with naturally occurring MVD, and that no significant adverse effects were observed. All three dogs' CHF were resolved following treatment, although the success cannot be attributed to the IV-NTG because of the small number of cases and the other medications used to treat the dogs' conditions.

ITI-214 is an inhibitor of phosphodiesterase type-1 (PDE-1), one of eleven main phosphodiesterases. (For example, PDE-3 is the phosphodiesterase inhibited by pimobendan, thereby increasing cardiac contractility.) In a July 2018 article, medical researchers report finding that, "The combination of effects [of ITI-214] in both dog and rabbit results in a rise in cardiac output with negligible changes in cardiac preload and arterial systolic pressure." ITI-214 is a product of Intra-Cellular Therapies, Inc.

 Digoxin (Lanoxin, Digitek, Digox, Lanoxicaps, Cardoxin), a cardiac glycoside extracted from the foxglove plant (digitalis), may be used to improve heart muscle strength to help the heart contract more strongly. Hydralazine (Apresoline, BiDil)  is another arteriodilator which may be prescribed.

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--- ACE-inhibitors in Stage C

ACE-inhibitors include:

• Enalapril (Enacard, Vasotec, Prilenal, Envas)
• Benazepril (Lotensin, Fortekor, Banacep Vet, Benefortin, Benazecare, VetACE, Prilben, Nelio)
• Imidapril (Tanatril)
• Ramipril (Altace, Tritace, Vasotop)
• Alacepril
• Captopril (Capoten)
• Fosinopril
• Lisinopril (Zestril, Prinivil)
• Quinapril (Accupril)
• Temocapril (Acecol)
• Zofenopril 

ACE-inhibitors (ACE-Is) usually also will be prescribed to dogs in Stage C. ACE inhibitors have been believed to block the angiotensin converting enzyme, which is necessary to produce a substance that causes blood vessels to tighten. So, ACE-Is serve to relax the blood vessels, thereby lowering the blood pressure and increasing the supply of blood and oxygen to the heart. The result is that in dogs in heart failure (HF), they are intended to blunt the enlargement of the heart and slow the progression of heart failure.*

* See, the IMPROVE Study, the COVE Study, and this 1997 article.

Nevertheless, the most recent studies of ACE-I, especially the VALVE Study, have concluded that ACE-Is serve no useful purpose in treating MVD, even at Stages C and D.

The most popular ACE-inhibitors among veterinary cardiologists are enalapril and benazepril. There are a few differences between enalapril and benazepril. For example, enalapril is excreted fully through the kidneys, while benazepril is excreted 50% by the kidneys and 50% by the liver, Threfore, for dogs diagnosed with kidney problems, benazepril likely will be prescribed instead of enalapril. Because of the possible affect of any ACE-inhibitor upon the kidneys, the best practice is for the dog's renal system to be re-examined within a week to ten days following starting being given the drug.

ACE-inhibitors usually are prescribed once a day and increased to twice daily as the MVD progresses.

A few studies have concluded that diuretics such as furosemide should be used only combined with ACE inhibitors -- which also prevent fluid retention -- so that the diuretic dosage may be sharply reduced to avoid the worst of its negative side effects. Researchers have found that extensive use of diuretics alone may contribute to renal dysfunction by activating the renin-angiotensin aldosterone system (RAAS) , as well as dehydration, azotemia (elevation of blood urea nitrogen [BUN]), and hypokalemia (low potassium).

However, in a September 2014 study of ten healthy hounds, researchers found that benazepril did not prevent the activation of the renin-angiotensin aldosterone system (RAAS), a cause of renal dysfunction. This is called “aldosterone breakthrough” (ABT). In a similar study in September 2015, researchers found that enalapril also did not prevent activation the RAAS. In a November 2015 study, researchers found that high doses of benazepril or enalapril were not any more effective than standard doses of those drugs in suppressing the RAAS. In a May 2017 report, the investigators found that ABT occurs in approximately 30% of MVD-affected dogs receiving ACE-inhibitors.

A baseline renal panel should be conducted before treatment is initiated and again three to five days later. Adverse reactions to the drug typically occur within three to five days of therapy initiation.

In a July 2015 opinion, the European Medicines Agency's Committee for Medicinal Products for Veterinary Use has recommended granting marketing authorization for Fortekor Plus, a combination of benazepril and pimobendan. The committee warns that the combination "should only be used in patients whose clinical signs are successfully controlled by administration of the same doses of the individual components (pimobendan and benazepril hydrochloride) given concurrently."  In a July 2017 article, a team of investigators employed by Elanco Animal Health, which markets Fortekor Plus, conducted a study of 67 dogs (including 9 cavalier King Charles spaniels) at a clinic in Japan. All of the dogs were in congestive heart failure (Stage C) due to mitral valve disease (MVD). The dogs were divided into three groups. The test group received the Fortekor Plus, while two control groups received separate doses of benazepril and pimobendan. The researchers found no significant differences between groups. They reported that the frequency of vomiting (emesis) was significantly lower in the Fortekor Plus group. They concluded that:

"Fortekor Plus had non-inferior efficacy and was associated with significantly less emesis compared to administration of Fortekor and Vetmedin in dogs with CHF caused by MMVD."

In a September 2020 article -- The VALVE Study, a team of German and Swiss researchers compared treating MVD-affected dogs in congestive heart failure (CHF - Stage C) with and without the ACE-Inhibitor ramipril. They divided 158 dogs (only 8 cavaliers - 5%) diagnosed with MVD and in CHF into two groups. Group DT (double therapy) consisted of 77 dogs (including 4 cavaliers - 5%) treated with furosemide (Lasix) and pimobendan (Vetmedin). Group TT (triple therapy) included 79 dogs (4 CKCSs - 5%) treated also with ramipril. They hypothesized that the addition of the ACE-Inhibitor would extend the survival time compared to the double therapy group. They found and concluded:

"In conclusion, the addition of an ACEI [ACE-Inhibitor] to pimobendan and a diuretic, as recommended in the ACVIM guidelines for the treatment of chronic stage C MMVD, did not have a significant effect on survival time in dogs with CHF caused by MMVD. Therefore, recommending TT as standard treatment for such dogs does not seem justified."

Indeed, the results of this study showed that not including ramipril extended the average survival time by 41 days longer than adding the ACE-Inhibitor to the treatment cocktail. In effect, ramipril caused the MVD to progress more rapidly than just treating with a diuretic and pimobendan.

In a March 2018 article, a team of Japanese cardiologists switched 73 MVD-affected dogs in CHF, including 6 cavalier King Charles spaniels, from other ACE-inhibitors (either benazepril, enalapril, ramipril, or temocapril), to the ACE-inhibitor alacepril. All dogs had been treated with the other ACE-inhibitors for at least one month prior to the switch. They compared the degrees of mitral valve regurgitation (HR), activeness, appetite, responsiveness, body weight, and cough frequency and found "significant improvement" following two weeks of treatment with alacepril. After four weeks of alacepril treatment, they report observing an overall reduction of murmur intensity. They concluded:

"In this study, switching to alacepril from other ACE-Is has shown to reduce HR, and improve the clinical symptoms of CHF, in particular the frequency of cough. The improvement of the clinical symptoms was related to the improvement in the class of heart failure. In addition to the influence on the renin-angiotensin-aldosterone system (RAAS), alacepril is known to have a wide range of actions, including inhibitory effects on the sympathetic nervous system and negative chronotropic effects. Although with the results of this study one cannot be certain, however, it is most likely that multiple factors are involved in the cough suppressive effect of alacepril."

In a February 2020 article, Dr. Mark Rishniw carefully dissected all five drug-company-funded studies of the ACE-inhibitor enalapril (the IMPROVE, COVE, LIVE, SVEP, and VETPROOF studies) to determine whether the drug would delay the onset of cardiac death in MVD-affected dogs in heart failure (CHF) or would delay the onset of CHF in pre-clinical MVD-affected dogs (i.e., in Stages B1 or B2). While the conclusions of some of the studies were muddled by drug-company interference, Dr. Rishniw's analysis of the underlying data showed that ACE-inhibitors have not been scientifically shown to delay the onset of either CHF or cardiac death due to MVD. He goes on to determine that:

"In retrospect, it became clear that the veterinary community was hoodwinked into believing that ACE-I were the medical cure for CHF dogs because of corporate marketing decisions."
"So, what does all this mean? My interpretation of all this literature suggests that ACE-I have no place in managing mitral valve disease, whether in dogs with CHF or dogs with subclinical disease."
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--- natural alternatives to ACE-inhibitors in Stage C

A natural supplement as an alternative to ACE-inhibitors is a combination of active fish petides, including LKPNM, from the bonito fish (Sarda orientalis), such as Vasotensin, manufactured by Metagenics, Inc., and PeptACE by Natural Factors.  Holistic supplements should be taken only if prescribed by a licensed veterinarian who also is holistically trained in TCM. Search webpages for finding holistic veterinarians  in the United States and Canada are located here, and in the United Kingdom, here.

Other Chinese herbal alternatives include Salvia Shou Wu, a Seven Forests patented supplement which consists of Salvia extract, and several other herbs and flowers.  Salvia Shou Wu encourages blood circulation.

LASSBio 897 is a new prototype drug produced from safrole substrate, a compound extracted from the “sassafras oil”, found in Brazilian plants like “canela-branca” (Ocotea pretiosa), caused vasodilation after two hours of their administration, similar to what was observed with benazepril.

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--- mineralocorticoid receptor antagonists (MRA)

Mineralocorticoid receptor antagonists (MRA), also referred to as aldosterone receptor antagonists (ARB), include:

• spironolactone
• eplerenone (Inspra)
• finerenone
• Losartan potassium (Cozaar)

 Aldosterone is a hormone in the mineralocorticoids group. Its function is to regulate blood pressure and sodium potassium levels. High levels of this hormone may have harmful effects in the heart, including as mechanism of cardiac remodeling, meaning enlargement.

Spironolactone has been approved within the European Union for use in dogs with clinical signs of HF secondary to MVD, as additional therapy. It typically acts as a comparatively weak diuretic, when
administered alone, but has synergistic effects when combined with other diuretics. The main reason for prescribing it is to protect the dog against the harmful effects of aldosterone on the heart and blood vessels.

However, spironolactone reportedly may lead to excessively high, life-threatening levels of potassium in the dog's blood, particularly when combined with ACE inhibitors. Some veterinary cardiologists recommend that potassium levels be carefully monitored when using spironolactone in combination with ACE inhibitors by drawing blood at regular intervals until it is evident that the potassium level is or is not going to be a problem.

The usual dosage of spironolactone is 1 to 2 mg/kg once a day with food.

In a 2013 study of the possible increased risk of adverse events for dogs taking spironolactone in addition to conventional therapies, the researchers concluded that dogs with heart failure receiving spironolactone in addition to conventional treatment are not at a higher risk for any adverse events, death caused by cardiac disease, renal disease, or both, hyperkalemia, or azotemia. The study was funded by the manufacturer of Prilactone. See also this May 2016 review of the use of spironolactone as a diuretic.

In a May 2021 article, Dr. Clarke Atkins reported the results of a study (the "BESST Study") of 569 dogs (including 40 cavaliers -- 9.66% -- the highest number of a single breed) in a comparison of treating MVD-affected dogs in Stage C (heart failure) with the ACE-inhibitor benazepril (BNZ) alone or adding spironolactone (S+BNZ). In both groups of dogs -- the BNZ group and the S+BNZ group -- the loop diuretic furosemide also was administerered. Twenty cavaliers were in each of the two groups. Of the 569 dogs, 155 were excluded for various reasons, leaving only 414 to participate in the efficacy portion of the study. Twenty-seven specialty clinics in the USA participated in the study. Spironolactone is a mineralocorticoid receptor antagonist (MRA) intended to inhibit the dogs' renin-angiotensin-aldosterone system (RAAS) from activiating in response to furosemide's effects upon the kidneys. ACE-inhibitors also are designed to inhibit activation of the RAAS system. See this section for details about ACE-inhibitors in general. The authors concluded:

"A combination of the MRA, spironolactone, and the ACE-I, benazepril, in a fixed 8:1 ratio, is more effective than benazepril alone when included in the medical management of new-onset CHF, due to MMVD. The use of the combination of spironolactone and benazepril results in reduced or delayed recurrence of CHF and its associated clinical signs, while reducing death rate over the 12-month study. Furthermore, under clinical field conditions, the safety profile of the combination product is indistinguishable from that of benazepril alone."

Cardalis is a tablet which combines spironolactone with the ACE-inhibitor benazepril. Aldactazide is a combination of spironolactone and hydrochlorothiazide (see thiazide diuretics, below),  which inhibits the activity of aldosterone. Aldactazide is intended to block the adverse effects of aldosterone on the heart muscle and enhance the diuretic effects. 

