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A Vet’s Viewpoint
MITRAL REGURGITATION IN CAVALIER KING CHARLES SPANIELS: WHAT
SHOULD WE DO DURING THE ASYMPTOMATIC PHASE?
Eric de Madron, dipl ACVIM (Cardiology), dipl ECVIM (Internal Medicine), Alta Vista Animal Hospital, Ottawa, ON, Canada
Mitral valve regurgitation (MR) is a prevalent heart disease in CKCS. It also occurs in other breeds of dogs (mostly small breeds), but it seems to have a particularly early onset in CKCS (dogs may show signs of MR at 2 years of age). The prevalence increases with age. Screening and removal from breeding programs of lines prone to develop early onset MR has helped reduce the prevalence of this disease in CKCS, but it still remains common.
This disease is characterized by a progressive thickening and remodeling of the mitral valve (endocardiosis). This leads to leakage of the valve, with progressive dilation of the left atrium and of the left ventricle. The contractility of the ventricle will eventually decline but not to the extent of what we see with dilated cardiomyopathy (DCM). This process is called “myocardial remodeling”. Eventually, congestive heart failure (CHF) with pulmonary edema will supervene, with associated signs of dyspnea and cough.
The phase preceding CHF (called the asymptomatic phase) can be quite long (years). During that phase, the only sign of heart disease is the presence of a heart murmur.
When CHF is present, the need for treatment is quite obvious. The strategies are based on reduction of lung con-gestion using diuretics (Furosemide), blocking of the key neurohormonal substances activated in CHF using angio-tensin-converting enzyme inhibitors (ACEI: Enalapril, Benazepril, Ramipril), vasodilation to counteract the exces-sive vasoconstriction accompanying CHF (Amlodipine, Hydralazine, ACEI, Pimobendan), and reinforcement of the failing cardiac contractility (digoxin, Pimobendan). The end-points are: control of the symptoms of dyspnea, improvement of the quality of life and increased survival. Several veterinary studies have shown that the combina-tion of furosemide-ACEI, furosemide-Pimobendan, furosemide-Pimobendan-ACEI are effective in achieving these end-points.
What about the asymptomatic phase? Since there are no clinical signs to improve, then the desired goal of any pharmacological intervention should be to alter the mechanisms at play (i.e. progressive remodeling of the mitral valve of the left ventricle) in order to delay the onset of CHF. Two approaches have been tried: 1) interfering with the myocardial remodeling, and 2) reducing the mitral regurgitation.
Slowing down the myocardial remodeling: ACEI, beta-blockers
In humans with heart disease, ACEI can slow down the myocardial remodeling when prescribed to asymptomatic patients. In dogs, we have two sets of data: experimental and clinical.
In dogs with experimental MR, ACEI failed to block the myocardial remodeling. However, drugs blocking the catecholamines (Beta-Blockers) were effective.
Two large scale studies have been conducted in dogs with natural, asymptomatic MR: one conducted solely in CKCS in Sweden, and the second in the US, using multiple breeds. Both studies investigated whether administra-tion of an ACEI (Enalapril) during the asymptomatic phase could delay the onset of CHF, when compared to pla-cebo. The Swedish study concluded that Enalapril did not delay the onset of CHF in CKCS. The second study was more nuanced: it did show a small beneficial impact of Enalapril on the time to onset of CHF, and that more dogs
on Enalapril were CHF-free at 500 and 1500 days. Interestingly, this study also showed that the overall survival was extended by 10.6 months in the dogs in which Enalapril had been started prior to CHF.
As mentioned earlier, Beta-blockers have been showing promising effects experimentally. Currently, there are no studies available that have evaluated the impact of beta-blockers in asymptomatic MR dogs. However, administra-tion of the beta-blocker Carvedilol in symptomatic dogs with MR and DCM has not been shown to block remodel-ing in any measurable way.
It is possible to reduce the degree of MR by using pure vasodilators such as Hydralazine or Amlodipine. By dilat-ing the peripheral arteries, these drugs will drop the intraventricular pressure, which will reduce the MR. Echocar-diographic studies have shown that the amount of leakage can be substantially reduced using Amlodipine. What we do not know yet is whether this can translate into a significant prolongation of the asymptomatic phase.
