ResearchPDF Available

Mitral Valve Disease and the Cavalier King Charles Spaniel

October 2015

DOI:10.13140/RG.2.1.4901.7042

Authors:

Blenheim Company

Heart 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.

Content uploaded by Rod Russell

Content may be subject to copyright.

Page 1 of 39

MITRAL VALVE DISEASE AND THE CAVALIER KING CHARLES SPANIEL

By Rod Russell

Note: This is an excerpt of the article at webpage

cavalierhealth.org/mitral_valve_disease.htm

with hyperlinks to referenced articles

Degenerative 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 and greater than 90% by age 10+ years, should

they survive that long.

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.

What It Is

Mitral 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, causing death, because MVD does not develop

early in a dog’ s life, and does not progress rapidly.

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, as noted above. For most breeds, MVD is an old-age disease, and the age of onset

is between 10 and 15 years of age.

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

Page 2 of 39

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.

MVD 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. 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 are comprised of three layers of tissue (atrialis, fibrosa, and

spongiosa) and are very thin and nearly transparent. They are connected by tendons (chordae

tendineae) to the muscles of the left ventricle.

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 con rolled

by the tendons, which serve as thin “struts” shaped much like the chords of a parachute.As the

diseased mitral valve degenerates, myxomatous transformation -- the development of excess

connective tissue that thickens the spongiosa and separates collagen 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 at right above), allowing blood to jet backwards through them from the

ventricle back into the atrium. As the Healthy Valve versus Damaged Valvecondition worsens,

advanced lesions cause the leaflets to fold, invert, and displace toward the left atrium. In the

photo at right, LA is the heart’ s left atrium, LV is the left ventricle, and in-between, the opening

of the mitral valve shows thickened, shortened leaflets which no longer fully close. More and

more blood is able to backflow through the damaged valve, causing both the left atrium and the

left ventricle to enlarge. In the final stages, the valve’ s chordae tendineae sometimes rupture,

and if they are major chords, causing the valve to collapse completely.

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 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 veins and capillaries, leading to fluid

buildups in the lungs (edema) or elsewhere (effusions).

The decrease in output forces the body to compensate by activating angiotensin-

Page 3 of 39

converting enzyme (ACE) to excessive levels, forming angiotensin II, which causes the veins

and arteries to constrict. Angiotensin II also releases aldosterone, resulting in sodium and water

retention. The left atrium 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.

To a lesser extent, cavaliers also suffer from deterioration of their tricuspid valves. 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.

Symptoms

As MVD progresses towards congestive heart failure (CHF), early symptoms which may

occur are exercise intolerance, breathlessness, a distended abdomen, lack of appetite, restlessness

at night, weight loss, and fainting. Breathlessness is a most common sign, starting as excessive

panting on exercise. 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.

Productive coughing or a hacking cough can be an early symptom of CHF, due to the

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 atrium gradually begins to swell and enlarge –

called myocardial remodeling – 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.

Also, due to the increasing lack of blood being pumped throughout the body,

non-essential blood vessels begin to shut down, to conserve blood flow for vital organs, such as

the brain and the heart itself, and reducing the flow to the skin and the kidneys. This causes the

skin to pale and the kidneys to retain fluids in the circulation, because the circulation identifies

the low cardiac output as dehydration. The excess fluid retention results in further stretching of

the heart and greater mitral valve leakage. If the tricuspid valve is also affected, the retained

fluid, called ascites, is squeezed into other body tissues, the liver, chest, and peritoneal cavity of

the abdomen. See photo below right of dog with ascites.

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.

The enlarged size of the heart fills the voids in the chest cavity and causes pressure on the

main airway – the left main bronchus, resulting in a dry, hacking cough and breathlessness. It

may even cause the trachea to collapse. However, in a June 2011 preliminary study report,

researchers were unable to confirm an association between left atrial enlargement and airway

collapse in dogs with MVD. The study suggested that airway inflammation was common in the

affected dogs.

Page 4 of 39

Also, 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, with pulmonary edema.

Cavaliers with murmurs of between Grade 3 and Grade 6 may display episodic weakness

of the hindquarters, ataxia, or collapse, which is called presyncope, or combined with loss of

consciousness, which is called syncope, due to a sudden decline in blood flow to the brain. See

Syncope for a discussion of this disorder and its causes.

