Treatment of hypertrophic cardiomyopathy lost dreams (Proceedings)

Treatment of cats with hcm and no clinical signs

There currently is no evidence that any drug alters the natural history of hypertrophic cardiomyopathy (HCM) in cats until they are in heart failure. Diltiazem, atenolol, ACE inhibitors and, possibly, spironolactone are commonly administered by veterinarians to cats with mild to severe HCM that are not in heart failure on an empirical basis in the hope that they will slow the progression of the disease. A recent survey of veterinary cardiologists revealed that less than 20% use diltiazem in these cases. However, 80% indicated that they did use some drug to try to slow the progression in those cats even with moderate disease.

Recent studies by the presenter have shown that ramipril, an ACE inhibitor, and spironolactone have no beneficial effects on HCM prior to the onset of heart failure (J Vet Intern Med 2006;20(5): 1093-1105; J Vet Intern Med 2008;22(2): 335-341). In addition, spironolactone produced severe skin lesions in some cats. In the first study we administered ramipril, an ACE inhibitor, to 13 Maine Coon and Maine Coon cross cats with HCM but without evidence of heart failure from the presenter's research colony at UCDavis for one year and placebo to the same number of cats in a blinded fashion. Left ventricular mass was quantified using MRI at baseline and again at the end of the study. Tissue Doppler imaging (TDI) was used to assess diastolic function over the year. Plasma neurohormones and ACE activity were measured. Ramipril adequately reduced (97%) plasma ACE activity, meaning the dose administered was therapeutic. Ramipril did not reduce LV mass nor did it improve diastolic function. There was no change in plasma aldosterone and BNP concentrations. We concluded that ACE inhibition is not beneficial for cats with HCM that are not in heart failure.

In the second study, we examined spironolactone in the same colony in the same types of cats. It was hypothesized that spironolactone would reduce myocardial fibrosis and in so doing improve diastolic function and possibly also reduce LV mass. Two-dimensional echocardiography and TDI were used to assess LV mass and diastolic function respectively in 13 Maine Coon and Maine Coon cross cats administered spironolactone and were compared to 13 cats on placebo. Cats were studied over a 4 month time frame. Plasma aldosterone concentration did increase in the cats on spironolactone, which documented that the dose was appropriate. There was no change in LV mass or improvement in LV diastolic function. In addition, 4 of the 13 cats on spironolactone developed a severe ulcerative dermatitis on their face. We concluded that spironolactone is not an appropriate drug in this population.

Beta-adrenergic receptor blockers

Beta blockers are primarily used to reduce systolic anterior motion (SAM) of the mitral valve and heart rate in cats with HCM. In humans, beta blockers are almost routinely used in an attempt to improve symptoms due to HCM although the exact means by which symptoms are improved is poorly understood. However, it is a consensus that beta blockers, when given in high doses to humans, reduce SAM during exertion. To quote a recent consensus statement by the American College of Cardiology and European Society of Cardiology regarding the use of beta blockers in human patients with HCM, “experience suggests that standard dosages of these drugs can mitigate disabling symptoms and limit the latent outflow gradient provoked during exercise when sympathetic tone is high and heart failure symptoms occur. However, there is little evidence that beta-blocking agents consistently reduce outflow obstruction under resting conditions. Consequently, beta-blockers are a preferred drug treatment strategy for symptomatic patients with outflow gradients present only with exertion.”

There is little doubt that the practice of using beta blockers in cats with HCM is a direct extrapolation from human medicine. That may be problematic. First of all, cats generally don't exert themselves. Instead, cats spend 85% of their life asleep and sleep certainly reduces sympathetic activity in cats better than any beta-adrenergic blocking drug. There is little doubt that cats with mild to moderate SAM in a veterinary clinic have no or milder SAM at home and the same can be said for tachycardia. However, it is also apparent that cats can get into very stressful situations (e.g., cat fights, chased by a dog) at times and it is possible that a beta blocker in those brief instances could be beneficial in preventing acute heart failure. Second, the dose used in cats by veterinarians is generally small in comparison to that used in humans.

Beta blockers are effective for reducing the severe SAM observed in clinical situations. At least one study has examined the effects of esmolol, a short-acting β1 - adrenergic blocking drug, in cats with HCM and obstruction to left ventricular outflow due to SAM and shown a reduction in the pressure gradient across the outflow tract. In that study the degree of outflow tract obstruction decreased and the heart rate slowed and esmolol was more effective than diltiazem.