Pimobendan is a relatively new drug on the market that has two main effects: it stimulates the contractility of the ventricle, and also dilates the blood vessels, which is a beneficial feature in MR. This drug is quite helpful in pa-tients with CHF. What about the asymptomatic phase?
Recent evidence has shown that Pimobendan may have some disturbing side effects, if prescribed in asympto-matic patients. There is a report of 2 cases of dogs in which inappropriate prescription of Pimobendan led to tachycardia, left ventricular hypertrophy, and mitral regurgitation. These anomalies all reversed after cessation of the pimobendan. Experimental toxicity data has also shown that pimobendan can induce mitral regurgitation in normal dogs due to its potent inotropic effect. Another study has shown that long term administration of Pimoben-dan (256 days) in mild asymptomatic mitral regurgitation without initial cardiomegaly can WORSEN the mitral regurgitation by Pimobendan (increase in the size of the mitral regurgitation jet, increase in the loudness of the heart murmur).
To be fair, there are a couple of studies that have shown that Pimobendan prescribed in more advanced asympto-matic mitral regurgitation cases did in fact improve the mitral regurgitation and reduced the cardiac size. So it ap-pears that Pimobendan becomes more useful as the disease progresses in severity, but its routine use in asympto-matic patients cannot be recommended.
At this stage, we know that a lot is going on during the asymptomatic phase of mitral regurgitation, both at the level of the mitral valve and of the left ventricle. It makes sense to attempt to prolong this phase with medications. The issue is that we do not yet know what works. ACEI may have a role to play but the data is far from being con-vincing. Beta-blockers appear promising experimentally, but this has not been confirmed in real patients. Pimoben-dan is potentially dangerous if prescribed too early. Reduction of the mitral regurgitation with vasodilators seem promising, but again there is not enough data.
Sisson D, Kittleson MD: “Management of heart failure: principles of treatment, therapeutic strategies, and pharmacology” in Fox PR, Sisson D, Moise NS (eds): Textbook of Canine and Feline Cardiology (2nd ed), WB Saunders, Philadelphia, 1999, 216
Colucci WS: “Pathophysiologic and clinical considerations in the treatment of heart failure: an overview” in Antman AN (ed): Cardiovascular Therapeutics (2nd ed), WB Saunders, Philadelphia, 2002, 293-299
The SOLVD investigators. “Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.” New England J Med 1991; 325: 293.
The IMPROVE Study Investigators. “Clinical effects of enalapril maleate in dogs with naturally acquired heart failure: results of the invasive multicenter prospective veterinary evaluation of enalapril.” J Vet Intern Med 1995; 9: 234
COVE Study Group: Controlled clinical evaluation of enalapril in dogs with heart failure: results of the Cooperative Veterinary Study Group. J Vet Intern Med 1995; 9: 243
Ettinger SJ, Benitz am, Ericson GF et al: “ Effects of enalapril maleate on survival of dogs with naturally occurring acquired heaqrt failure. The Lomg-Term Investigation of Veterinary Enalapril (LIVE) Study Group. J Am Vet Med Assoc 1998; 213: 243-252
BENCH Study Group: “The effect of benazepril on survival times and clinical signs of dogs with conges-tive heart failure: Results of a multicenter, prospective, randomized, double-blinded, placebo-controlled, long term clinical trial” J Vet Cardiol 1999; 1: 7-18
Fuentes VL, Corcoran B, French A et al : « A double-blind, randomized, placebo-controlled study of Pimo-bendan in dogs with dilated cardiomyopathy.” J Vet Int Med, 2002; 16: 255-261
Smith PJ, French AT, Van Israel N, et al: “Efficacy and safety of Pimobendan in canine heart failure caused by mitral valve disease.” J Small Animal Practice, 2005; 46: 121-130.
The PICO trial investigators: “Effect of Pimobendan on exercise capacity in patients with heart failure: main results from the Pimobendan in congestive heart failure (PICO) trial.” Heart 1996; 76: 223-231
The EPOCH study group: “Effects of Pimobendan on adverse cardiac effects and physical activities in pa-tients with mild to moderate chronic heart failure. The effect of Pimobendan on chronic heart failure study (EPOCH study). Circ J 2002; 66: 149-157.