A loss of appetite, resulting in possibly severe weight loss (called cardiac cachexia),

particularly of lean muscle mass, is another symptom of advanced MVD.

The ultimate consequence of mitral valve disease is heart failure. The median survival

period for dogs once they develop severe congestive heart failure (CHF) due to MVD is

approximately seven 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.

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.

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.

Diagnosis

Cavaliers should be screened for heart murmurs annually, beginning at age one year.

Once mitral valve disease (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.

Also, ask the cardiologist about the American College of Veterinary Internal Medicine

(ACVIM) Registry of Cardiac Health (ARCH), a new 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

Page 5 of 39

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.

– auscultation (stethoscope)

Auscultation of a cavalierThe first indication of MVD which is detectible apart from a

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. 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.

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 of the University of Pennsylvania has stated 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.”

– x-rays (radiography)

Radiography (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).

Once MVD is diagnosed, annual x-rays are very useful in charting the progression of the

disease. Mild to moderate heart enlargement indicates moderate progression, with the heart

compensating for the effects of mitral valve disease by enlarging. When moderate to severe heart

enlargement develops, early clinical signs such as breathlessness or rapid breathing would be

Page 6 of 39

expected. Severe heart enlargement indicates impending heart failure.

Cardiologists use x-rays to evaluate the size and shape of the heart in order to assess the

severity of MVD. Cavaliers with episodic falling on YouTubeThey measure the the length and

width of the heart and compare those dimensions to the number of veterbrae from T4 to T12, to

calculate the Vertebral Heart Score (VHS). See 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. In a 2012

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

The radiograph image at the right above shows vertebral heart scale measurements.

Periodic 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).

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.

– respiratory rates

An ever increasing respiratory rate, while the dog is asleep or resting, which approaches

or exceeds 30 breaths per minute, is an indication that the dog is approaching heart failure. 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 or resting, 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 of less than 30 breaths per minute and rarely exceed that count.

While the dog is resting or sleeping (preferably sleeping), count the number of breaths

the dog takes in 15 seconds. Then multiply that number by four to get the number of breaths per

minute. If that respiratory rate increases by more than 20 percent over 2 to 3 days, or exceeds 30

breaths per minute, many treating veterinarians would advise the dog’ s owner to report to them.

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.”

Page 7 of 39

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 or at rest. Several cardiologists

are recommending that owners become familiar with their MVD-affected cavaliers’normal

resting 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 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.

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.

– ultrasound (echocardiography)

Echocardiography (ultrasound scanning) 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 prolapse (MVP).

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. (The color Doppler view below shows

red blood at the top, regurgitating from the mitral valve of this CKCS.)

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). See this 2002 report by

Drs. Jens Häggström, Kjerstin Hansson, Clarence Kvart, and the 2012 PREDICT Cohort Study,

for more information.

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

Page 8 of 39

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.

For cavaliers’hearts, it is recommended that ultrasound scanning be conducted by

specialists, preferably board certified veterinary cardiologists.

As of December 2011, 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.

Due to the necessity of anaesthetizing the dogs for the cMRIs, the researchers are seeking

to recruit dogs already scheduled for MRIs for other reasons, such as syringomyelia

examinations. All dogs will undergo conventional echocardiography to assess their heart disease

prior to anaesthesia and the MRI scan, and only dogs with stable heart disease will be recruited.

The researchers expect to be able to provide more accurate information for the individual

dogs on the severity of their valve disease as a result of the MRI scan, and new echo score. They

believe that the scoring system should be particularly useful for standardizing the severity of

MVD at entry for clinical studies.

– electrocardiography (ECG or EKG)

Electrocardiography (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. 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).”

– 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 (HF) in dogs, by measuring “cardiac biomarkers”, such as

Page 9 of 39

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.

In a 2014 Swedish study of 535 healthy dogs of nine breeds, 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.

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.

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.

Page 10 of 39

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 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.”

Finally, 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 later (pmol/l). They also 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. 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.

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

Page 11 of 39

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.”

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.

–other cardiac biomarkers

Other cardiac biomarkers include cardiac troponin I (cTnI), and high-sensitivity cardiac

troponin I (hscTnI), and C-reactive protein (CRP), and sodium-calcium exchanger (NCX-1), and

leptin.