In a recent pilot study we examined the effects of atenolol (12.5 mg BID for one month) on serum troponin level and NT-proBNP in 6 cats with severe HCM that were not in heart failure. The atenolol did not decrease either variable suggesting that it did not reduce myocardial hypoxia nor resultant myocyte necrosis.

Atenolol is a specifβ1 - adrenergic blocking drug that needs to be administered twice a day, usually at a total dose of 6.25 to 12.5 mg PO q12h. In cats, atenolol has a half-life of 3.5 hours. When administered to cats at a dose of 3 mg/kg, atenolol attenuates the increase in heart rate produced by isoproterenol for 12 but not for 24 hours.

In a recent survey of veterinary cardiologists regarding their preferences for treating cats with HCM, 70% used atenolol to treat cats with severe SAM while 50% used it to treat cats with mild SAM.

Treatment of cats in heart failure due to HCM

Cats that present in left heart failure primarily have clinical signs referable to pulmonary edema and/or pleural effusion. Consequently, therapy is generally aimed at decreasing left atrial and pulmonary venous pressures in these cats and physically removing pleural effusion. In some cats with severe heart failure, clinical evidence of hypoperfusion (low-output heart failure) may be apparent in addition to the signs of CHF (e.g., cold extremities, total body hypothermia).

Pulmonary edema is primarily treated with diuretics (almost exclusively with furosemide) acutely and chronically and an ACE enzyme inhibitor chronically, although there is some evidence to suggest that ACE inhibition may not be that helpful in prolonging survival in cats with HCM. Diltiazem and beta adrenergic blockers, usually atenolol, have been commonly used as adjunctive agents. Again, there is some evidence to suggest that diltiazem is not helpful in prolonging survival in cats with heart failure due to severe HCM and that atenolol may actually shorten survival time. Pleurocentesis is most effective for treating cats with severe pleural effusion. Furosemide is usually helpful at slowing effusion re-accumulation but repeated pleurocenteses are often needed to keep signs of heart failure in check.

Acute therapy

Cats that present with respiratory distress suspected of having heart failure secondary to HCM need to be placed in an oxygen enriched environment. If possible the cat should be initially evaluated by doing a cursory physical examination, taking care not to stress the patient during this or any other procedure since stress exacerbates dyspnea and arrhythmias and often leads to death. Most, but not all, cats with severe HCM that are in heart failure will have a heart murmur and many will have a gallop sound (gallop rhythm). A butterfly catheter should be used to perform thoracentesis on both sides of the chest to look for pleural effusion as soon as possible. Generally this should be done with the cat in a sternal position so that it does not become stressed during the procedure. Clipping of the hair is not needed. If fluid is identified, it should be removed. If none is identified, a lateral thoracic radiograph to identify pulmonary edema may be taken with the veterinarian present to ensure that the cat is not stressed.

Cats present in respiratory distress due to a number of respiratory and thoracic cavity diseases in addition to heart failure. Differentiation between left heart failure and respiratory failure may be difficult. Almost all cats with left heart failure will have moderate to severe left atrial enlargement. Consequently, if differentiation is difficult, assessment of left atrial size via radiography or echocardiography is one of the most useful diagnostic tests available. This is not always possible radiographically because of the presence of pleural effusion or other complicating factors. In general, it is relatively easy to determine left atrial size echocardiographically from the right side of the chest. Visualizing the left atrium and comparing it to the size of the aorta from a right parasternal short-axis view at the base of the heart is the most accurate means of doing this. A recent report has suggested that measurement of NT-proBNP serum concentration may be a reasonable means of making this differentiation. Unfortunately, no cageside test yet exists for doing this.

Furosemide

Furosemide should initially be administered IV or IM to the cat in severe respiratory distress due to pulmonary edema. Cats that can tolerate an IV injection may benefit from the more rapid onset of action (within five minutes of an IV injection vs. 30 minutes for an IM injection). The initial furosemide dose to a cat in distress should generally be in the 2-4 mg/kg range IM or IV. This dose may be repeated within 1 hour to 2 hours. Dosing must be reduced sharply once the resting respiratory rate starts to decrease to avoid severe dehydration.