Lombard CW, Jons O, Bussadori CM: “Clinical efficacy of Pimobendan versus Benazepril for the treat-ment of acquired atrioventricular valvular disease in dogs.” J Am Anim Hosp Assoc 2006; 42: 249-261.
Dell’Italia LJ: “The renin-angiotensin system in mitral regurgitation: a typical example of tissue activation.” Current Cardiology Reports 2002; 4: 97-103
Kvart C, Haggstrom J, Pedersen HD et al : « Efficacy of Enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral valve regurgitation » J Vet Int Med 2002, 16 : 80-88
Atkins CE, Keene BW, Brown WA et al: “Results of the veterinary enalapril trial to prove reduction in on-set of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency.” J Am Vet Med Assoc 2007; 231: 1061-1069
Tissier R, Chetboul V, Moraillon R et al: “Increased mitral valve regurgitation and myocardial hypertrophy in two dogs with long term Pimobendan therapy” Cardiovascular Toxicology (2005), 05 43-51.
Schneider P, Guttner J, Eckenfels et al: “Comparative cardiac toxicity of the IV administered benzimida-zole pyridazinon derivative Pimobendan and its eninatomers in female Beagle dogs.” Exp Toxic Pathol 1997, 49: 217-224
Chetboul V, Lefebvre HP, Sampedrano CC et al: “Comparative adverse cardiac effects of Pimobendan and Benazepril monotherapy in dogs with mild degenerative mitral valve disease : a prospective, controled, blinded and randomized study. » J Vet Intern Med 2007; 27: 742-753.
Kanno N, Kuse H, Kawasaki M et al: “Effects of Pimobendan for mitral regurgitation in dogs” J Vet Med Sci 2007: 69: 373-377.
b. Marcondes-Santos M, Tarasoutchi F, Mansur AP et al: « Effects of carvedilol in dogs with chronic mi-
tral valvular disease ». ACVIM Forum, Seattle, 2007.
c. Ouellet M, Di Fruscia R, Belanger MC : Evaluation of Pimobendan in the treatment of early mitral
valve disease. ACVIM Forum, Seattle, 2007.
d. Oyama M et al: “Carvedilol in dilated cardiomyopathy” ACVIM Forum, Baltimore, MD, 2006
TREATMENT OF MITRAL VALVE INSUFFICIENCY IN ASYMPTOMATIC DOGS
GENERALLY IS NOT NECESSARY
Rebecca Manley, DVM & Etienne Côté DVM, DACVIM (Cardiology, Small Animal Internal Medicine), Atlantic Veterinary College, University of Prince Edward Island
Mitral valve insufficiency (MVI) is a hereditary, noninflammatory, slowly progressive disease that causes degen-eration of the heart valves. This condition has many names, including myxomatous mitral valve disease, chronic degenerative valve disease, and mitral endocardiosis. The Cavalier King Charles Spaniel (CKCS) is one of the breeds most commonly affected, suggesting that, as in humans, there may be a genetic cause.1,2 MVI is suspected when a heart murmur is heard with the stethoscope; confirmation requires cardiac ultrasound (echocardiography).
In advanced stages of MVI, evidence of deteriorating cardiac function, such as laboured breathing and fluid reten-tion in the lungs, can be seen on physical exam and on chest X-rays (radiographs), respectively.3-5 At that point, congestive heart failure is said to be present and daily medication is then indispensable for life. There is near-universal consensus on treatment when such symptoms of congestive heart failure are present.
Much more controversial, however, is the approach to dogs with MVI that do not show obvious symptoms because they are much earlier in the disease process- the so-called “murmur-only” dogs who feel fine but have MVI.
In this situation, the absence of overtly visible symptoms means that the body is offsetting MVI by using its own compensatory mechanisms, and many cardiologists feel that interfering with this process too early can eventually be detrimental. Conversely, other cardiologists feel that beginning treatment early offsets future problems. For the reasons to follow, we feel that early treatment of asymptomatic MVI patients is usually unnecessary and may cause harm.