Other aldosterone receptor blockers (ARBs) include eplerenone (Inspra), finerenone, and Losartan potassium (Cozaar).

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--- angiotensin receptor blockers (ARBs) in Stage C

Angiotensin receptor blockers (ARBs) are drugs intended to block activation of the renin-angiotensis-aldosterone system (RAAS) due to RAAS' known contribution to the development of CHF in MVD-affected dogs. ARBs include

• telmisartan (Micardis)
• sacubitril/valsartan (Entresto)
• valsartan (Diovan)

 Studies currently are underway or planned to determine if some of these ARBs will significantly lower the incidence of ABT than will treatment with ACE-inhibitors.

Telmisartan (Micardis): In an October 2018 article, Japanese researchers reported that the ARB telmisartan did not suppress RAAS activation in five healthy laboratory beagles.

In a December 2020 article, University of Pennsylvania researchers compared the effectiveness of angiotensin converting enzyme inhibitors (ACE-I) -- enalapril and benazepril -- with the angiotensin receptor blocker (ARB) telmisartan in offsetting the activatation of the renin-angiotensin-aldosterone-system (RAAS) in the kidneys of dogs in Stage B2 of mitral valve disease. Eight MVD-affected dogs were included in the study, all diagnosed with Stage B2 of MVD, including two cavalier King Charles spaniels (25%). They report finding that telmisartan treatment resulted in higher activity of favorable angiotensin peptide (AP) concentrations, as compared to ACE-I treatment. They concluded that:

"Treatment with ARBs, such as telmisartan, or combined ARB and ACE2 [angiotensin converting enzyme 2] treatment represents a potential treatment strategy for dogs with DMVD and warrants additional preclinical study."

Sacubitril/valsartan (Entresto): In an August 2018 article, a team of Auburn University researchers examined the effectiveness of a combination of an aldosterone receptor blocker and a neprilysin (NEP) blocker, sacubitril/valsartan (S/V), in 7 dogs diagnosed with mitral valve disease (MVD), compared to 6 MVD-affected dogs in the placebo group. They report finding that S/V is effective at lowering the urine concentration of aldosterone and that it was safe, with no deleterious effects on BUN, creatinine, and electrolyte concentrations, or systolic arterial pressure.

In a July 2021 article, Thai investigators compared sacubitril/valsartan (Entresto) with the ACE-inhibitor ramipril in treating dogs diagnosed with Stage C (heart failure) due to MVD, along with both pimobendan and the diuretic furosemide. Twenty-one dogs -- none being cavaliers -- were divided into the S/V group (11 dogs) and the ramipril group (10 dogs) for four weeks. The investigators report that short-term administration of SV in dogs with MVD stage C resulted in a greater extent of reverse myocardial remodeling of both the left atrium and the left ventricle than in the ramipril group, as indicated by several echocardiographic parameters. They concluded:

"The current study suggested that the short-term effects of SV can reverse myocardial remodeling, as inferred from several echocardiographic indices (i.e., the reduction in LA/Ao, LVIDDN, EDVI and ESVI) in dogs with MMVD stage C. These findings would support the use of SV in clinically symptomatic heart failure in dogs."

However, they warn of a few limitations: (a) a very small sample size, with a much larger sample size needed to confirm the findings; (b) the study was for a very short term -- four weeks -- and a longer term study should be conducted; (c) the results thus far "do not suggest that ACEi should be replaced with S/V in dogs with MMVD stage C."

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--- alpha & beta blockers in Stage C

Alpha and beta blockers and alternatives include:

• Carvedilol (Coreg)
• Bisoprolol
• Nebivolol (Bystolic)
• Propranolol
• Phenoxybenzamine ( Dibenzyline)
• Atenolol (Tenormin, Tenoretic)
• Nicorandil (Ikorel, Angedil, Dancor, Nikoran-PCA, Aprior, Nitorubin, Sigmart)

Carvedilol (Coreg), bisoprolol, nebivolol (Bystolic), and propranolol also are being prescribed for Stage C MVD by some cardiologists. They are non-selective beta-and alpha-blockers with anti-oxidant effects -- also known as beta- (β-) adrenergic receptor antagonists (BARA) -- which reduce the heart's rate and the force of its contraction, thereby reducing the work of the heart. Also, in a 2009 study, it has been suggested that BARA have the potential to slow the progression of the mitral valve's degeneration by interfering with the serotonin signaling pathway -- a possible major factor in MVD progression -- and by reducing the "wear and tear" of the valve by reducing the pressure differences between the left ventricle and atrium. See also this January 2015 report regarding Carvedilol's effect upon hypertension.

Phenoxybenzamine ( Dibenzyline) is another alpha-blocker, with vasodilator properties.

A less expensive alternative beta-blocker is atenolol (Tenormin, Tenoretic). However, atenolol lacks the vasodilatory and antioxidant properties of carvedilol. Other beta blockers include metoprolol (Lopressor, Toprol). In a June 2021 article, Brazilian researchers reported that 30 days of metoprolol associated with at least 2 months of classic treatment for MVD-affected dogs in Stace C improved their quality of life and cardiac autonomic function.

Nicorandil (Ikorel, Angedil, Dancor, Nikoran-PCA, Aprior, Nitorubin, Sigmart), is an alternative to beta-blockers and/or calcium antagonists. It is a potassium channel activator with arterial vasodilator and venodilating properties. It increases blood flow through the heart, improves the heart's blood and oxygen supplies, and reduces its workload. Nicorandil is not available in the United States. See this January 2011 article on nicorandil.

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--- sildenafil and other hypertension medications

• Sildenafil (Viagra, Revatio) (a/k/a sildenifil)
• Diltiazem (Cardizem, Diltstar, Tiazac, Tildiem)
• Bosentan (Tracleer)
• Hydralazine (Apresoline, BiDil)
• Phenoxybenzamine ( Dibenzyline)

Primary pulmonary hypertension (pulmonary arterial hypertension -- PH) is not a common condition in dogs. However, secondary PH, as a complication of mitral valve disease, is more commonly diagnosed in dogs. PH is higher diastolic or systolic pulmonary arterial pressure than normal pressure. This high pressure may lead to increased right ventricular pressure and right atrial chamber enlargement, leading to possible right side heart failure.

 This high pressure may lead to increased right ventricular pressure and right atrial chamber enlargement, leading to possible right side heart failure. In a March 2015 study of 212 dogs, including 30 cavaliers, diagnosed with either Stage B2 or Stage C MVD, the researchers found that 39% of the dogs had PH, and that PH was more commonly found in Stage C. They concluded that the presence of moderate to severe PH predicted a shorter survival time in dogs with MVD.

In an April 2018 abstract, UK cardiologists studied 94 MVD-affected cavaliers and 93 MVD-affected non-CKCSs, all in either Stage B2 or C, and found that cavaliers were more likely than non-CKCS to develop PH due to MVD, and that PH was associated with a greater likelihood of CHF and death (cardiac-related and all-cause mortality).

Sildenafil (Viagra, Revatio) (a/k/a sildenifil) a phosphodiesterase (PDI) 5 inhibitor, is being prescribed to lower pulmonary hypertension by some cardiologists for dogs with congestive heart failure, often in combination with pimobendan. In an October 2020 article, Thai researchers found that sildenafil, when added to conventional medical therapy for treating Stage C MVD-affected dogs with pulmonary hypertension aided in reducing systolic pulmonary artery pressure (sPAP).

In an April 2006 French study report, tadalafil (Cialis), a long-acting PDI-5 inhibitor, belonging to the same family as sildenafil, has been shown to have decreased systolic pulmonary arterial pressure significantly. Another such pde-5 inhibitor is varenafil (Levitra). However, in a March 2012 article, researchers opined that "further studies are required to delineate the clinical effects and potential clinical value of these medications."

To the contrary, research by Dr. Rosemary A Henik, of the University of Wisconsin-Madison, has indicated that pulmonary venous hypertension due to left heart disease, is managed best with "afterload" reduction, and not sildenafil. More recently, a 2007 study by Drs. Joao S. Orvalho, William P. Thomas, and P. H. Kass found that "these data suggest that oral tadalafil, when added to conventional heart failure therapy, decreases the pulmonary artery pressure in this group of dogs."

Diltiazem hydrochloride (Cardizem, Diltstar, Tiazac, Tildiem) is a calcium channel blocker (CCB) medication used to treat hypertension in dogs. Calcium channel blockers, also called calcium antagonists, decrease the flow of calcium into muscle cells. It is similar to amlodipine. Another calcium channel blocker, clevidipine, which also lowers blood pressure is being studied at the Univeristy of California - Davis veterinary school, for its usefulness in treating MVD-affected dogs.

Bosentan (Tracleer) is a non-selective endothelin antagonist acted by blocking at the endothelin (ET)-1 receptor. In a 2000 Korean study, bosentan was found to have significantly lowered pulmonary arterial pressure in the treated dogs. In a 2000 US study, bosentan was given to dogs with moderate heart failure. The researchers found that long-term therapy with bosentan prevented progression of left ventrical (LV) dysfunction and reduced LV chamber remodeling.

Hydralazine (Apresoline, BiDil)  is another arteriodilator which may be prescribed for high blood pressure. Phenoxybenzamine ( Dibenzyline) is an alpha-blocker with vasodilator properties, which also may be prescribed for high blood pressure.

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--- reducing and increasing plasma NT-proBNP

• Aldactazide
• Nesiritide (Natrecor)

B-type natriuretic peptide (BNP) is a natriuretic, diuretic, vasodilatory, and anti-remodeling hormone produced by myocardial cells in response to heart failure due to MVD (and other causes of heart failure). ("Natriuretic" means: causing the excretion of an excessively large amount of sodium in the urine.) BNP is activated during heart failure to counteract the effects of activation of the renin angiotensin aldosterone system (RAAS) in the heart, kidneys, and blood vessels. However, as the MVD progresses, the dog's ability to produce active BNP declines, lessening its ability to counter the effects of RAAS activation.

 In a June 2015 abstract, PennVet researchers found that by tweaking medications (furosemide, enalapril, pimobendan) and adding Aldactazide, they were able to reduce the concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP), the peptide hormone discussed above, in dogs in CHF. They noted evidence in human patients with CHF that therapies reducing NT-proBNP improved their outcomes. Depending upon the results of periodic blood tesing over 21 days, if NT-proBNP was above 1500pmol/L in the test group, the researchers would increase the dosages of the medications. They reported :

"In conclusion, a pre-specified treatment escalation algorithm in dogs with stable CHF due to MMVD and with NT-proBNP ≥1500pmol/L resulted in significant decreases in plasma NTproBNP concentration over time. Serum BUN and creatinine measurements significantly increased over baseline in these dogs, suggesting that careful monitoring of renal function is necessary during therapeutic escalation. Further study is warranted to determine whether targeted reductions in NT-proBNP result in improved outcomes in dogs with CHF secondary to MMVD."

Oddly enough, on the other hand, in a May 2017 article, a team of US researchers which included two of the same PennVet investigators, discuss the feasibility, safety, and tolerance of injecting synthetic canine B-type natriuretic peptide (syncBNP) in four healthy dogs and two dogs with stage B1 mitral valve disease, including a cavalier. They also gathered data regarding the effect of syncBNP on plasma cGMP, kidney function, and RAAS. The found that syncBNP was feasible, well tolerated at all doses, and safe, and that it significantly increased median plasma cGMP. They recommended further studies using syncBNP for treatment of MVD.

In a January 2019 article, in which seven MVD-affected dogs (2 CKCSs) in CHF were tested, the researchers found that synthetic canine BNP1-32 produced no measurable beneficial cardio-renal effects, leading them to suggest that dogs with chronic CHF may have a reduction in natriuretic peptide responsiveness.

Nesiritide (Natrecor), the recombinant form of  B-type natriuretic peptide (BNP1-32), the peptide hormone discussed above, has been shown in studies of induced severe CHF in dogs, when combined with the diuretic furosemide, to inhibit activation of aldosterone while maximizing natriuresis and diuresis and preserving renal function. See, for example, this 2004 report.

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--- other drugs for treating Stage C

• Capadenoson
• Ivabradine
• Elamipretide (Bendavia, SS-31)

Capadenoson is a partial adenosine A1 receptor agonist which has been shown in an April 2013 study to improve left ventricular function and prevent progressive heart enlargement in dogs in heart failure.

