Geriatric cardiology: Managing endocardiosis (Proceedings)

Endocardiosis is the most common cause of heart failure in small breed dogs and the most common cause of heart failure in dogs in general. Therapy is initiated once clinical signs of heart failure are present as well as consistent imaging studies which reveal in most cases significant left atrial enlargement with or without pulmonary edema. Which treatments are appropriate will depend on which signs of heart failure are manifested.

Angiotensin Converting Enzyme Inhibitors (ACE inhibitors)

These medications have proven to be one of the most significant breakthroughs in cardiac therapeutics for both humans and our small animal patients. Though there are many cardiac medications available, few have been shown to prolong life. ACE inhibitors not only prolong the lifespan of our cardiac patients in heart failure, but they also improve their quality of life. Quality of life is a vital issue in veterinary medicine, since owners can resort to euthanasia if the pet is perceived to be suffering or not living a good quality life anymore.

Mechanisms of ACE Inhibitor Action

ACE inhibitors have a variety of effects in heart failure. One of the hallmarks of heart failure is thought to be activation of the Renin-Angiotensin-Aldosterone System (RAAS). This certainly does apply to dogs with dilated cardiomyopathy (DCM). It does not seem to be as uniform in dogs with valvular heart disease, however. It has been shown that use of diuretics such as furosemide or marked salt restriction can lead to activation of the RAAS. Activation of the RAAS leads to vasoconstriction, water and salt retention. Angiotensin II (AT-II) is also thought to play a role in cardiac remodelling, a process that leads to progressive cardiac dysfunction. This may relate more to local concentrations of AT-II rather than circulating blood levels.

Effects of ACE Inhibitors in Congestive Heart Failure

A variety of studies have looked at the affects of ACE inhibitors in patients with symptomatic heart failure.1-4 In dogs with marked heart failure from mitral valve disease, life expectancy more than doubled with ACE inhibitors when compared to placebo. This applies to both enalapril and benazapril. In dogs with DCM enalapril had the same effect. Statistically it was not possible to show the same benefit with benazapril, though this may have related more to the small size of the group investigated rather than any true differences between the medications. The ability to exercise is also significantly improved as is the patient's overall well-being when these medications were given.

There is little doubt that a dog with congestive heart failure should be placed on an ACE inhibitor unless it absolutely cannot tolerate the drug. This is especially true if diuretics are being used or is a salt restricted diet has been prescribed. Adverse side effects are rare in dogs. The greatest concern is the development of azotemia. This usually only occurs when diuretics and/or salt restriction are concurrently being used and can often resolve when the diuretic dose is reduced. In fact in some studies renal values improved in those dogs that were receiving an ACE-I in comparison to placebo.

When to Start a Patient on an ACE inhibitor

The question arises whether to start using these medications in dogs with heart disease without clinical signs. Goal of starting these medications early would be to slow the progressive changes associated with heart disease and prolong the amount of time till heart failure develops. It appears that this does occur in humans, however in humans one of the most common causes of heart failure is myocardial infarction, a disease where progressive cardiac remodelling plays a significant role in future decompensation. Until recently there was little data to guide veterinarians in this regard. A recent publication has looked at this important question in detail. The study was a prospective, placebo-controlled double blind study involving 229 Cavalier King Charles Spaniels with mitral valve disease that had no evidence of heart failure.5 The dogs were evaluated by physical examination, electrocardiography and radiographs. The dogs were randomized to either receive placebo or enalapril at standard dosages. The study revealed that patients with cardiomegaly or louder murmurs progressed more rapidly to heart failure. The study however failed to show any preventive benefit from using enalapril in these asymptomatic dogs, whether or not cardiomegaly was present at enrolment. There are obvious limitations to this study in that only one breed and only 1 ACE inhibitor was studied. Nonetheless, given the scope of the study, similarity in progression of valvular endocardiosis in dogs and the similar effects various ACE inhibitors it is likely that this study does apply to most dogs with mitral valve disease.

Unlike dogs with mitral valve disease, the situation in dogs with dilated cardiomyopathy may be dramatically different. This may because RAAS activation is more pronounced in DCM. A study in Dobermans tried to determine if early therapy was able to slow the progression of DCM and positively influence lifespan. The study group consisted of dogs with evidence of DCM such as increased left ventricular diameter, decreased contractility and arrhythmias without having clinical signs.6 Administering enalapril in the occult phase was able to significantly prolong lifespan and increase the time to onset of congestive heart failure. Overall it is recommended to start an ACE inhibitor in dogs suspected of having DCM as early as possible, independent of whether or not they have evidence of decompensation.

Digoxin

Digoxin is commonly used in heart failure patients. It has inotropic effects and can be quite useful in controlling supraventricular tachycardias. It is excreted through the kidney and it is probably best to avoid its use in patients with compromised renal function. Even in normal animals, use of other cardiac medications can lead to significant increases in digoxin levels, potentially leading to toxicity. This has occurred in cats concurrently given diuretics, a low-salt diet and aspirin concurrently with digoxin. It is very important to monitor digoxin levels periodically because blood levels can be quite unpredictable. Current evidencde from humans suggests that digoxin per se does not increase life expectancy, though it may improve quality of life.

Diuretics

Are generally only given as needed to control congestion.

Furosemide remains the most commonly used diuretic. Generally 1-2 mg/kg SID to BID are given. Loop diuretic, causes potassium wasting, highly effective diuretic, causes RAAS activation. The combination of high dose furosemide, ACE inhibitors and low salt diet can very easily cause renal dysfunction. Has some bronchodilator effect so will also improve dogs with respiratory disease, this means that response to furosemide is not an adequate way to determine if a dog has congestive heart failure. Once patients no longer respond to furosemide other diuretics such as spironolactone or chlorthiazides can be added.