The drugs most commonly needed by dogs with MVI are well-known. They are medications used late in the dis-ease process- when symptoms of congestive heart failure have occurred, making daily treatment essential. They include ACE-inhibitors, such as enalapril (Enacard, Vasotec) or benazepril (Fortekor, Lotensin) (typical cost for CKCS= $22/month), which are vasodilators that reduce the heart’s workload; diuretics like furosemide (Lasix, Salix; $10/month), which help prevent fluid retention by the body; and in some advanced cases positive inotropes, including pimobendan (Vetmedin; $40/month), which both vasodilates and helps strengthen the contractility of failing heart muscle fibres. These same medications also have been tried in asymptomatic MVI, with generally unimpressive results.
In human patients with even very mild heart disease, ACE-inhibitors significantly increase survival time.6 This information has been used for supporting the assumption that dogs, likewise, must benefit similarly from early intervention with ACE-inhibitors. This assumption, however, has been shown not to be true. In dogs with MVI we know that ACE-inhibitors prolong the time to relapse of congestive heart failure once it has occurred and been controlled with diuretics.7 In the asymptomatic stage, however, long term ACE-inhibitor therapy has been shown to provide no measurable benefit in terms of delaying the deterioration of MVI and eventual progression to conges-tive heart failure.8 One possible exception shown in a recent study may be ACE-inhibitor treatment of MVI when it is asymptomatic but very advanced- the heart is grossly enlarged and the left atrium is clearly increased on car-diac ultrasound. In these cases where congestive heart failure was thought to be imminent, treatment with ACE-inhibitors delayed congestive heart failure in some dogs and allowed it to occur in others, providing an insignifi-cant benefit, if any.9 Even with the very advanced stage of the asymptomatic state, then, the length of time it takes for a Cavalier with MVI to develop congestive heart failure is not convincingly different whether the dog is treated with an ACE inhibitor or nothing at all (placebo).8 Finally, it appears that ACE-inhibitors lose some of their effi-
cacy when given over many years, an observation that, if confirmed in dogs with MVI, would further support with-holding treatment until the time of congestive heart failure.6
Some degree of compromise of the kidneys and heart valves has been seen when pimobendan, a recently-approved positive inotrope, has been given prior to cardiac decompensation in dogs. Increased heart murmur intensity, in-creased thickening of the heart valves and myocardium (heart muscle tissue), worsening of valve leakage, and de-creased filtration ability of the kidneys are some of the changes that have been observed when pimobendan is given to asymptomatic MVI patients.10
Finally, diuretics that are given prior to the onset of heart failure put a dog at higher risk of experiencing side ef-fects, including dehydration, electrolyte imbalances, and acceleration of the progression towards congestive heart failure. For example, furosemide (a loop diuretic) can create prerenal azotemia and metabolic alkalosis, potentially life-threatening imbalances, while providing no benefit, when given prematurely.
A valid question could be: “Why, given this information, would anyone treat MVI at all during the asymptomatic stage?” The answer is likely multifactorial: the results of even the best clinical trials leave room for speculation; veterinarians generally wish to do something to help patients if they can, even if the benefit is unproven; such in-tentions can be supported when there is a strong marketing push by pharmaceutical companies to encourage medi-cation prescription, and a lack of familiarity with the intricacies of new treatments or specific diseases on the part of veterinarians; dog owners may have, or be perceived to have, a desire to “just do something” and to judge a vet-erinarian’s skill by whether concrete action results from a veterinary visit; and many adverse effects of premature treatment of patients are likely cumulative on the scale of months to years in these dogs and would likely not stand out as deterrents, since they could not be clearly separated from the natural progression of the disease.
In conclusion, treatment of MVI in the asymptomatic state generally is not beneficial, can be costly, and may be detrimental. With the possible exception of those asymptomatic dogs in which advanced MVI has been docu-mented on radiographs and echocardiography, asymptomatic MVI should not be treated.
(1) Badano JL, Katsanis N. Beyond Mendel: an evolving view of human genetic disease transmission. Nat Rev
(2) Srivastava D, Olson EN: A genetic blueprint for cardiac development. Nature
(3) Häggström J, Kvart C, Pedersen D. Acquired valvular heart disease. In: Ettinger SJ, Feldman EC, eds. Textbook
of Veterinary Internal Medicine,
6th ed. (St. Louis, MO, USA: Saunders Elsevier, 2005), 1022-39.