Ivabradine is a selective sinus node If Channel (funny channel) inhibitor which may be used to lower and maintain heart rate without affecting cardiac function. In this January 2017 article, ivabradine reportedly was found to be safely administered to dogs with congestive heart failure. See also this November 2017 abstract which reports finding that ivabradine lowers the heart rate in dogs, with no clinical discernable side effect, and therefore is safe to use in dogs with mitral regurgitation. In a May 2018 study of seven laboratory Beagles with naturally-occuring asymptomatic MVD (ACVIM Stage B), The researchers reported that a single oral dose of ivabradine for dogs with asymptomatic MVD reduced both the dogs' heart rate (HR) and the hearts' consumption of oxygen (MVO2) without significantly affecting blood pressure. They concluded that ivabradine may be promising for management of an elevated HR in asymptomatic MVD-affected dogs. In a September 2018 article, the same team of Thai veterinary researchers conducted a long term (3 months) study of oral doses of ivabradine in four MVD-affected Beagles with heart enlargement (Stage B2). They evaluated the dogs'heart rate (HR), blood pressure (BP), myocardial oxygen consumption (MVO2), and heart rate variability (HRV). They report finding that "the results revealed that chronic administration of ivabradine significantly decreased HR, BP, and RPP without adverse effects. All indices of time- and frequency- domain of HRV at M3 were significantly increased when compared with baseline values)." They conclude that "The findings of this study imply that long-term treatment with ivabradine at a dose of 1.0 mg/kg twice daily in dogs with asymptomatic DMVD stage B2 decreased the HR, BP, MVO2 and improves HRV. This makes ivabradine potentially promising for management of elevated HR and impaired HRV in asymptomatic dogs with DMVD stage B2."

Elamipretide (Bendavia, SS-31) is a mitochondrially-targeted tetrapeptide that reportedly restores protein and mRNA levels in the left ventricle (LV) of dogs in heart failure (HF). In this May 2018 abstract, researchers at the Henry Ford Hospital report that mRNA and protein levels are decreased in LV of HF dogs and are normalized after chronic therapy with Elamipretide, resulting in observations of improved LV function and rate of ATP synthesis.

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--- bronchial dilators for coughing

Many veterinarians associate a dry, hacking cough with heart failure. They call it a "cardiac cough" and attribute it to fluid build-up in the lungs (pulmonary edema) due to CHF. In most all cases, however, the term cardiac cough is a misnoner because the true cause of the cough probably is respiratory related and completely independent of any heart disorder.

Some cardiologists may prescribe a bronchial dilator (bronchodilator), such as a methylxanthine, for example, aminophylline, millophyline, oxtriphylline, theophylline* (Corvental, Apo-Theo-LA, Theo-Dur), or terbutaline (Brethine, Bricanyl) which are human grade prescription medications which relax and open air passages in the lungs, making breathing easier.** A narcotic, hydrocodone bitartrate with homatropine MBr or guaifenesin  (Hycodan, Hydromet, Tussigon, Mycodone), or butorphanol tartrate (Torbutrol, Stadol, Torbugesic)  may be prescribed to suppress the coughing by affecting the brain's cough centers.

* Theophylline is a PDE inhibitor which should not be given concurrently with pimobendan, which is another PDE inhibitor, unless the combination of those two drugs is carefully balanced.
** Fluoroquinolone antibiotics should not be given concurrently with any methylxanthines.

The cough could be due to a combination of factors, which include the enlarged left atrium of the heart pressing against and compressing the left mainstem bronchus, but more likely to airway disorders independent of any relationship with the heart. It may even cause the trachea to collapse*.

* Trachea collapse also may be due to Brachycephalic airway obstruction syndrome (BAOS).

In a March 2012 article, USA researchers found no association between left atrial enlargement (LAE) and bronchial collapse in MVD-affected dogs with moderate-to-severe LAE and chronic coughing, but they did find that airway inflammation is common in dogs with airway collapse.

In a January 2019 article, a pair of experts concluded that a cough in the absence of rapid and labored breathing would indicate that it is due mainly to a respiratory disease rather than a cardiac disease. Coughing is a hallmark sign of bronchitis. Dogs with severe pulmonary edema can cough but coughing is much more common with primary lung disease. By severe pulmonary edema, they mean that the fluid has completely filled the lungs and also has started to fill the upper airway passages, as well.   (The x-ray below shows the heart's enlarged left atrium impinging upon the left main bronchus.).

One of the most common -- and potentially dangerous -- misjudgements some veterinarians tend to make is to assume that such a cough indicates the onset of CHF and the need for immediate treatment with a diuretic. Cardiologist Dr. Michele Borgarelli has warned:

"It should be stressed that cough is a general clinical sign of respiratory disease and its presence in a dog with a murmur is not an indicator for starting treatment for CHF."

So if a dog has had a cough for months and unchanged and the dog is not being treated with a diuretic, the cough is very unlikely due to heart failure.

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--- treating exercise intolerance and loss of muscle mass (cardiac cachexia)

General nutrition is very important. Cavaliers at this advanced stage may suffer severe weight loss, called progressive cardiac cachexia, and they should be fed any protein-rich palliative food to maintain muscle mass. Read about cardiac cachexia as a symptom of MVD here. See this January 2012 article about cardiac cachexia and the importance of maintaining body weight as a preventative measure.

In the ACVIM’s 2019 Consensus Statement on diagnosing and treating MVD, the panel of cardiologists recommend maintaining an adequate calorie intake to minimize weight loss that often occurs in CHF. Specifically, they advise a maintenance calorie intake in Stage C of approximately 60 kcal/kg of body weight. They suggest warming food, mixing wet food with dry food, and offering a variety of foods, to encourage the affected dogs to eat.

Cardiologists may prescribe an appetite stimulant, such as mirtazapine (Remeron) or meclizine (Antivert, Bonine, Dramamine II, Driminate II), or capromorelin (Entyce).

In a November 2016 article by a team of French cardiologists and specialists, Figure 10they reported on the use of a palatable high-energy complementary feed composed of high-energy ingredients (glucose syrup, soybean oil and cod liver oil), hydrolyzed animal proteins, vitamins and oligo-elements, called Nutri-Plus Gel, in five case studies.

Case Report 4 in that study was of a female 13-year-old cavalier (right) in Stage C2 (advanced heart failure) of mitral valve disease, which had lost 1.5 lbs. in the previous month and now weighed 11.5 lbs. She exhibited signs of fatigue, lack of appetite, and diarrhea. Her MVD treatment had been the standard four medicines for cavaliers in heart failure (diuretic, pimobendan, ACE-inhibitor, and spironolactone). They reported:

"Nutri-Plus Gel was also prescribed to stimulate appetite, limit the already considerable loss in body weight (10% of the initial weight in one month), and facilitate treatment compliance (six drugs in all, requiring eleven oral doses). During the follow-up visit one week later, the owner reported that the digestive and cardiac symptoms had disappeared (stage C1). One month later, a gain in weight was noted (200 g [0.44 lb.]). Two years after this episode, the dog was in good general condition and no change in the medical treatment was proposed, as the symptoms had not returned. As the animal’s weight is now stable, Nutri-Plus Gel is recommended solely on demand, during phases of hyporexia (infrequent to date, according to the owner)."

In May 2016, the USA's Food & Drug Administration (FDA) approved the canine appetite stimulant Entyce (capromorelin). Capromorelin is a ghrelin receptor agonist which mimics the activity of ghrelin, a hormone which reportedly causes a sense of hunger.

In a May 2017 abstract, a team of researchers at Henry Ford Hospital in Detroit reported on the success of a new drug, Neladenoson bialanate hydrochloride (BAY1067197), a partial adenosine A1-receptor agonist, in improving the function of mitochondria in the skeletal muscles of dogs in heart failure. The drug company Bayer AG has been funding this project. In a November 2016 abstract, the researchers concluded that Neladenoson has beneficial effects on mitochondria function in dogs in heart failure. They report improvement in mitochondria function after treatment with Neladenoson within one hour after initiation of therapy.

 Mitochondria are organelles in the muscle cells, which take in nutrients, break them down, and create energy rich molecules for the cell. As heart failure progresses in MVD-affected dogs, the mitochondria reduce in size, resulting in reduced capacity to create energy. See our discussion of exercise intolerance in our Symptoms section, for more information.

The researchers opine that treating dogs in heart failure with Neladenoson can potentially reduce or reverse exercise intolerance and skeletal muscle weakness. 

Our Blog: "Your Stage C, MVD-affected cavalier is losing weight. What to do?"

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 --- natural alternatives

 In addition to the natural alternatives to diuretics and ACE inhibitors described above, natural supplements which may help to strengthen and energize the heart of a dog with severe MVD include:

Coenzyme Q10 (CoQ10) -- Read about CoQ10 here. Doses are 100 mg. twice daily for cavaliers and other small dogs.
• D-Ribose (Corvalen Ribose or Pure Encapsulations Ribose), also known as alpha-D-ribofuranoside, for MVD-affected dogs in Stage B2 or Stage C. Read about D-Ribose here as a supplement to strengthen the heart muscle and otherwise energize MVD-affected dogs with enlarged left atriums and/or left ventricles. Doses are of 1/4 to 1/2 teaspoon with meals, twice daily.

A good general health supplement for older dogs in congestive heart failure is N, N-Dimethylglycine (DMG). Vetri-DMG is a pure DMG product offered by Vetri-Science Laboratories of Vermont (www.vetriscience.com). DMG is said to support the immune system, promote oxygen utilization, improve cardiovascular function, support liver function, and support ocular health.

Holistic supplements should be taken only if prescribed by a licensed veterinarian who also is holistically trained in TCM. Search webpages for finding holistic veterinarians  in the United States and Canada are located here, and in the United Kingdom, here.

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--- removal of retained fluids in abdomen (abdominocentesis)

Adominocentesis at Mount Pleasant Vet GroupAs discussed above (See Right-sided heart failure), the tricuspid valve, which is located opposite the mitral valve (on the right side of the heart, between the right atrium and right ventricle), often develops regurgitation leakage as the MVD progresses.

Much as advanced mitral valve backflow results in fluid in the lungs (pulmonary edema), tricuspid valve backflow causes fluid to accumulate in the cavity of the abdomen. This is called cardiac effusion. If the fluid retention is affecting the dog's ability to breathe, and diuretics are not sufficient to ease the breathing issue, then these retained fluids, called ascites (or abdominal effusion), must be removed periodically by aspiration with a hypodermic needle periodically by aspiration with a hypodermic needle, a process called abdominocentesis.  The needle is inserted into the abdominal wall to drain excess fluid so that the dog will be more comfortable breathe more easily. (See photo of abdominocentesis in process at left, courtesy Mount Pleasant Vet Group.) An x-ray prior to the procedure, or use of ultrasound during the procedure, to find the fluid pocket, is recommended, to avoid cutting into an organ in an unexpected location. Alternatively, a larger surgical incision may be necessary, called a laboratomy, to drain the fluid.

Many cardiologists prefer increasing diuretic doses rather than frequent draining of fluids. However, if the fluids reach high pressures, they can cause respiratory distress, which would require draining. Many ascites patients also eventually will suffer severe weight loss (cardiac cachexia).

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--- avoid vaccines

Vaccine WarningVaccine manufacturers provide warnings on their products' data sheets and labels, advising that only healthy dogs should be vaccinated. (Click on the thumb-nail image at right to view a typical warning on a rabies vaccine data sheet.)

Some veterinarians recommend that dogs with advanced mitral valve disease not be vaccinated with the usual serums, including rabies, because of possible adverse reactions which might accelerate damage to the dogs' hearts. In such cases, the veterinarians will write letters to the county licensing authorities which require periodic vaccinations, and in many instances, the counties will accept the veterinarians' letters and excuse the dogs from having to be vaccinated.

A list of states in the United States which will accept letters from veterinarians, certifying that rabies vaccinations would interfere in the health of the dog is available on-line here: RabiesAware.org. Note that any dog not vaccinated for health reasons should be kept from coming into contact with potential sources of rabies, such as racoons and  other wild animals. This would be true for other diseases for which the dog has not been vaccinated, as well, and in addition, the dog should avoid events where many other dogs would be present, such as dog shows and dog parks.

Dr. Larry Glickman, veterinary immunologist at Purdue University's veterinary school, wrote regarding cavaliers:

“Our ongoing studies of dogs show that following routine vaccination, there is a significant rise in the level of antibodies dogs produce against their own tissues. Some of these antibodies have been shown to target the thyroid gland, connective tissue such as that found in the valves of the heart, red blood cells, DNA, etc. I do believe that the heart conditions in Cavalier King Charles Spaniels could be the end result of repeated immunisations by vaccines containing tissue culture contaminants that cause a progressive immune response directed at connective tissue in the heart valves. The clinical manifestations would be more pronounced in dogs that have a genetic predisposition [although] the findings should be generally applicable to all dogs regardless of their breed.”
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--- hospitalization

Cavalier in Oxygen CageAs noted above, dogs with severe (acute) signs of HF -- Stage C1 -- require hospitalization for stabilization. In cases of acute heart failure, the hospitalized dog may also be treated with intravenous injections of diuretics and pimobendan. Oxygen may be administered by either housing the dog in an oxygen cage (right) or a nasal tube, called a cannula. The dog also may be sedated to counter any anxiety it may be experiencing from its condition.