—cardiac troponin I (cTnI)

Page 12 of 39

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.”

—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.”

—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.

—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

Page 13 of 39

activity. Cardiac troponin I could be a valuable biomarker for myocardial fibrosis in dogs

with chronic cardiac diseases.” (Emphasis added.)

—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 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 August 2014 report finding serotonin concentration high in cavaliers.

—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.

—histamine concentration

In a May 2014 report, Japanese cardiologists found that histamine concentration was

Page 14 of 39

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.

—Galectin-3

In an April 2015 abstract, 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 the results suggested that the

expression of Gal-3 is associated with cardiac fibrosis.

—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.

—microRNAs

In a June 2015 study, researchers examined the role circulating microRNAs (miRNAs)

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

Page 15 of 39

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 the 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.

DNA Testing

– gene identification

In 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.”

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

Page 16 of 39

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.

– cell transitions

In 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.

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

Page 17 of 39

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.

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.”

Progression & Prognosis

The progression of mitral valve disease can be rapid or slow. 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.

Page 18 of 39

Once the dog reaches the stage of congestive heart failure (CHF), the average time until

death is nine months.

In the cavalier King Charles spaniel, some cardiologists have found prognostic value

from the degree of mitral valve prolapse, the thickness of the leaflets, and whether ruptured

tendinous chords are observed on the echocardiogram. 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.

Drugs may help to minimize the symptoms, but eventually the drugs may be unable to

control them. Severe symptoms in some cavaliers will appear more quickly, although previously

having been stable. If the tendinous chords rupture, and the valve leaflets cannot continue to

open and close with each heart beat, death could be almost immediate.

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. In an October 2012

study, 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.

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.

Stages of MVD

In a very important 2009 “Consensus Statement” published by a panel of the 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 state:

“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).

Page 19 of 39

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.

Stage B2 refers to asymptomatic patients that have hemodynamically significant valve

regurgitation, as evidenced by radiographic or echocardiographic findings of left-sided

heart enlargement.

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 animals presenting with heart failure for the 1st time may have severe clinical signs

requiring aggressive therapy (eg, with additional afterload reducers or temporary

ventilatory assistance) that more typically would be reserved for those with refractory

disease (see Stage D).

Stage D refers to patients with end-stage disease with clinical signs of heart failure

caused by CVHD that are refractory to ‘standard therapy’ (defined later in this

document). Such patients require advanced or specialized Dr.Andrew Beardowtreatment

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.”

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.

Treatment

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,

Page 20 of 39

explain MVD.

– valve replacement

Replacement of the defective mitral valve is available in veterinary medicine. For

example, Colorado State University’s James L. Voss Veterinary Teaching Hospital has such a

surgical program under the direction of Dr. E. Christopher Orton, whose cardiac surgery team

has been replacing canines’ heart valves since 1997. (See “Surgery” below for more information

about various surgical techniques being used on dogs’ mitral valves.) However, surgical

replacement usually is cost-prohibitive and would require that the dog’s renal system and other

vital organs be in ideal condition. Therefore, MVD typically is treated by managing heart failure.

The goals of the veterinary cardiologist are to improve the dog’s quality of life and to increase

the length of its life.

– stem cells

Also, in 2008 in at least one 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.

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 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 have 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.

– 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.

– inflammation

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. Therefore, among the treatments to consider would be

methods of reducing inflammation by diets and supplements.

– mild murmur (Stage B1)

Page 21 of 39

A 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.

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.”

— supplements

Also, supplements (Vitamin C and Vitamin E and CoQ10 and Udo’s Choice Oil 3.6.9 Blend and

fish oils) should be considered after MVD murmurs are detected, along with:

• Bio-Cardio, a Thorne Veterinary Products multi-vitamin, mineral, and herbal extract

supplement (which includes Vitamin E, magnesium, potassium, L-Carnitine, L-Taurine,

coenzyme Q-10, Hawthorne extract, Eleuthero extract, and Arjuna extract).

• Canine Cardiac Support, and human-grade supplements, including Cardio-Plus,

Cardiotrophin PMG, Cataplex E, and Vasculin, which are nutritional whole food

supplements offered by Standard Process, Inc.