(4) Beardow AW, Buchanan AW. Chronic mitral valve disease in cavalier King Charles spaniels: 95 cases (1987-
1991). J Am Vet Med Assoc
(5) Root C, Bahr R. The heart and great vessels. In: Thrall, D. Textbook of Veterinary Diagnostic Radiology,
(Philadelphia, PA, USA: Saunders, 2002) 402-419.
(6) The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asympto-
matic patients with reduced left ventricular ejection fractions. N Engl J Med
(7) Ettinger SJ, Benitz AM, Ericsson GF, et al. Effects of enalapril maleate on survival of dogs with naturally ac-
quired heart failure. J Am Vet Med Assoc
(8) Kvart C, Häggström J, Pedersen D, et al. Efficacy of enalapril for prevention of congestive heart failure in dogs
with mitral valve disease and asymptomatic mitral regurgitation. J Vet Intern Med
(9) Atkins C, Keene B, Brown W, et al. Results of the veterinary enalapril trial to prove reduction in onset of heart
failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insuffi-
ciency. J Am Vet Med Assoc
Chetboul V, Lefebvre H, Sampedrano C, et al. Comparative adverse cardiac effects of pimobendan and
benazepril monotherapy in dogs with mild degenerative mitral valve disease: a prospective, controlled,
blinded, and randomized study. J Vet Intern Med
RESPONSE TO MANLEY AND COTE
Eric de Madron, dipl ACVIM (Cardiology), dipl ECVIM (Internal Medicine), Alta Vista Animal Hospital, Ottawa, ON, Canada
ACEI: the data is not totally black and white. In the Swedish (SVEP) trial, Enalapril was prescribed to dogs with and without cardiomegaly. The number of dogs with cardiomegaly was small when compared to the second study, conducted in the US: VETPROOF. This study, in which Enalapril was started only in dogs with documented cardiomegaly showed a positive impact both on numbers of CHF free days and overall survival. The overall survival for dogs in which the Enalapril was started prior to CHF was prolonged by 10.6 months, which is far from negligible. Furthermore, neither the VETPROOF nor the SVEP data showed any WORSENING of the natural progression of the disease with ACEI. I think that the jury is still out re-garding the benefits of ACEI in the asymptomatic phase. However, I do agree with NOT treating patients with NORMAL heart size.
Pimobendan: Here, I do agree that the evidence is AGAINST the use of Pimobendan in the asymptomatic phase, since toxic effects can be seen. There seems to be a difference in the outcome between dogs with minimal and those with more advanced MR. Pimobendan is a drug that should be reserved for the treatment of overt CHF (ie pulmonary edema present).
Diuretics: These drugs are absolutely not indicated in asymptomatic MR patients.
Other drugs: We cannot exclude the possibility that other approaches using vasodilators like Amlodipine may have beneficial effects in the asymptomatic phase. I agree that we only have pilot studies so far, and that large scale studies are necessary. But, in my experience, the reduction of the regurgitant fraction by Amlodipine is too striking to be ignored. As far as beta-blockers, positive evidence still has to be provided.
The cost issue: This is a problem only if the treatment recommended has absolutely no documented effi-cacy, which we cannot say.
In conclusion, evidence justifying pharmacological intervention in asymptomatic MR patients is not strong, but not nil either. Continuing efforts to find effective strategies to deal with this very active phase of heart disease are still warranted. We may very well find out that COMBINATION of drugs will be more effective that any one drug alone.
RESPONSE TO de MADRON
Rebecca Manley, DVM & Etienne Côté DVM, DACVIM (Cardiology, Small Animal Internal Medicine), Atlantic Veterinary College, University of Prince Edward Island
Dr. de Madron provides a clear, balanced discussion of the known and suspected benefits and side effects of the drugs used for managing mitral valve disease (MVD) in Cavaliers. We agree with him on many points, including treatment of advanced heart disease (congestive heart failure) and the possible, though inconclusively demon-
strated, benefit of ACE inhibitors in cases of severe asymptomatic MVD. We base our conclusions on experiences and sources of information similar or identical to those of Dr. de Madron, yet the conclusions we reach are differ-ent. Therefore, with regards to the earlier, asymptomatic stages of MVD, a difference of opinion remains in the veterinary cardiology community over whether or not to treat these dogs.