Some drugs not discussed in any detail here -- such as nitroglycerin ointment (Nitro-Bid), sodium nitroprusside (NitroPress), dobutamine, and  hydalazine (Apresoline) -- likely also will be administered during hospitalizations. Briefly, dobutamine is a synthetic balanced catecholamine which stimulates cardiac contractility and coronary blood flow without causing a significant change in vascular resistance.

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-- Stage D -- end stage MVD

Follows the Pimobendan box just below.

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A Few Words About Pimobendan (Vetmedin, Cardisure)

Vetmedin ContainerCavalier King Charles spaniels suffering from mitral valve disease (MVD) received a dose of really good news in April 2007, when the U.S. Food and Drug Administration approved the use of pimobendan to treat dogs suffering from heart failure (HF), a particularly common disorder in cavaliers. (See FDA Approval Report.)

Pimobendan (Vetmedin, Cardisure, Safeheart, Pimocard, Pimotab, Zelys, Fortekor Plus*) has been shown to improve the quality of life for dogs suffering from CHF due to MVD. Pimobendan technically is a benzimidazole pyridazinone derivative and is classified as an inodilator (a calcium sensitizer and phosphodiesterase-III inhibitor and a positive inotrope and arteriovenous dilator) which reportedly has a positive affect upon the force with which the heart muscle contracts, and also eases the resistance in the circulatory system by dilating blood vessels.  Other inodilators are milrinone, levosimendan, and SCH00013.

* Fortekor Plus is a combination of benazepril and pimobendan.

Cardisure brand of pimobendanOften, the cavalier in the late stage of heart failure suffers from a progressive deterioration of the quality of its life, which is due to the combination of an inability to comfortably keep the dog free from fluid congestion in its heart, lungs, and abdominal cavity, together with enlarged heart chambers, lethargy, collapse, and deterioration of its kidney and/or liver functions. Eventually diuretics, ACE inhibitors, and other drugs no longer are able to remove enough of the fluids and increase the supplies of blood and oxygen to the heart. At that point, often the owner elects euthanasia, rather than to allow the dog to continue to suffer.

Pimobendan now may be called to the rescue. In addition to dilating the blood vessels like ACE inhibitors do, pimobendan increases the strength with which the heart muscle contracts, which improves the heart’s efficiency to function as a pump, and increases the blood flow to major organs. It even has been shown, in some studies, to actually reduce the amount of backflow of blood through the mitral valve and reverse the enlargement of the heart chambers. It also reportedly makes the ill dog perk up as if from a caffeine-like rush, due to its purportedly neuro-stimulatory properties. And, it may be administered safely with diuretics, ACE inhibitors, and digoxin. The FDA report states that pimobendan "is indicated for use with concurrent therapy for heart failure (e.g., furosemide, etc.) as appropriate on a case-by-case basis." Furosemide is a diuretic.

Remarkably, pimobendan also has been shown to have fewer severe side effects than its main rival drugs, the ACE inhibitors benazepril (brand names Lotensin, Fortekor) and enalapril maleate (brand names Enacard, Vasotec). See ACE Inhibitors -- More Pluses Or Minuses? Many dogs with overt signs of advanced heart disease are reported by their owners to act as if they feel better and have improved activity tolerance within a few days of beginning pimobendan treatment. However, researchers report that the clinical improvement may not correlate with hemodynamic improvement. They opine that pimobendan may have a central nervous system effect that promotes a feeling of physical and mental well-being in dogs as demonstrated by other phosphodiesterase inhibitors, such as propentofylline. See this November 2007 article.

CAUTION!

Before prescribing pimobendan, cardiologists may require an echocardiogram to measure the heart's contractility (the efficiency of the pump function of the heart). This precautionary test is recommended, because a negative effect reportedly has been instances of pimobendan improving the heart’s pumping ability and contractility to the extent that the mitral valve's major chordae tendineae have been overworked and have actually ruptured, causing immediate death. Therefore, the drug should not be prescribed for dogs whose hearts have remained strong despite the MVD. Cavalier owners should never self-prescribe pimobendan for their dogs suffering from mitral valve disease.

Owners also should be wary of general practice veterinarians prescribing pimobendan without first consulting with a cardiologist about performing an echocardiogram to resolve the contractility issue. Also, pimobendan should not be prescribed by a non-cardiologist for CKCSs which are not in heart failure (HF). Researchers have reported severe adverse cardiac effects upon pimobendan-treated dogs not in HF, including increased blood backflow through the valve, heart enlargement, and deterioration of the chordae tendinae. We have found, now that pimobendan is available to the general practice veterinarians, that many of them are prescribing it without taking the precautions which would be instinctive to cardiologists and internal medicine specialists.

Vetmedin Container Warnings

On the container of Vetmedin tablets, there is this warning:

"Contraindications: Vetmedin should not be given in cases of hypertrophic cardiomyopathy, aortic stenosis, or any other clinical condition where an augmentation of cardiac output is inappropriate for functional or anatomical reasons.

Warnings: Only for use in dogs with clinical evidence of heart failure."

Also, on Vetmedin's website, it has this warning:

"The safety of VETMEDIN has not been established in dogs with:

Asymptomatic heart disease
Heart failure caused by etiologies other than atrioventricular valvular insufficiency or dilated cardiomyopathy
Dogs younger than 6 months of age
Dogs with congenital heart defects
Dogs with diabetes mellitus or other serious metabolic diseases
Dogs used for breeding or pregnant or lactating bitches."

And, on the vetmedin.com website, there are these "Adverse Reactions" warnings:

Vetmedin Adverse Reactions


However, in a September 2016 article, an international team of veterinary cardiologists report that the administration of pimobendan to MVD-affected dogs with echocardiographic and radiographic evidence of heart enlargement results in prolonging the pre-heart failure period by approximately 15 months over non-treatment (a placebo), which represents a substantial clinical benefit. The is called the EPIC Study. (Note that this study was entirely funded by the manufacturer of pimobendan.)

The bottom line of the EPIC Study is:

(1) The dog must be in Stage B2 of mitral valve disease; AND
(2) Have a murmur of at least Grade 3; AND
(3) The dog must NOT be on any other cardiac medication; AND
(4) An echocardogram must be conducted and show valvular lesions of the mitral valve, regurgitation through the mitral valve (MR) on the color Doppler echocardiogram, and have echocardiographic evidence of left atrial and left ventricular dilation; AND
(5) X-rays showing evidence of enlargement with a vertebral heart size (VHS) greater than 10.5.

This essentially means that once the MVD-affected dog develops a Grade 3 murmur and an x-ray showing enlargement, the owner should have a board certified veterinary cardiologist perform the echo exam.

Pimobendan in solid formulation was developed by Boehringer Ingelheim GmbH, a German pharmaceutical company, and is marketed under the registered brand name "Vetmedin". In Europe and elsewhere apart from the United States, it has been studied since the late 1980s and prescribed by veterinarians since the 1990s. There, it is offered by EuroVet Animal Health BV, a Netherlands company, as "Cardisure". Pimobendan can be expensive. It has become a popular item on the underground drug market and on international Internet websites. As long as Boehringer Ingelheim holds the FDA’s grant of marketing exclusivity in the U.S., it should not be expected to be sold as a reduced price generic drug. However, the Australian company, Luoda Pharma, has registered a liquid formulation of pimobendan.

Pimobendan is available through an accredited compounding pharmacy on the Internet, Premier Pharmacy Labs, Inc., in dosages different from the limited choices offered by Boehringer Ingelheim for Vetmedin, including flavored oral liquids and capsules sized to order. Veterinarians' prescriptions are required.

Several veterinary research studies of pimobendan have been published leading up to the FDA’s report. In studies of dogs with mitral regurgitation, it has shown improved survival, heart and respiratory rate, and left atrial size, without evidence of arrhythmogenesis. It has been compared favorably with ramipril in a March 2005 study report. In a March/April 2006 study report, Texas A&M University Drs. Sonya G. Gordon, Matthew W. Miller, and Ashley B. Saunders find that "pimobendan is safe, well tolerated, and leads to enhanced quality of life in dogs with CHF secondary to...chronic valvular disease when used in combination with furosemide or other conventional therapies (e.g., angiotensin-converting enzyme inhibitors, digoxin)" and that "ongoing studies are evaluating its effects on mortality associated with chronic valvular disease." See Veterinary Resources for citations.

In a January 2007 article, UK cardiologists compared the affect of pimobendan versus ramipril on the vertebral heart score of 42 MVD-dogs in congestive heart failure, including 24 cavaliers. They found that for the first few months of the 21 dogs treated with pimobendan, their VHS heart size decreased, meaning a reduction in the heart enlargement, while during the same period, the 21 dogs treated with rampilril experienced a continued increase in their VHS heart size.

In July 2008, Drs. Häggström, Boswood, O'Grady and several others reported that in a comparison study of pimobendan and benazepril hydrochloride (the QUEST Study): "Pimobendan plus conventional therapy prolongs time to sudden death, euthanasia for cardiac reasons, or treatment failure in dogs with CHF caused by MMVD [myxomatous mitral valve disease] compared with benazepril plus conventional therapy." Of the 190 dogs, the median time to death (called the "endpoint") was 267 days for pimobendan and 140 days for benazepril. They concluded that "the benefit of pimobendan persisted after adjusting for all baseline variables. A longer time to reach the endpoint was also associated with being a cavalier King Charles Spaniel, requiring a lower furosemide dose, and having a higher creatinine concentration." In a September 2013 follow-up analysis of the same QUEST Study patients, the same researchers also found that the two medications resulted in similar quality of life during the study. However, they found that pimobendan conferred increased time before the progression of CHF and resulted in smaller heart size, higher body temperature, and less retention of water.

In an October 2013 report issued by Swedish cardiologists J. Häggström, P.F. Lord, K. Höglund, I. Ljungvall, O. Jöns, C. Kvart and K. Hansson, they studied 16 dogs in congestive heart failure (CHF) due to mitral valve disease, including eleven cavaliers, They compared pimobendan to benazepril and found that in dogs with CHF caused by MVD, pimobendan significantly reduces the heart rate (HR), left ventricle (LV) and atrium (LA) dimensions, heart rate-normalized pulmonary transit time (nPTT), and N-terminal proatrial natriuretic peptide (NT-proANP), and increases the ejection fraction, in comparison to benazepril. The reduction in heart size in response to pimobendan treatment in dogs with CHF is in agreement with previous studies, but reductions in HR, NT-proANP, and nPTT in response to pimobendan treatment have not previously been described in naturally occurring MVD.

The dangers of giving pimobendan to dogs not yet in heart failure

Pimobendan also is being considered for cavaliers just beginning to develop heart failure and even in earlier stages of MVD. In a September 2016 article, an international team of veterinary cardiologists report that the administration of pimobendan to MVD-affected dogs with echocardiographic and radiographic evidence of heart enlargement results in prolonging the pre-heart failure period by approximately 15 months over non-treatment (a placebo), which represents a substantial clinical benefit. (Note that this study was entirely funded by the manufacturer of pimobendan.)

To be included in the study, a dog had to be 6 years of age or older, have a mitral valve murmur of at least Grade 3 of 6, have echocardiographic evidence of advanced MVD consisting of characteristic valvular lesions of the mitral valve, regurgitation through the mitral valve (MR) on the color Doppler echocardiogram, and have echocardiographic evidence of left atrial and left ventricular dilation, plus radiographic evidence of enlargement with a vertebral heart size (VHS) greater than 10.5. The researchers warn that:

"... it should be borne in mind when interpreting these results that all dogs included in the analyses also met the echocardiographic inclusion criteria and these results therefore might not be generalizable to all dogs with a VHS > 10.5 in the absence of concurrent echocardiographic measurements and a confirmed diagnosis of MMVD."

Therefore, to apply the results of this study to future treatment of MVD-affected dogs, an x-ray of the heart, showing a VHS over 10.5, is not sufficient by itself, and that the two echo measurements must also be confirmed.

Of 354 dogs in the study, 161 (45.5%) were cavalier King Charles spaniels (CKCS). Of those 354 dogs, 178 of the dogs were treated with pimobendan, and 180 received the placebo. Of those 178 dogs treated with pimobendan, 59 (33.1%) reached congestive heart failure (CHF), 15 (8.4%) died of cardiac-related deaths during the treatment. The authors explained that:

"Although a greater number of dogs in the pimobendan group experienced spontaneous cardiac death (12 versus 5), the proportion of dogs in each group experiencing this event was not significantly different."