Omega 3 Fatty Acid Supplementation

Initially it was tempting to use EFA supplements to help with thrombosis in cats with cardiomyopathy as EFA supplements have been shown to inhibit platelet function significantly in a variety of animal species. In humans considerable benefit is seen with diets rich in fish oil. Giving 1 g of omega 3 a day in 11,300 patients resulted in a reduction of fatal and non-fatal cardiac events by 10- 15%. Recently research has been performed that showed no effect of omega 3 supplementation on clotting in cats, so that it is not likely to be of benefit in preventing thrombosis in this species.

An antiarrhythmic effect has been seen with increased n-3 levels in people. This has been a very significant finding. Experimental studies in animals using ischemia and reperfusion to induce arrhythmias have shown a benefit in regard to arrhythmias, independent of the effect of these fatty acids on atherosclerosis. These effects can be seen with the acute infusion of the fatty acids so that the effect does not even completely depend upon incorporation of the fatty acids into the cell membranes. Certainly the exact mechanism by which this benefit is seen is unknown. Recent work has shown that Omega 3 supplementation to Boxers with arrhythmias appears to reduce the prevalence of ectopic beats.

A more unique and probably very useful indication for n-3 supplementation in dogs with heart disease has been reported. Cachexia is a major problem in dogs with CHF. This will of course cause the owner to perceive a reduction in the quality of life in their pet that might lead to euthanasia. Giving 27 mg/kg/day EPA and 18 mg/kg/day of DHA when compared to placebo resulted in reduced cachexia, probably by decreasing various cytokines. This improves the owners perception of quality of life which could well influence whether the dog is euthanized or not.

Spironolactone

Spironolactone has been used for many years in human and veterinary cardiac patients. Generally it was used as a diuretic that had a mechanism of action different from the other diuretic groups. This medication is an aldosterone inhibitor. It is often given as a combination product also containing a thiazide diuretic. Interest in this drug was heightened when a study in humans (RALES) showed that use of spironolactone at dosages where no diuretic effect was expected significantly improved life expectancy. This was attributed directly to the aldosterone blockade, since aldosterone is one of the hormones that is secreted in response to chronic heart disease and which may have negative effects on the myocardium. There are no research results in veterinary medicine that have shown a similar effect, however it is not too big of a stretch to assume similar results could be achieved. Dosage for this effect is probably 1 mg/kg once or twice daily, diuretic effects are expected at 2 mg/kg SID to BID though recent work has shown that spironolactone is not a diuretic in healthy dogs.

Pimobendan

Pimobendan is a novel agent that is both a positive inotrope and a vasodilator. It has other effects as well such as antioxidant capacity and antiplatelet effects. This agent has been marketed in Europe for many years and recently in Canada. It has been shown to be superior to ACE inhibitors as a sole agent in Dobermans with DCM. Inotropes had initially been the source of much interest in human cardiology. These medications will make the patient feel better. They however rapidly lost favor as they shortened lifespan considerably, probably by causing fatal arrhythmias. Pimobendan in human medicine has not been shown to have such a dramatic life-shortening effect, in some studies it even prolonged life. Of course in veterinary medicine quality of life has a major effect on quanitity of life since euthanasia is a common occurrence in patient's perceived to have a poor quality of life. This medication has much promise, though it is a yet unclear where exactly it fits in with standard therapy in many heart diseases. My experience with the medication has been very satisfactory.

The evidence does support that pimobendan is a superior drug to ACE inhibitors in dogs with mitral valve disease and heart failure as a sole agent. What we don't know yet is if the combination of an ACEi and pimobendan is as good or better than pimobendan as a sole agent. One concern is that pimobendan is clearly not indicated with early mitral changes, only once the dogs are in failure. It has been shown that in dogs with mitral valve disease that are not in failure pimobendan resulted in damage to the mitral valves and worsened the regurgitant fraction. As such veterinarians must be sure of their diagnosis which means that excellent radiographs and sometimes echocardiography are needed to be sure that failure is present, otherwise you could be doing harm to your patient.

References

COVE Study Group. Controlled clinical evaluation of enalapril in dogs with heart failure: results of the cooperative veterinary enalapril study group. JVIM 1995;9:243-252.

Hamlin RL, Benitz AM, et al. Effects of enalapril on exercise tolerance and longevity in dogs with heart failure produced by iatrogenic mitral regurgitation. JVIM 1996;10:85-87.

Ettinger SJ, Benitz AM et al. Effects of enalapril maleate on survival in dogs with naturally acquired heart failure. JAVMA 1998;213:1573-1577.

BENCH Study Group. The effect of benazapril on survival times and clinical signs of congestive heart failure: results of a multicenter, prospective, randomized, double-blinded, placebo-controlled, long-term clinical trial. J Vet Cardiology 1999;1:7-18.

Kvart C, Häggström J, et al. Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and symptomatic mitral regurgitation. JVIM 2002;16:80-88.

O'Grady, Proceedings ACVIM.

Rush JE, Freeman LM, et al. The use of enalapril in the treatment of feline hypertrophic cardiomyopathy. JAAHA 1998;34:38-41.

Amberger CN, Glardon O, et al. Effects of benazapril in the treatment feline hypertrophic cardiomyopathy: results of a prospective, open-label multicenter clinical trial. J Vet Cardiology 1999;1:19-26.