High-dose parenteral furosemide therapy commonly produces electrolyte disturbances and dehydration in cats. Cats with severe heart failure that require intensive therapy are often precarious. They may be presented dehydrated and electrolyte-depleted because of anorexia. They may remain anorexic and consequently dehydrated and depleted of electrolytes once the edema and/or the effusion are lessened. Judicious intravenous or subcutaneous fluid administration may be required to improve these cats clinically. Overzealous fluid administration will result in the return of CHF. If fluid administration is required, the furosemide administration must be discontinued for that time.

Nitroglycerin

Nitroglycerin cream might be beneficial in cats with severe pulmonary edema secondary to feline HCM. However, no studies have examined any effects of this drug in this species and its efficacy is suspect. Nitroglycerin is certainly safe and some benefit may occur with its administration in some cats. Consequently, 1/8 "-1/4" of a 2% cream may be administered to the inside of an ear every 4-6 hours for the first 24 hours as long as furosemide is being administered concomitantly. However, one should never rely on nitroglycerin to produce a beneficial effect and its use is by no means mandatory. Nitroglycerin tolerance develops rapidly in other species and probably does so in the cat. Consequently, prolonged administration is probably of even lesser benefit.

Sedation or anesthesia

In some cats sedation with acepromazine (0.04 - 0.1 mg/kg subQ) may help by producing anxiolysis. Oxymorphone (0.04-0.1 mg/kg q6h IM, IV, or subcutaneously) or butorphanol tartrate (0.08 mg/kg IV or 0.36 mg/kg q4h subcutaneously) may also be used but can produce respiratory depression.

Once drug administration is complete the cat should be left to rest quietly in an oxygen enriched environment. Care should be taken not to distress the cat. A baseline measurement of the respiratory rate and assessment of respiratory character should be taken when the cat is resting. This should be followed at 30 minute intervals and furosemide administration continued until the respiratory rate starts to decrease (a consistent decrease of the respiratory rate from 70 to 90 breaths/minute into the 50 to 60 breaths/minute range is a general guide) and/or the character of the cat's respiratory effort improves. When this occurs, the furosemide dose and dosage frequency should be curtailed sharply.

In some cats with fulminant heart failure, anesthesia, intubation, and ventilation are required to control the respiratory failure. Although this method is not preferred for most severely dyspneic cats, it can be life-saving in some.

Chronic Therapy 

Many aspects of chronic therapy of HCM are controversial. All therapy is palliative and ultimately futile in most cases. Furosemide is the only drug that has a clearly beneficial effect chronically on survival in cats with HCM. An ACE inhibitor is usually given concomitantly. In a recent survey of veterinary cardiologists, all that returned the survey treated cats with HCM that were in heart failure with furosemide and an ACE inhibitor.

Pleurocentesis

Many cats with HCM are dyspneic because of pleural effusion that re-accumulates despite appropriate medical therapy. These cats need periodic pleurocentesis.

Furosemide

 In cats with CHF due to HCM, furosemide administration, once initiated, should almost always be maintained for the rest of the cat's life. In a few cases, furosemide can be discontinued gradually once the cat has been stabilized. This usually only occurs in a cat that has had a precipitating stressful event (e.g., chased by a dog) that does not have underlying severe HCM and does not have severe left atrial enlargement.

The maintenance dose of furosemide in cats usually ranges from 6.25 (½ of a 12.5 mg tablet) once a day to 12.5 mg PO q8h although the dose may be increased further if the cat is not responding to a conventional dose. We have administered higher doses (up to 37.5 mg q12h) than commonly recommended to a few cats with severe heart failure without identifying severe consequences as long as the cats were eating and drinking. Cats on high-dose furosemide therapy are commonly mildly dehydrated and mildly to moderately azotemic. However, they often continue to maintain a reasonable quality of life and so even moderate azotemia can often be ignored. The azotemia in this situation is prerenal in origin.

The furosemide dose needs to be titrated carefully in each patient. The owner should be taught how to count the sleeping respiratory rate at home and instructed to keep a daily written log of the respiratory rate. This is highly beneficial for making decisions regarding dosage adjustment in individual patients. Normal sleeping respiratory rate in a cat is usually in the 15-30 breaths/minute range but some cats will go up to as high as 40 breaths/minute.