They concluded:

"Chronic oral administration of pimobendan to dogs with echocardiographic and radiographic evidence of cardiomegaly secondary to MMVD, in the absence of concurrent cardiovascular medication, results in the prolongation of the preclinical period, and is safe and well tolerated. The median time to the onset of CHF or cardiac-related death was prolonged by approximately 15 months, and the risk of a dog experiencing this event was reduced by approximately one-third; the majority of the benefit observed was attributable to delaying the onset of CHF. This substantial degree of prolongation of the preclinical period is f clinical relevance and is of importance to veterinarians and owners of dogs affected by this common disease."

So, the bottom line is:

(1) The dog must be in Stage B2 of mitral valve disease; AND
(2) Have a murmur of at least Grade 3; AND
(3) The dog must NOT be on any other cardiac medication; AND
(4) An echocardogram must be conducted and show valvular lesions of the mitral valve, regurgitation through the mitral valve (MR) on the color Doppler echocardiogram, and have echocardiographic evidence of left atrial and left ventricular dilation; AND
(5) X-rays showing evidence of enlargement with a vertebral heart size (VHS) greater than 10.5.

This essentially means that once the MVD-affected dog develops a Grade 3 murmur and an x-ray showing enlargement, the owner should have a board certified veterinary cardiologist perform the echo exam.

It is troubling that the study report fails to note that normal, heart-healthy cavaliers typically have VHS measurements as high as 11.0, which is notably higher than the >10.5 criterion for beginning pimobendan treatment. Considering that nearly half of the dogs in the study were CKCSs, this oversight is rather inexplicable. Also, the study's scientifically-baseless, species-wide definitions of left atrial enlargement ((LA:Ao ≥ 1.6) and left ventricle enlargement (LVIDDN ≥1.7) necessarily include MVD-affected dogs with normal-sized hearts in Stage B2 and other MVD-affected dogs with enlarged hearts in Stage B1.

It also is disappointing that the study does not go into any details about those 8.4% of dogs being treated with pimobendan and which died cardiac-related deaths while only in Stage B2. While the authors do acknowledge that "concerns had previously been raised about possible detrimental effects of the administration pimobendan to dogs with preclinical MMVD", they provide nothing to explain whether pimobendan played a role in those sudden and unexpected Stage B2 deaths. To the contrary, they seem to be patting themselves on the back for even including any data on these premature cardiac deaths, stating:

"If our primary endpoint had focused exclusively on the onset of CHF, with dogs that died being censored, it might have appeared that we were choosing to ignore potentially detrimental effects of the treatment."
Nevertheless, they minimize this 8.4% premature deaths of pimobendan-treated dogs by stating:
"We found, not unexpectedly, that only a small number of dogs met the primary endpoint in this way. Although a greater number of dogs in the pimobendan group experienced spontaneous cardiac death (12 versus 5), the proportion of dogs in each group experiencing this event was not significantly different."

Despite this "EPIC Study", great caution should be taken when considering treating any dog suffering only from mild, asymptomatic MVD. There is evidence from recent studies that treatment with pimobendan of dogs not in CHF may accelerate the symptoms of MVD, including increased regurgitation of blood through the mitral valve, deterioration of the chordae tendinea, and enlargement of the left side of the heart. Most recently, in the 2007 French study, "Comparative Adverse Cardiac Effects of Pimobendan and Benazepril Monotherapy in Dogs with Mild Degenerative Mitral Valve Disease: A Prospective, Controlled, Blinded, and Randomized Study", the researchers found (a) "increased systolic function in the PIMO group by comparison to baseline value as assessed by fractional shortening"; (b) "the maximum area and peak velocity of the regurgitant jet signal increased, whereas these variables remained stable in the BNZ group"; (c) "histologic grades of mitral valve lesions were more severe in the PIMO group than in the BNZ group"; and (d) "acute focal hemorrhages, endothelial papillary hyperplasia, and infiltration of chordae tendinae with glycosaminoglycans were observed in the mitral valves of dogs from the PIMO group but not in those of the BNZ group." They concluded:

"This study demonstrates that long-term administration of PIMO in dogs with asymptomatic MVD is associated with an increase in systolic function and, concomitantly, a progressive worsening of MVD with development of specific mitral valve lesions."

Bottom line: pimobendan can be hazardous to the health of cavaliers with MVD murmurs but no symptoms.

See also the 2005 study "Increased Mitral Valve Regurgitation and Myocardial Hypertrophy in Two Dogs With Long-Term Pimobendan Therapy", in which normal doses of pimobendan were determined to have increased mitral valve regurgitation and caused ventricular hypertrophy. Read also warning comments by Drs. Amara Estrada, Mark Rishniw, and George A. Kramer.

In a 2007 study, "Evaluation of Pimobendan in the Treatment of Early Mitral Valve Disease", the researchers concluded from their study of 26 dogs that their "data suggest a possible non-sustained positive inotropic effect and a reduction of the (mitral regurgitation fraction) at 90 days with the administration of pimobendan in early chronic MVD." They concluded, however, that more data are needed to further assess their findings. A positive inotropic effect means that the drug increases the strength with which the heart muscle contracts.

Dogs with CHF treated with pimobendan also have been found to live longer. In a July 2006 Swedish study of 76 dogs with acquired atrioventricular valvular disease, sponsored by Boehringer Ingelheim, the manufacturer of Vetmedin, which is pimobendan's brand name, researchers report that dogs treated with benazepril hydrochloride, an ACE inhibitor, lived an average of 128 days, while those treated with pimobendan lived an average of 415 days, a difference between four months and thirteen months. The study reportedly also found that within seven days of treatment with pimobendan, over half of the dogs were symptom free. Most of the dogs were treated concurrently with furosemide.

To the contrary, in an October 2006 report, University of Georgia internal medicine specialists Drs. Justin D. Thomason and Clay Calvert conclude that pimobendan may benefit dogs with congestive heart failure secondary to dilated cardiomyopathy or valvular insufficiency, only when used in conjunction with other cardiac drugs, such as ACE inhibitors.

Possible negative side effects of pimobendan include ventricular arrhythmias, particularly in dogs previously diagnosed with that disorder. In this 1989 article, researchers found "strong trends toward increasing incidences of sudden ischemic ventricular fibrillation in the presence of ... pimobendan. ... Hence, these findings suggest that with both positive inotropic agents ... sudden death may be increased via a reduction in ventricular refractoriness in the ischemically injured heart." However, in a 2007 study by Canadian Drs. M. Lynne O'Sullivan, Michael R. O'Grady, and C. Walker, which included eight cavaliers out of 23 dogs, they concluded that "Pimobendan did not result in an increase in frequency of ventricular arrhythmias in comparison to benazepril." A majorly significant side effect of pimobendan in human studies has been a high mortality rate. In the "Pimobendan in Congestive Heart Failure (PICO) trial", a 1996 study of 317 human patients, the researchers found that: "In both pimobendan groups combined the hazard of death was 1.8 times higher than in the placebo group."

In a study published in 2003 of the effect of pimobendan on rats, Spanish researchers found that "pimobedan ... administration [was] associated with an increased mortality from dysrhythmias." Similarly, in a June 2016 study, Thai researchers found that 10 of 19 dogs treated at least one month with pimobendan had developed cardiac arrhythmias, including atrial fibrillation, sinus tachycardia, second degree AV block, ventricular premature beat, and junctional premature beat. They warned that "cardiac arrhythmias may develop in some dogs treated chronically with pimobendan", and that "ECG monitoring should be performed in dogs chronically administered with pimobendan."

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-- Stage D -- end stage of MVD

Oxygen maskOften, the cavalier in the late stage of congestive heart failure suffers from a progressive deterioration of the quality of its life, which is due to the combination of an inability to comfortably keep the dog free from fluid congestion in its heart, lungs, and abdominal cavity, together with enlarged heart chambers, lethargy, collapse, and deterioration of its kidney and/or liver functions. Eventually diuretics, ACE inhibitors, other drugs, and even pimobendan, no longer are able to remove enough of the fluids and increase the supplies of blood and oxygen to the heart. This period of MVD is called Stage D and also refractory CHF because the standard medications prescribed for CHF no longer manage the MVD. At this stage, more powerful medications might be prescribed, (Photo is of is a Stage D dog under the 2009 ACVIM Consensus Statement.)

In a June 2016 abstract, a team of Tufts University researchers reviewed 43 cases of dogs in Stage D of mitral valve disease (MVD). Nine of the dogs were cavalier King Charles spaniels. In summary:

• Median duration between diagnosis of congestive heart failure (CHF) and Stage D was 157 days.
• Median duration between diagnosis of Stage D and death was 311 days.

A good general health supplement for older dogs in congestive heart failure is N, N-Dimethylglycine (DMG). Vetri-DMG is a pure DMG product offered by Vetri-Science Laboratories of Vermont. DMG is said to support the immune system, promote oxygen utilization, improve cardiovascular function, support liver function, and support ocular health.

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--- appetite stimulants -- cardiac cachexia

General nutrition is very important. Cavaliers at this advanced stage may suffer severe weight loss, called progressive cardiac cachexia, and they should be fed any protein-rich palliative food to maintain muscle mass. See this January 2012 article about cardiac cachexia and the importance of maintaining body weight as a preventative measure.

In the ACVIM’s 2019 Consensus Statement on diagnosing and treating MVD, the panel of cardiologists recommend maintaining an adequate calorie intake to minimize weight loss that often occurs in CHF. Specifically, they advice a maintenance calorie intake in Stage C of approximately 60 kcal/kg of body weight. They suggest warming food, mixing wet food with dry food, and offering a variety of foods, to encourage the affected dogs to eat.

Cardiologists may prescribe an appetite stimulant, such as mirtazapine (Remeron) or meclizine (Antivert, Bonine, Dramamine II, Driminate II), or capromorelin (Entyce).

In a November 2016 article by a team of French cardiologists and specialists, Figure 10they reported on the use of a palatable high-energy complementary feed composed of high-energy ingredients (glucose syrup, soybean oil and cod liver oil), hydrolyzed animal proteins, vitamins and oligo-elements, called Nutri-Plus Gel, in five case studies.

Case Report 4 was of a female 13-year-old cavalier King Charles spaniel (right) in Stage C2 (advanced heart failure) of mitral valve disease, which had lost 1.5 lbs. in the previous month and now weighed 11.5 lbs. She exhibited signs of fatigue, lack of appetite, and diarrhea. Her MVD treatment had been the standard four medicines for cavaliers in heart failure (diuretic, pimobendan, ACE-inhibitor, and spironolactone). They reported:

"Nutri-Plus Gel was also prescribed to stimulate appetite, limit the already considerable loss in body weight (10% of the initial weight in one month), and facilitate treatment compliance (six drugs in all, requiring eleven oral doses). During the follow-up visit one week later, the owner reported that the digestive and cardiac symptoms had disappeared (stage C1). One month later, a gain in weight was noted (200 g [0.44 lb.]). Two years after this episode, the dog was in good general condition and no change in the medical treatment was proposed, as the symptoms had not returned. As the animal’s weight is now stable, Nutri-Plus Gel is recommended solely on demand, during phases of hyporexia (infrequent to date, according to the owner)."

In May 2016, the USA's Food & Drug Administration (FDA) approved the canine appetite stimulant Entyce (capromorelin). Capromorelin is a ghrelin receptor agonist which mimics the activity of ghrelin, a hormone which reportedly causes a sense of hunger.

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--- bronchial dilators for coughing

Dogs with severe flooding of the lungs should not be exerted in any way. Some cardiologists may prescribe a bronchial dilator (bronchodilator), such as a methylxanthine, for example, aminophylline, millophyline, oxtriphylline, theophylline* (Corvental, Apo-Theo-LA, Theo-Dur), or terbutaline (Brethine, Bricanyl) which are human grade prescription medications which relax and open air passages in the lungs, making breathing easier.** A narcotic, hydrocodone bitartrate with homatropine MBr or guaifenesin  (Hycodan, Hydromet, Tussigon, Mycodone), or butorphanol tartrate (Torbutrol, Stadol, Torbugesic) may be prescribed to suppress the coughing by affecting the brain's cough centers.

* Theophylline is a PDE inhibitor which should not be given concurrently with pimobendan, which is another PDE inhibitor, unless the combination of those two drugs is carefully balanced.
** Fluoroquinolone antibiotics should not be given concurrently with any methylxanthines.

The onset of acute pulmonary edema requires immediate recognition and therapy, including oxygen treatment, in order to save the dog's life. (See the Darcy's Daily Blog entry dated 8/25/06 for details of symptoms requiring oxygen treatment.) Retained fluids (ascites), which fill the peritoneal cavity of the abdomen due to tricuspid valve deterioration, may be removed periodically by aspiration with a hypodermic needle (abdominocentesis).