The presence of opinion in this exchange, rather than absolute facts, underscores the ongoing need for further in-formation. Many avenues of research could help here. For example, in the future, we may be able to identify sub-groups of asymptomatic dogs that respond better to treatment and subgroups that do not, and by doing so, refine the target populations for effective treatment. We invite breed associations and breeders to remain vigilant for ways to support efforts that help breeds in a long-term way, including screening clinics, enrolment in clinical trials, and financial support of research projects.
Until further studies are conducted, the negative physiological side effects, the accrued cost of the medication, and potential decrease in efficacy over time, make the treatment of asymptomatic MVD inappropriate in our opinion.
Every time a breed becomes popular in the public eye where there is the potential for money making, there
can be managed. Intact ovaries are potential killers.
are show breeders who will flood into a breed. Often
Reproductive specialists have been suggesting for years
they are breeders who have been involved in other
that bitches should have their breeding careers earlier
popular breeds, but as the popularity wanes and many
than later and then be spayed. The potential for ovarian
breeders are unable to sell puppies or the prices drop
cancer and pyometra are good reasons to follow this
due to flooded markets, they bail on that breed and
advice. Particularly in a breed like Cavaliers that have
move to the next. Those types of show breeders are
early onset heart problems. An older Cavalier with a
leeches and have no real interest in the long term wel-
heart problem would likely not survive an emergency
fare in the breed. They can contribute to the health
spay along with the massive infection associated with
problems and an increased need for rescue due to indis-
pyometra. Certainly there is no good reason to keep a
criminate breedings and little effort to vet potential
Anyway it is with sad heart that I say good bye to my
If prices and sales drop, will this be such a bad thing?
little Christa, Rhiannon’s It’s a Mystery. I smile a little
Those who see Cavaliers as a cash cow will hopefully
less with her gone and one of the worst things for a
move on to other breeds and those breeders who re-
breeder, because of her early death, I have nothing of
main will have to become more selective about breed-
hers to carry on with and remind me of her through the
ing because of a difficulty in finding sales for their
puppies. I remember an article on the waning of the popularity of Afghan Hounds (in an issue of Dogs in
Supply and demand – pricing tends to reflect the avail-
Canada some years ago) which stated that at the height
ability of any product or service
of the breed’s popularity you would see dozens of the
According to some discussions on various email lists it
dogs in the breed ring. Most of inferior quality. Some
is getting more difficult to find sales for Cavaliers in
years later when no longer quite so popular, the author
North America and the prices are dropping in some
stated that you might see just a handful of Afghan
areas. I’m not sure why anyone who has been in dogs
Hounds in the breed ring but they were all of high
long enough finds it surprising. The same thing has
quality. The conclusion being that because of lack of
always happened to most new and popular breeds down
easy sales breeders became more selective in their
breedings and so the quality in the breed increased.
We show breeders like to blame the backyard breeders
(breeders of pets trying to make a quick buck) and the
How well do you vet your buyers? Merely a telephone
puppy millers/farmers for the situation and they cer-tainly play a part but there are many within the “show
call or two, an email, a form filled out and then you
community” who have a part to play for the over pro-
ship that puppy off, confident that your abilities to make decisions about people will ensure that the puppy
will live out life healthy and safe? How will you ever
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RENDERED: NOVEMBER 21, 2008; 2:00 P.M. Commonwealth of Kentucky Court of Appeals HONORABLE JUDITH E. MCDONALD-BURKMAN, JUDGEBEFORE: MOORE AND THOMPSON, JUDGES, HENRY, SENIOR JUDGE. MOORE, JUDGE: Arturo Portales appeals from the Jefferson Circuit Court’s Opinion and Order affirming the Kentucky Board of Medical Licensure’s (KBML) revocation of Portales’s medical license. Having ful