ACE inhibitors

Although furosemide has been used to treat heart failure secondary to feline HCM for decades, the use of ACE inhibitors in cats with HCM is relatively recent because veterinarians shared the fears of their human medical counterparts that they would worsen SAM. Over the past 10 - 15 years it has become obvious to most veterinary cardiologists that ACE inhibitors do not worsen the clinical signs referable to HCM and a study has documented that SAM is not worsened by enalapril administration in cats. Many have believed and one study has suggested that ACE inhibitors improve the quality and quantity of life of cats with HCM. Preliminary evidence from a recent placebo-controlled and blinded clinical trial suggests that enalapril produces little to no benefit when compared to furosemide alone in cats with heart failure due to HCM. However, this study also included cats with unclassified (restrictive) cardiomyopathy and both cats with and without SAM. Subgroup analysis failed to change the conclusions of the study but the subgroups were small. In addition, this study has only been presented in abstract form (Fox, 2003). Consequently, it is the recommendation of this author to continue to use an ACE inhibitor such as enalapril in cats in heart failure due to HCM at a dose of 1.25 to 2.5 mg PO q24h. Generic enalapril maleate is available in 2.5 mg tablets.     

Diltiazem

 In cats with severe HCM that have or have had evidence of CHF, diltiazem or a beta adrenergic blocking agent are often administered. Beta blockers and calcium channel blockers (usually verapamil) provide symptomatic benefit in human patients. Their utility in cats with HCM is controversial although there is little doubt that neither drug produces dramatic benefits. Diltiazem, however, appears to produce no harm. Diltiazem is a calcium channel blocker previously reported to produce beneficial effects in cats with HCM when dosed at 7.5 mg q8h. Beneficial effects that have been reported include lessened edema formation and decreased wall thickness in some cats. In the author's experience only the rare cat appears to experience a clinically significant decrease in wall thickness and it is impossible to tell if this is due to drug effect or simply time. Rarely does it appear clinically that diltiazem controls CHF on its own or helps control pulmonary edema or pleural effusion when added on to furosemide therapy. Diltiazem does improve the early diastolic relaxation abnormalities seen in feline HCM. Whether this helps decrease diastolic intraventricular pressure and so decrease edema formation is unknown. Theoretically it should have little benefit in the resting cat with a slow heart rate. Slower myocardial relaxation during rapid heart rates may not allow the myocardium enough time to relax, resulting in increased diastolic intraventricular pressure. Consequently, diltiazem may help protect a cat that undergoes a stressful event. Incomplete relaxation and decreased compliance, however, are more plausible explanations for increased diastolic pressure due to diastolic dysfunction in feline HCM. In humans, diltiazem does not change left ventricular chamber stiffness and so does not alter passive diastolic function. Diltiazem decreases SAM, which may decrease the amount of mitral regurgitation, but beta blockers generally produce a greater decrease in the amount of SAM. Recent evidence suggests that diltiazem has no effect on survival time in cats with severe HCM and heart failure. Consequently, there currently appears to be no ethical mandate for its use in cats with heart failure due to HCM and it would appear that many veterinary cardiologists have abandoned its use.

In addition to its regular formulation (30-mg tablets in the USA), diltiazem is supplied as slow-release (long-acting) products. Cardizem CD is supplied as 180 mg capsules that contain hundreds of small capsules. The larger capsule can be opened and a number of the smaller capsules divided into groups of four (45 mg each) and placed in smaller gelatin capsules for administration. One capsule is then administered q24h. Dilacor XR capsules can be opened to yield 2, 3, or 4 60-mg tablets. This drug is dosed at 30 mg per cat PO q12h and produces a significant decrease in heart rate and blood pressure in cats with HCM for 12-14 hours. However, a recent study in dogs showed that breaking the tablet in two alters the pharmacokinetics of Dilacor XR.

Pimobendan

Pimobendan is generally thought to be contraindicated in cats with HCM. A positive inotropic agent should increase the severity of SAM and worsen end-systolic cavity obliteration. Pimobendan's effects on myocardial hypoxia are potentially detrimental. However, a recent abstract suggested that the drug can be used in cats with HCM that also have myocardial failure (increased end-systolic diameter and decreased shortening fraction).