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--- emergency room care

If an MVD-affected dog incurs an instance of severe cardiac failure and is taken to a veterinary emergency room, the likely care would consist of:

• Oxygen therapy: either by placing the dog in an oxygen cage or attaching an oxygen mask to insure that the dog inhales oxygen.
• Diuretic therapy: initially inject a large dose (bolus) of a diuretic, such as furosemide, and establish a constant-rate flow of the diuretic intravenously.
• Pimobendan therapy: inject pimobendan intravenously.
• Rest: provide the dog with a cage in which to rest while being treated and monitored.
• Monitoring: Provide continuous heart monitoring -- pulse, blood pressure measurements, electrocardiogram, and blood tests.

A strong vasodilator, such as sodium nitroprusside, may be injected into a vein to restabilize a dog with acute pulmonary edema.

If the dog also has right-sided heart failure, in which fluid has caused congestion in the gastrointestinal tract, oral medications may be less effective because of a decrease in the dog's ability to absorb them. In such cases, injections of a diuretic -- furosemide usually -- may help restabilize the dog.

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--- quality of life questionnaire

The Functional Evaluation of Cardiac Health Questionnaire is a set of 18 questions for MVD-affected dog owners to answer. It has been developed based on widely accepted clinical signs of heart disease in dogs. (See box below.) The questionnaire consists of 18 questions to be answered by the dog's owner, who grades the severity of symptoms on a scale from 0 to 5, in which 0 = few symptoms and 5 = several symptoms, with higher scores indicating a poorer health-related quality of life. The questionnaire has been found to be valid as an independent measure of evaluating aproaching death due to MVD. See this March 2017 article.

Quality of Life Questionnaire

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--- euthanasia

At this stage of deterioration, inability to breathe, and suffering, the owner may elect euthanasia, rather than to allow the dog to continue to suffer.

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-- Experimental drugs

--- serotonin blockers

One study involves blocking the cavalier's excessive production of serotonin. Research thus far has suggested that: (a) serotonin (5HT) activates growth activity in canine mitral valves; (b) dogs with MVD have more serotonin receptors in their valve cells than other dogs; (c) mitral valve cells have the capacity to make their own serotonin; and (d) cavaliers also have a higher level of serotonin in their bloodstream. See, e.g., this June 2011 report.

Researchers are exploring the possibility that if serotonin levels can be reduced, by blocking the receptors in the mitral valves, then the progression of the deterioration of the valves and their leaflets can be slowed.  One existing drug, approved for use by humans in Europe, is being tested on dogs with MVD to determine its effectiveness in reducing the level of serotonin and slowing the progression of MVD in cavaliers.

These drugs may include ketanserin (Ketensin, Vulketan, Sufrexal), a 5HT-R2A receptor blocker, or GR55562 dihydrochloride, a 5HT-R1B receptor blocker, based upon suggestions made by Dr. Mark Oyama in his September 2009 report and January 2010 report. See also this 1985 report about ketanserin.

In a December 2017 article, a team of human and veterinary researchers, including Dr. Oyama, studied the relationship between serotonin receptors and mitral valve interstitial cells (MVICs) and leaflet remodeling in humans and cavalier King Charles spaniels. Mitral valve specimens from four deceased cavaliers with severe mitral valve prolapse (MVP) and mitral regurgitation and four normal controls showed that serotonin 5HT receptors (5HTRs) signaling contributes to MVP deterioration, in particular, 5HTR2B upregulation. While this was primarily a study of human MVP, it indicates a possible relationship between the upregulation of 5HTR2B in cavaliers and the progression of mitral valve deterioration. It also shows that a 5HTR2B antagonist -- a drug called LY 272015 hydrochloride -- reduces MVICs activation in humans and mice. Since the cavaliers in this study all were deceased, the application of LY 272015 to dogs was not part of this study. LY 272015 is a beta-carboline derivative drug developed by the Eli Lilly company which is known to act as a potent and selective antagonist at the serotonin 5-HT receptor.

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Surgery

Replacement of the defective mitral valve is available in veterinary medicine and has been for several years. However, surgical replacement usually is cost-prohibitive (in a price range of $30,000 to $45,000) and would require that the dog's renal system and other vital organs be in ideal condition. Also, surgeries which include inserting mechanical devices into the heart, must overcome innate reactions by the dog's systems, including blood clotting (thrombosis) and the development of layers of  fibrovascular tissue or granulation tissue (pannus formation) around the device.

Therefore, MVD typically is treated by managing heart failure with medications. The goals of the veterinary cardiologist are to improve the dog's quality of life and to increase the length of its life.

Cavalier Noah after heart surgery• Cardio-pulmonary By-pass (CPB) Surgeries

Most all mitral valve surgeries involve stopping the heart and by-passing it using an external circuit connected to the carotid artery and the jugular vein. The procedures are called cardiopulmonary bypass (CPB) surgeries These surgeries may involve replacing the the mital valve tendons (chordae tendineae) and/or the valve with either (a) implants, such as pig or cow heart valves or mechanical devices, or (b) inserting a ring-like device to surround the valve, called an annuloplasty device, which pulls the leaflets together to improve the valve's function and reduce backflow of blood through the valve. This procedure of implanting these rings is called mitral annulus plasty. See a typical annuloplasty device below at left.)

Usually in all such surgeries, the chordae tendineae are Typical mitral valve annuloplasty devicereplaced, most commonly with polytetra-fluoroethylene (PTFE) and expanded polytetra-fluoroethylene (ePTFE) implants, which are made of a carbon and fluorine based synthetic polymer (Gore-Tex and SoftForm) that is biologically inert and non-biodegradable in the body. (See a typical annuloplasty device at left.) In a 2012 article, Japanese veterinary surgeons report that using ePTFE "has excellent tissue compatibility and durability and can be effectively used for canine mitral valve repair."

In an April 2017 article, Japanese heart surgeons report case studies of two small dogs (a Maltese and a Shi Zhu) surviving 9 and 7 years following mitral valve plasty, showing the durability of ePTFE sutures as artificial chordae and long term success of semicircular suture annuloplasty. In another April 2017 article, Japanese researchers compare the suitability of ePTFE and polypropylene as artificial suture materials for chordal reconstruction in mitral valve plasty in the dog. They conclude that in their surgeries, ePTFE was superior.

For a detailed description of the cardio-pulmonary bypass procedure, see the Mighty Hearts Project website.

Dr. Masami Uechi -- Japan

Dr. Masami UechiJapanese veterinary heart surgeon Dr. Masami Uechi (right) and his team at JASMINE Veterinary Cardiovascular Medical Centre in Yokohama, Japan, have been conducting open-heart mitral valve plasty surgeries on small dogs since 2006.

Any cavalier owners interested in contacting JASMINE about having their dog surgically cared for should have their dog's cardiologist email Dr. Uechi at muechi@jasmine-vet.co.jp with the following information:

Dog’s name:
Breed:
Body weight:Age:
F/M:
MVD Stage:
Current Medicines:
Quarantine end date:
Other underling medical conditions:
Owners email address:
Include these medical records: (1) Echocardiogram videos and still images in AVI or DICOM format (via dropbox or google drive would be fine; (2) Latest echo report with value ( LA/Ao, LVIDd…etc.; (3) Chest Xrays; (4) Abdominal ultrasound report (used to rule out potential surgical risks) report only and no image is needed.
If there are any other items theye need after they review those records, theye will ask the cardiologist what additional tests or information is needed by emailing him/her directly.
Also have your Veterinarian CC you on all communications so you are aware of the current progress.

 Here is a chronological summary of Dr. Uechi's reports and veterinary journal articles on these surgeries:

In a March 2012 report, Dr. Uechi stated that open-heart mitral valve repair consisting of installing a ring around the valve, a procedure called mitral annuloplasty, and/or replacing chordae tendineae with durable, artificial chordae have improved long-term clinical outcomes in small breed dogs, without the need for long-term anti-clotting therapies. He reported that post-operative improvements have included reduced regurgitation, decrease in heart size, reduction in murmur grade, improved appetite, elimination of cough, dyspnea, and anorexia. In a July 2015 article, Dr. Uechi reported open-heart surgeries on 370 dogs between 2006 and 2014. He wrote:

"After MVR [mitral valve repair], the heart rate significantly decreased from 118–164 bpm to 75–138 bpm. The grade of cardiac murmur was significantly reduced to 0/6–3/6, three months postoperatively, and the cardiac silhouette was reduced (VHS 9.8–11.5) in the chest X-rays. Echocardiography confirmed the marked reduction in both the mitral regurgitant ratio (62–87% to 4–64%, P<0.05) and the left atrial dimensions (LA/Ao 1.2–2.2). Mitral valve repair reduced cardiac size by reduction of the regurgitant rate. After surgery, clinical signs improved and patients were discharged within 12 days post operatively. Several dogs died within 10 days after surgery as a result of bleeding or pancreatitis. In the postoperative physical examination, cough was no longer present, and the animal’s appetite had improved. In addition, with the improvement in general condition, body weight increased. The clinical signs had essentially disappeared by 1 month after surgery. In addition, cardiac reverse remodelling was also observed at 1 month post operatively. Based on the reduction in class of The International Small Animal Cardiac Health Council classification, the clinical signs had improved after MVR. In addition, the number of medications used decreased by 1 month post operatively. By 3 months after the surgery, many dogs did not require medication."

In a June 2017 article, Dr. Uechi and his team reported that in a study of 65 dogs, including 12 cavaliers, severe mitral regurgitation (MR) was detected in 38 dogs before the surgeries, but in none following the surgeries. They concluded that mitral valve repair in dogs decreased MR volume, and that quantifying the MR volume is an effective method for evaluating the success of mitral valve repair.

In an August 2020 article, Dr. Uechi summarized his team's current techniques of surgical repairs to dogs' mitral valves. He stated that, "High survival rates can be expected in dogs if the appropriate surgery is performed." He has  found that optimal timing of the surgery does not depend upon the stage of the MVD.

He described each part of the mitral valve and how it is repaired. These parts include the septal (anterior) leaflet, the mural (posterior) leaflet, the chordae tendineae (chords), and the papillary muscle. The septal leaf is repaired by inserting r4 to 8 pairs of artificial chords. If the septal leaf itself needs additional work, suture techniques are used to lengthen and straighten it. The mural leaf is repaired by adding 1 or 2 pairs of artificial chords and if necessary, sutures. Obtaining the normal shape of the mitral valve "is crucial", and that is done by mitral annuloplasty -- inserting a ring around the valve. Common complications include thrombus (blood clot) and hematoma (the collection of blood outside of a blood vessel). He suggested that dogs may be more susceptible to thrombus formation upon exposure to prosthetics than humans. Continuous suture method with ePTFE sutures is used, and limiting the exposure of blood to artifical surfaces. He stated that "Recently, however, the incidence of thrombosis in annuloplasty by mitral annuloplasty using continuous suture with ePTFE sutures has decreased to approximately 5%."

Hematoma of the left ventricular wall is a critical post-surgical complication. Hematoma may cause premature ventricular contraction, low blood pressure and, in some cases it can lead to death. Although the cause remains unknown, it is reasonable to suspect that ventricular extrasystoles and the persistence of hypotension after surgery are caused by left intraventricular hematoma. In left intraventricular hematoma with a significant decrease in blood pressure, left ventricular function can be recovered by reopening the heart and making an incision in the hematoma to reduce its size. Hematomas that do not affect blood pressure shrink in several days to several weeks. Other complications could include respiratory failure, anemia, and renal failure.

Dr. Uechi reported in January 2017 that he has performed MVD repair surgery on nearly 700 dogs over the previous 12 years, with an 85% survival rate. His contact information is: email: uechi.masami@cardiovets.jp; address: 2-7-3 Nakagawa, Tsuzuki, Yokohama, Kanagawa 224-0001 Japan; telephone: +81-45-532-8451; telecopier: +81-45-532-8456.

In a September 2014 paper before the WSAVA Congress, Dr. Isamu Kanemoto  summarized the current methods of mitral valve surgeries and their pitfalls for small dogs. The primary difficulty in small dog surgeries is the need for miniaturization of devices and surgical tools. He wrote:

"There are two mitral valve operations for mitral regurgitation (MR); mitral valve plasty (MVP) and mitral valve replacement (MVR). In MVP, the self-valve is preserved and repaired. The advantage is no reaction of a foreign substance, though it requires the skilled techniques. On the other hand, the MVR technique is simple, but anticoagulant therapy is needed during life. As in humans, the first choice is MVP in dogs. ... On chordal reconstruction, shortening of prolonged chorda, and shifting of approximate chorda technique are very difficult in small dogs."

Cavaliers with episodic falling on YouTubeIn an April 2017 article, Japanese veterinarians report on the success of long term (90+ minutes) open heart surgeries of small dogs with severe MVD.

A YouTube video of the actual open-heart mitral valve repair surgery is available here.