• Vetri-Cardio Canine Chews, a Vetri-Science chewable supplement (which includes

L-Carnitine, L-Taurine, Arginine, Hawthorn [Crataegus oxycantha], Berry Extract,

Magnesium [Mg Oxide], N,N-Dimethylglycine HCl [DMG], Berberine [Hydrastis

Canadensis] HCl, Coenzyme Q10, Folic Acid, and Potassium [K Citrate]). Vetri-Science

also offers Vetri-Science Cardio-Strength capsules.

• Flavonex, a salvia and gingko extract herbal supplement made by Health Concern.

• (Natural supplements which may help to strengthen and energize the heart of a dog with

severe MVD include D-Ribose (Corvalen Ribose or Pure Encapsulations Ribose), also

known as alpha-D-ribofuranoside, which reportedly improves ventilatory efficiency in

Page 22 of 39

patients with heart failure (HF). See 2009 report. It also reportedly boosts the energy

level of heart muscle cells, improving cardiovascular function and the flow of blood.)

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.

---- taurine

If cavalier owners choose to ignore this 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.

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:

— ACE-inhibitors in Stage B1

Angiotensin 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, the results have been more mixed and less favorable.

ACE-inhibitors 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.

Veterinary ACE-I include enalapril maleate (Enacard, Vasotec, Prilenal), benazepril

hydrochloride (Lotensin, Fortekor, Benefortin, VetACE, Prilben), imidapril (Tanatril), ramipril

(Altace, Tritace, Vasotop), captopril, and lisinopril.

As noted, the ACVIM Consensus Statement does not recommend ACE-inhibitors for

Stage B1 (or Stage B2) dogs. This is because they have never been approved for veterinary

medicine for MVD dogs in Stage B1 (or Stage B2) by regulating authorities. They have been

approved only for MVD dogs in heart failure (HF) -- Stage C -- when combined with other

therapies, such as diuretics. The reason for not prescribing ACE-inhibitors prior to heart failure

(HF) is obvious: A 2002 Scandinavian study (the “Scandinavian Veterinary Enalapril Prevention

Page 23 of 39

[SVEP] Trial”) of 229 asymptomatic cavalier King Charles spaniels with mild MVD murmurs

(therefore, at Stage B1) 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. A 2007 study (the

“VETPROOF Trial”), sponsored by a drug 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.)

Because ACE-inhibitors have the potential to adversely affect renal function, a baseline

renal panel should be conducted before treatment was 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.

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.

— 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

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. A less expensive alternative beta-blocker is atenolol (Tenormin, Tenoretic).

However, atenolol lacks the vasodilatory and antioxidant properties of carvedilol.

Cardiologists often refer to these drugs as beta- (β-) adrenergic receptor antagonists

(BARA).

— pimobendan in Stage B1

Finally, pimobendan (Vetmedin, Cardisure, Safeheart 5), which has been prescribed for

dogs in heart failure with systolic dysfunction, is the subject to research for treatment of dogs in

the early stage of MVD. In October 2010, cardiologists worldwide began a five-year study (the

“EPIC Trial”) giving pimobendan to cavaliers with low grade MVD murmurs to see if the drug

Page 24 of 39

will slow the progression of MVD to heart failure. The final report of the EPIC Trial is expected

to be published in 2015. 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” for details.

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.

– moderate MVD (Stage B2)

Moderate MVD is indicated by a louder murmur and some enlargement of the heart on

x-rays or 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.

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.

— diuretics

Loop diuretics (furosemide [such as Lasix, Diuride, Frudix, Frusemide, Salix],

hydrochlorothiazide [Dyazide, Thiuretic, Esidrix, Hydrodiuril], and co-amilozide [Moduretic,

Moduret], a combination of amiloride and hydrochlorothiazide), which are drugs which cause

the kidneys to excrete more fluid than normal, may be used to remove excess fluid from the

blood system. Furosemide reduces the total circulating blood volume, which in turn reduces

pressure in the left atrial and left ventricle chambers of the heart. Side effects would be that the

dog is thirstier than normal, and increased urination.

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. Furosemide 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.

* 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.”