• Dr. Dan Brockman -- United Kingdom

Dr. Dan BrockmanIn a November 2017 interview, Dr. Dan Brockman (right) at the Royal Veterinary College in the UK answered questions about his team's mitral valve open heart surgery program. He said that RVC surgery center performs about two operations per month but is expected to increase that rate to one per week. The cost, which includes a pre-operative consultation, surgery, and one week of post-operative hospitalization is £10,000. His survival rate currently is 83% for dogs in Stage C, and 100% since July 2017.

Asa of Augsut 2021, Dr. Brockman's surgery clinic has re-opened after a lengthy pause. the clinic is accepting applications. He still expects to ba able to perform two surgeries per month. For more information about RVC's open heart surgery program, email the team at qmhaheartsurgery@rvc.ac.uk

• Dr. Peter Modler -- Austria

Dr. Peter ModlerIn a February 2015 report, Dr. Peter Modler (right), Austrian cardio-surgeon, reported on a case of mitral valve replacement surgery using Gore-Tex chordae and leaflets, which he performed on a 6 year old cavalier in congestive heart failure due to advanced MVD. In February 2017, Dr. Modler announced that he is performing surgical mitral valve repair on a routine basis to dogs with advanced degenerative mitral valve disease. Thus far, he has concentrated on treating cavalier King Charles spaniels in congestive heart failure. His open-heart surgical procedure includes installing a Gore-Tex annuloplasty ring around the valve, and also replacing diseased valve chords with Gore-Tex, while the dog is on cardiopulmonary bypass.

Dr. Modler's clinic is located in Sattledt, Austria. His contact information is:

Traunkreis Vet Clinic - Tierklinik Sattledt
Kirchdorfer Strasse 7
A-4642 Sattledt, Austria
Tel: +43 7244 8924
Email: office@tierklinik-sattledt.at
www.tierklinik-sattledt.at

 He advises that he is able to provide travel and accommodation assistance, as well.

His exclusion criteria for surgery are:
• Severe pulmonary hypertension (more than 60 mm Hg)
• Clinical symptoms of syringomyelia
• Severe concomitant diseases (e.g. kidney failure, liver failure, malignant neoplasia) 

• Dr. Poppy Bristow -- United Kingdom

Dr. Poppy BristowDick White Referrals (DWR), a specialist veterinary hospital in Cambridge, UK offers open-heart mitral valve surgery to MVD-affected dogs, led by its cardiac surgery head, Dr. Poppy Bristow (right), and its cardiology head, Dr. Anne Kurosawa. DWR's contact information is:

 Dick White Referrals
Station Farm, London Road
Six Mile Bottom
Cambridgeshire CB8 0UH
Tel: 01638 572012
Email: reception@dwr.co.uk
www.dickwhitereferrals.com

• Dr. Sabine Bozon -- France

Dr. Sabine BozonIn Guyancourt, France, Drs. Sabine Bozon (right) and John-Hugues Bozon of Clinique Veterinaire Bozon, who trained under Dr. Uechi, are providing open-heart surgeries for mitral valve repairs.  Their contact information is:

Clinique Veterinaire Bozon
49 Rue Des Chantiers
78000 Versailles, France
Tel: +33 1 39 53 17 17
Email: contact@cliniqueveterinairebozon.fr
www.clinique-veterinaire-hopia.com

For more information:

For more information about all of these open heart surgery programs, see the Mighty Hearts Project website. The box below lists locations where mitral valve surgeries have been performed, with details about their techniques, success rates, and costs.

Canine Heart Valve Replacement & Repair Surgery

FT. COLLINS, CO: Dr. E. Christopher Orton of the James L. Voss Veterinary Teaching Hospital at Colorado State University (CSU) in Ft. Collins, Colorado, heads an animal cardiac surgery program which reportedly has consistently and successfully completed life-saving, open-heart surgeries on canines. Dr. Orton and his surgical team have performed over 100 open-heart surgeries since 1991 and began replacing heart valves in 1997. Valve surgery requires a team of six to eight people, additional staff in the critical care unit, and intensive monitoring of the dog before, during, and immediately after surgery, which limits the team's ability to conduct surgeries to only a few per month. The team replaces the defective valve with an artificial heart valve made from bovine pericardial tissue or with a mechanical valve prosthesis. The surgical procedure typically lasts about five hours, during which the new valve is placed in the dog's heart while its blood circulates through a heart-lung machine; then its heart is re-started, after which the dog is monitored in the surgical suite for two hours. The patient then is placed in the hospital's intensive care unit, where it is closely monitored for the next 72 hours.

The dog has to be monitored carefully for several months after it is discharged from the surgical unit. The surgery offers the dog the possibility of a lifelong cure, as long as the prosthetic valve continues to function well and does not develop complications, such as blood clots or tissue rejection. Dr. Orton's reports on his team's studies are cited below in Veterinary Resources. See 2004 MVD Surgery Report and 2005 MVD Surgery Report.

MitralSeal Canine Mitral Valve Replacement Technology

MitralSeal Canine Replacement ValveBeginning in July 2011, Dr. Orton and board certified veterinary cardiologist Dr. Allison K. Adams have been conducting clinical trials replacing the mitral valve with an artificial heart valve (right) called MitralSeal developed by Avalon Medical, Ltd. This mechanical valve is designed to be installed using a minimally invasive approach into the beating heart. The process is called transcatheter mitral valve implantation (TMVI).

MitralSeal Canine Mitral Valve Replacement VideoWatch an animated demonstration of the installation of a MitralSeal valve on YouTube here (or click the YouTube icon at left).

Dr. Orton may be reached by telephone at 970-297-1250, and e-mail at corton@colostate.edu and Dr. Allison's email address is allison.adams@colostate.edu   For details, click here.

PITTSBURGH, PA: Research physicians at the University of Pittsburgh have conducted experimental mitral valve repairs on dogs, using radiofrequency ablation (RFA).  The RFA energy is applied to the deteriorating valve flaps and chords, resulting in controlled damage which has the affect of qualitatively reducing the leaflet surface and the chordal length.  The researchers found that the result of the application of RFA was to reduce the mitral regurgitation by statistically significant amounts.

COLLEGE STATION, TX: Dr. David A. Nelson of the Small Animal Medicine and Surgery Center at Texas A&M's College of Veterinary Medicine leads a similar veterinary surgical team which has specialized in canine open heart surgery, including mitral valve repair. The surgical center is a part of the Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices. It is researching effective ways to repair the valves, rather than replace them, in smaller dogs.

Dr. Nelson advises that, to be eligible for surgery, the dog's heart function must still be preserved. Dogs that have reached the end point of a lengthy cardiac disease cycle are not considered as candidates. The total number of cases performed is still too low to offer any probability of success. There are still great risks involved, and each dog's case is different. A normal healthy young dog could likely undergo and recover from cardiac surgery without complication. One that is older, with cardiac disease or other organ involvement, presents a much more difficult challenge.

All candidates are referred by veterinarians, who will make the first contact to with the Texas A&M surgical team and send pertinent medical information that allows the team to make an initial determination. A cardiac work-up examination of the dog then is scheduled. The work-up may be scheduled in connection with a tentative surgery date. However, only after the work-up and consultation with the team is a final decision made as to recommend surgery.

A modest amount of mitral valve leakage may continue following the successful surgical mitral valve repair. Changing the disease from a rapidly progressive one to a static, manageable situation is considered a very acceptable result. Following surgery, the dog may remain on some cardiac medications.

The costs of surgery and aftercare is determined on a case by case basis. A current range of costs is from $5,000.00 to $10,000.00 or higher. Higher costs usually are due to increased intensive care unit charges. The team will make an accurate estimate after the dog's cardiac work-up examination. Due to the nature and expense of the service, the surgical center requires a deposit of $4,500.00 prior to surgery. Conventional types of credit cards are acceptable.

Dr. Nelson may be reached by telephone at 979-845-2351 and email dnelson@cvm.tamu.edu.

SATTLEDT, AUSTRIA: Dr. Peter Modler is performing surgical mitral valve repair on a routine basis to dogs with advanced degenerative mitral valve disease. Thus far, he has concentrated on treating cavalier King Charles spaniels in congestive heart failure. His open-heart surgical procedure includes installing a Gore-Tex annuloplasty ring around the valve, and also replacing diseased valve chords with Gore-Tex, while the dog is on cardiopulmonary bypass. Dr. Modler's clinic is located in Sattledt, Austria. His contact information is: email: office@tierklinik-sattledt.at; telephone: +43 7244 8924; website: www.tierklinik-sattledt.at; address: Traunkreis Vet Clinic - Tierklinik Sattledt, Kirchdorfer Strasse 7, A-4642 Sattledt, Austria. He advises that he is able to provide travel and accommodation assistance, as well. His exclusion criteria for surgery are:
• Severe pulmonary hypertension (more than 60 mm Hg)
• Clinical symptoms of syringomyelia
• Severe concomitant diseases (e.g. kidney failure, liver failure, malignant neoplasia)

LONDON, ENGLAND, UK: Heart surgeon Dan Brockman (BVSc, CVR, CSAO, MRCVS, Diplomate ACVS/ECVS) at the Royal Veterinary College, University of London, in England, has begun a animal cardiac surgery program, which includes open-heart mitral valve surgeries on canines. He has consulted with Dr. Orton at Colorado State University, and the two surgeons have been working together to advance heart surgeries in the UK.

Mr. Brockman may be reached at The Queen Mother Hospital for Animals, Hawkshead Campus, the Royal Veterinary College, telephone +44 (0)1707 666366, email qmhaheartsurgery@rvc.ac.uk  The website is www.rvc.ac.uk/Hospitals/QMH/Index.cfm

FUJISAWA, JAPAN: Drs. M Nishida, M Uechi, T Mizukoshi, T Ebisawa, M Mizuno, T Mizuno, K Harada, M Fujiwara, N Nakayama of Nihon University, Fujisawa, Japan, have been conducting "mitral valve plasty" surgery on cavalier King Charles spaniels and other small dogs since 2006. Mitral valve plasty involves suture repairs to the mitral valve leaflets and includes the insertion of artificial chords made of a polymer, expanded polytetrafluoroethylene (e-PTFE). They report in a 2009 journal article, "Mitral Valve Plasty in 11 cavalier King Charles Spaniels", that "these results suggest that mitral valve plasty is beneficial in CKCS with MVD."

While two of their CKCS patients died during the post-operative study due to complications, and three were diagnosed with syringomyelia, the researchers found that among the nine survivors, "at 1 and 3 months after surgery, the left atrial to aortic root diameter ratio ... and the plasma atrial natriuretic peptide level ... were lower than those before surgery ... There were also significant improvements in the number of prescribed cardiovascular drugs 1 month after surgery ... and in the cardiac murmur grade ... ."

Read a 2010 report and a 2012 report with updates of their surgeries.

See, also, a 2011 article by Masami Uechi, Nihon University, Kanagawa, Japan, that mitral valve repair surgeries of 50 dogs with heart enlargement, overall the heart rate decreased and mitral regurgitation reduced, resulting in reduction of the enlargement of the hearts.

TOKYO, JAPAN: Drs. Midori Akiyama, Ryou Tanaka, Kohji Maruo, and Yoshihisa Yamane, of the Department of Veterinary Surgery, Tokyo University of Agriculture and Technology, in Tokyo, Japan, have conducted mitral valve repair surgery on at least one small dog, a 6-month-old, 15.6 lb., male Shiba Inu. They write in their 2005 article: A 6-month-old, 15.6 lb., male Shiba Inu with a cardiac murmur "due to an ostium primum septal defect, a ventricular septal defect, and mitral valve malformation with regurgitation. The mitral valve and tricuspid valve were separated and displaced at the same level as the ventricular septum. The mitral valve had a cleft in the septal cusp. ... An incision was made in the right atrium, and an ASD (25 x 15 mm in diameter) was identified in the lower portion of the atrial septum immediately above the ventricular septum. The mitral valve was seen through the ASD, and there was a cleft in the septal cusp. The cleft separated the septal cusps into two portions, both of which had thick edges. The cleft was repaired with mattress sutures of 5-0 polypropylenes. The ASD was then closed with sutures of 5-0 polypropylene using pledgets. A small VSD (5 mm in diameter) was observed behind the septal cusp of the tricuspid valve. The VSD was closed with simple mattress sutures of 5-0 polypropylene. The right atrium was sutured closed with a simple continuous pattern of 5-0 polypropylene." See their 2005 journal article. Their clinic is located at Department of Veterinary Surgery, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan; website: www.tuat.ac.jp/index-e.html

See also, a 2007 article by Drs. Koichi Tamura, Mayumi Murakami, and Makoto Washizu on post-mortem examinations of 12 dogs with suture-repaired mitral valve leaflets. Drs. Murakami and Washizu are at the Nippon Veterinary and Animal Science University, Tokyo, Japan, website: www.nvlu.ac.jp/e/index.html

In a May 2012 report on 48 surgeries, Japanese veterinarians Masami Uechi, Takahiro Mizukoshi, Takeshi Mizuno, Masashi Mizuno, Kayoko Harada, Takashi Ebisawa, Junichirou Takeuchi, Tamotsu Sawada, Shuhei Uchida, Asako Shinoda, Arane Kasuya, Masaaki Endo, Miki Nishida, Shota Kono, Megumi Fujiwara, and Takashi Nakamura reported success in 45 cases of mitral annuloplasties and replacing the chordae tendineae with ePTFE.