Page 25 of 39

Aldosterone receptor blockers (AFBs) include Losartan potassium (Cozaar), telmisartan

(Micardis), valsartan (Diovan). Direct renin inhibitors (DRIs) include aliskiren (Tekturna,

Rasilez).

Medications approved to treat humans with heart failure, such as the aquaretic

(vasopressin receptor anatagonist = vaptans), (tolvaptan), and another loop diuretic, torsemide

(Demadex), are being empirically considered as alternatives to diuretics such as furosemide. 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.” Torsemide is approximately 10-times as potent as furosemide

in dogs and cats.

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.

— natural alternative diuretics

Natural diuretics include urea (AC Carbamide) by Standard Process, and Wu Ling San by

Mayway and Alisma by Seven Forests, both traditional Chinese herbal medicines (TCM).

Holistic supplements should be taken only if prescribed by a licensed veterinarian who also is

holistically trained in TCM.

— ACE-inhibitors in Stage B2

ACE-inhibitors (enalapril maleate [Enacard, Vasotec, Prilenal], benazepril [Lotensin,

Fortekor, Benefortin, VetACE, Prilben], imidapril [Tanatril], ramipril [Altace, Tritace,

Vasotop]), captopril, lisinopril, may also be prescribed by some cardiologists. As stated in more

detail in the Stage B1 discussion above, ACE-inhibitors 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 ACVIM Consensus

Statement has not endorsed ACE-I therapy of MVD dogs at Stage B2 MVD. Further, ACE-Is

have not been approved for veterinary medicine for MVD dogs in Stage B2 by regulating

authorities. However, a majority of the ten members of the ACVIM Consensus Statement panel

did recommend starting an ACE-inhibitor at Stage B2 (although their reasoning was not included

in the Consensus Statement).

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

Page 26 of 39

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). A 2007 study (the “VETPROOF Trial”), sponsored by a drug

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.

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.

Recent 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, such as activation of the

renin-angiotensin aldosterone system (RAAS), a cause of renal dysfunction.

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.

Studies currently are planned to determine if aldosterone receptor blockers (AFBs) including

Losartan potassium (Cozaar), telmisartan (Micardis), valsartan (Diovan), and direct renin

inhibitors (DRIs) including aliskiren (Tekturna, Rasilez), will significantly lower the incidence

of ABT than will treatment with 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.

— 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.

Page 27 of 39

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.

— aldosterone antagonist in Stage B2

Spironolactone (Aldactone, Prilactone), an aldosterone antagonist (or mineralocorticoid

receptor blocker -- MRB), is known as a potassium-sparing diuretic. In a 2010 European study,

spironolactone, when added to conventional cardiac therapy (such as an ACE-inhibitor, plus

furosemide and digoxin if needed) decreases 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.*

*But see a 2011 report indicating that spironolactone did not extend survival times of dogs with advanced heart

failure.

Spironolactone has been approved within the European Union for use in dogs with

clinical signs of HF secondary to MVD (meaning, Stage C MVD), as adjunctive 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, 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.

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.

In 2010, a team of Italian cardiologists, led by Dr. Michele Borgarelli, began the DELAY

Study of 240 dogs to determine if giving combined doses of spironolactone and benazipril can

delay the onset of symptoms of heart failure in dogs with MVD. The study is scheduled to end in

December 2015.

— alpha & beta blockers

Page 28 of 39

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.

Other beta blockers include metoprolol (Lopressor, Toprol).

— pimobendan in Stage B2

A majority of the ACVIM panel who participated in its 2009 Consensus Statement did

not recommend prescribing pimobendan (Vetmedin, Cardisure, Safeheart 5) to Stage B2 dogs.

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.” See the “A Few

Words About Pimobendan” for details.

– severe MVD (Stage C -- heart failure)

Severe 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.

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 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

Page 29 of 39

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.

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.

— diuretics in Stage C

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. Loop diuretics (furosemide [such as Lasix, Diuride,

Frudix, Frusemide, Salix], hydrochlorothiazide [Dyazide, Thiuretic, Esidrix, Hydrodiuril], and

co-amilozide or amiloride/hydrochlorothiazide (Moduretic, Moduret), a combination of

amiloride and hydrochlorothiazide), which are drugs which cause the kidneys to excrete more

fluid than normal, may be used to remove fluid from the lungs. Side effects would be that the