   GUYANCOURT, FRANCE: Drs. Jean-Hugues Bozon and Sabine Bozon offer canine mitral valve repair surgeries at the Bozon Veterinary Clinic (Clinique Veterinaire Bozon-Versailles) in Guyancourt, France. Contact information is: Clinique Veterinaire Bozon-Versailles, 49-51 Rue des Chatiers 78000 Versailles, France, telephone: 01 39 53 17 17, email: contact@cliniqueveterinairebozon.fr website: www.cliniqueveterinairebozon.fr/


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Minimally Invasive Surgeries


Minimally invasive surgeries are not "open heart" surgeries and do not require cardio-pulmonary by-pass equipment. They may be called interventions.

--- epicardial mitral annuloplasty device

Mitral Valve Implant DeviceIn research, an implanted attachment to the mitral valve, called an "epicardial mitral annuloplasty device", has been inserted on dogs' beating hearts in less than 30 seconds and without the need for cardiopulmonary bypass surgery. In two published reports by researchers at the Cleveland Clinic (January 2010 and December 2010), the device (right) reduced the septal-lateral (S-L) dimension of the mitral annulus (the ring that is attached to the mitral valve leaflets) and eliminated the backflow of blood through the mitral valve, without requiring the use of a cardiopulmonary bypass procedure. See the diagram below.

The device, called Mitral Touch, has been manufactured by MAQUET Cardiovascular LLC of San Jose, California. It consists of a titanium wire backbone, silicone bulking, and polyester fabric cover with a flap of 1 cm for securing it to the heart. The device is secured with titanium helical tacks driven through the device into the ventricular wall.

In a 2014 report on what appears to be the same device but now manufactured by Infiniti Medical and called Mitrex, researchers reported the results of a six month trial of the device implanted on the beating hearts of ten swine. Necropsy was performed at 180 days. The researchers found that:

"Coronary flow, ejection fraction, left ventricular wall motion and mitral valve function were normal post implantation and at term. ... Devices were well tolerated causing only minimal to mild fibrosis and chronic inflammation. No significant changes were observed in the myocardium except for muscle fiber atrophy near the tip of the anterior arm. There appeared to be ample tissue over the tip and no danger of perforation in all but one subject. No meaningful changes were noted in cardiac shape, ventricular wall thickness, chamber size, heart valves, and blood vessels. The myocardial compression necessary to perform epicardial annuloplasty was well tolerated. The Mitrex device was safe and biocompatible."
Miitral Touch device implanted on heart

This same report also was presented to the June 2015 ACVIM Forum. The device currently is being tested by veterinary cardiac surgeons at clinics in California and Florida on MVD-affected dogs in congestive heart failure.

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CoApt Valve--- CoApt valve

Ultravet Medical Devices, led by board certified veterinary cardiologist Dr. George Kramer, is researching the viabilitity of a device, called the CoApt valve (right), which is designed to be inserted through a vein into the left ventricle chamber. A YouTube video of an animated diagram of how the CoApt valve is to be inserted and to operate is here.

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Tucker valve in place through tricuspid valve--- Tucker valve

Ultravet Medical Devices also has been researching the viabilitity of a device called the Tucker valve (named after his dog), which is inserted through either the mitral or the tricuspid valve in order to block regurgitation of blood through the valve back into the atrium. An animated diagram of how the Tucker valve is to be inserted and to operate is here. See this November 2015 article about the Tucker valve.  (The animated out-take at the right shows the Tucker valve through the tricuspid valve.)

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--- Harpoon TSD-5

Dr. Michele Borgarelli at Virginia Tech vet school is testing the feasibility of minimally invasive repair of the mitral valve using the Harpoon TSD-5 device developed by Harpoon Medical Inc. of Baltimore, Maryland. The device is designed to anchor artificial chords to the leaflets of the valve, to replace the vavle's natural chordae tendineae. The replacement cords are made of expanded polytetrafluoroethylene (ePTFE).

In a May 2017 article, Borgarelli reported the successful implantation of ePTFE replacement mitral valve chords in four of six healthy Beagles, using minimally-invasive surgical techniques in beating hearts (without cardio-pulmonary bypass or cardiac arrest). The investigators used a biomedical device called the Harpoon Medical TSD-5. The body cavity was opened to reveal the beating heart. Then a "valved introducer" was inserted into the left ventricle, and the thin metal shaft of the Harpoon TSD-5 was inserted through the introducer, leading to the mitral valve. When the shaft was in proper position, the trigger of the Harpoon TSD-5 (see image below) was pressed, and its needle pierced the mitral valve leaflet, forming a bulky knot of the ePTFE chord through the leaflet. The other end of the chord ultimately is extended and attached to the heart muscle through the intial insertion location. This video shows how the procedure is designed to operate.  The study authors concluded:

"This pilot study has demonstrated feasibility of using the Harpoon TSD-5 device to place and anchor ePTFE artificial chords to the MV of small dogs and that endothelialization of the synthetic cord and knots can start within 30 days."

Harpoon TS-5

As of June 2017, Dr.Borgarelli is seeking candidate dogs for a study to assess the efficacy and long-term effects of using the Harpoon Medical TSD-5 device. Dogs in Stage C, heart failure with significant enlargement, and weighing over 11 pounds. Details of the study are available here.

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--- edge-to-edge transcatheter device (ValveClamp)

ValveClampIn a December 2020 article, a team of Chinese veterinary surgeons report the successful preliminary outcomes in the surgical implantation of an edge-to-edge transcatheter device which they clamped on the mitral valves of eight dogs to control regurgitation. [See diagram at right.] All eight dogs had Stage B1 mitral valve disease. The procedure required anesthesia but not cardiopulmonary bypass. All reportedly survived without complications. Echocardiography revealed a significant reduction in mitral regurgitation severity in all dogs following the procedure based on both a reduced mitral regurgitant maximum jet area and a reduced mitral regurgitant maximum jet area to left atrial area. No major complications had been reported in any of the dogs during the follow-up periods of a range from 100 to 141 days. They concluded:

"[T]he dogs included in this study were limited to dogs with mitral regurgitation but no clinical signs and minimal, if any, chamber enlargement (stage B1 MMVD). The efficacy of this device still needs to be further tested on patients with varying stages of MMVD. ... In conclusion, the edge-to-edge valve closure using the ValveClamp mitral valve system is easy to perform and is highly effective at reducing the severity of mitral regurgitation. The system has good potential to be used in clinical practice on canine MMVD patients, although more data needs to be collected to prove its long-term safety and efficacy."
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--- injections of alginate hydrogel

Injecting Alginate Hydrogel into HeartIn a June 2013 study by a team of US cardiologists, they found that injecting alginate hydrogel directly into the left ventricle (LV) of the hearts of 7 dogs in advanced heart failure, increased the thickness of the LV wall, and LV structure and function improved. Alginate is a naturally derived polysaccharide that is used in drug delivery and as cell encapsulation material. (See a diagram of the injection at right.) The brand name Algisyl-LVR is manufactured by LoneStar Heart, Inc. of Laguna Hills, California.

See also these 2009 and August 2010 articles by the same research team.

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--- vagus nerve stimulation

VNS ImplantVagus, the tenth cranial nerve, controls a broad range of organs in the head, neck, and thorax, including the cardiac, pulmonary, esophagus, and gastrointestinal tract regions. It travels from the head along the carotid artery. The vagus nerve is responsible for the heart rate by secreting a substance called acetylcholine. Vagus nerve stimulation (VNS) therapy, an electrophysiology technique in which pulses of electrical activity are supplied to the vagal nerve, using a generator device (e.g., at right) implanted in the chest with its wires wrapped around the nerve, to stimulate branches of the vagus to control such things as seizures in epilepsy patients and clinical depression.

VNS also has been used experimentally to improve left ventricular dysfunction and slow the progression of heart failure in dogs. In a September 2009 article, a research team at the Cleveland Clinic performed VNS in 8 of 15 dogs and reported that, "chronic VNS improves cardiac autonomic control and significantly attenuates HF [heart failure] development in the canine high-rate ventricular pacing model. The therapeutic benefit of VNS is associated with pronounced anti-inflammatory effects. VNS is a novel and potentially useful therapy for treating HF." In a January 2014 study by the same team, they reported that: "VNS improved LA [left atrial] function and volumes and suppressed LA fibrosis in the canine high-rate ventricular pacing model. VNS is a novel and potentially useful therapy for improving LA function during HF."

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Anesthesia

Dogs with mitral valve disease may have an increased anesthetic risk, especially if pulmonary edema is present. Pre-anesthetic evaluation, premedication, induction, maintenance of anesthesia (anaesthesia), and monitoring of anesthetized dogs and possible complications need to be taken into account.

Cavalier under anesthesiaAnesthesia tends to reduce blood pressure, which in turn may slightly reduce the volume of mitral valve regurgitation. Particularly in older dogs, anesthesia may have an adverse effect upon the blood pressure and kidney function, rather than on any cardiac function. Nevertheless, dogs with severe left atrial enlargement cannot excrete a sodium load efficently, and therefore during an anesthetic procedure, administration of a saline or lactated Ringer's solution (which contains sodium) is not recommended. Instead, an intravenous sugar solution of 5% dextrose in water (D5W) is advised. Specialists recommend that an anticholinergic (Atropine or Glycopyrrolate) should be administered as needed during the procedure. The dog's heart rate and rhythm should be monitored durng the anesthetic procedure.

An excellent review of all aspects of anesthetizing dogs with MVD is discussed in this 2012 article by Austrian veterinarians Drs. Roswitha Steinbacher and René Dörfelt. See also this August 2016 article by Colorado State University vets Drs. Khursheed Mama and Marisa Ames.

See also our webpage on anesthesia and sedatives.

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Breeders' Responsibilities

Breeders' ResponsibilitiesEarly-onset mitral valve disease has been found to be "highly heritable" in the cavalier King Charles spaniel breed, and "selection against the disease should be successful.", according to an April 2011 research report.

Due to the pervasiveness of MVD in the breed worldwide, cavalier King Charles spaniels under the age of five years should not be bred (with one limited exception -- see MVD Breeding Protocol). Also, no cavalier should be bred after age five years if it developed an MVD murmur before the age of five years. Any littermates of breeding stock having early-onset MVD (mitral valve murmurs before age 5 years) should be taken into very serious consideration. All CKCS breeding stock should be examined by board certified veterinary cardiologists at least annually and cleared by the veterinary specialists for MVD, the closer the examination to the breeding the better. It is recommended that all cavaliers, breeding stock or not, be examined annually by board certified veterinary cardiologists after age one year. See the current list of health clinics for upcoming cardiologist examinations.

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What You Can Do

Avoid vaccines

Vaccine WarningVaccine manufacturers provide warnings on their products' data sheets and labels, advising that only healthy dogs should be vaccinated. (Click on the thumb-nail image at right to view a typical warning on a rabies vaccine data sheet.)

Some veterinarians recommend that dogs with advanced mitral valve disease not be vaccinated with the usual serums, including rabies, because of possible adverse reactions which might accelerate damage to the dogs' hearts. In such cases, the veterinarians will write letters to the county licensing authorities which require periodic vaccinations, and in many instances, the counties will accept the veterinarians' letters and excuse the dogs from having to be vaccinated.

For example, Dr. Larry Glickman, veterinary immunologist at Purdue University's veterinary school, wrote regarding cavaliers:

“Our ongoing studies of dogs show that following routine vaccination, there is a significant rise in the level of antibodies dogs produce against their own tissues. Some of these antibodies have been shown to target the thyroid gland, connective tissue such as that found in the valves of the heart, red blood cells, DNA, etc. I do believe that the heart conditions in Cavalier King Charles Spaniels could be the end result of repeated immunisations by vaccines containing tissue culture contaminants that cause a progressive immune response directed at connective tissue in the heart valves. The clinical manifestations would be more pronounced in dogs that have a genetic predisposition [although] the findings should be generally applicable to all dogs regardless of their breed.”
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Research News

 Go to MVD Page 2.

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Related Links


Veterinary Resources

 Go to MVD Page 3.

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INSIDE TOPICS