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Cardiology Clarke E. Atkins, DVM, DACVIM (Internal Medicine & Cardiology) Department of Clinical Sciences North Carolina State University College of Veterinary Medicine Therapeutic Advances in the Management of Heart Disease: An Overview The management of heart failure can be logically divided by the specific disease, its severity, and the type of signs present. Below is a figure outlining the use of drug classes for heart failure, according to severity (NYHA classification) and a table with indications and dosages. Although controlled exercise has proved beneficial in human cardiac disease, some exercise restriction is logical in all forms of heart failure and can be progressively curtailed as the disease progresses. Since sodium retention is a major contributor to congestion, dietary NaCl restriction has long been used in the management of heart failure. Recently, it has become clear that extreme sodium restriction actually activates the renin angiotensin aldosterone system (RAAS) and may contribute to renal dysfunction, particularly when ACE I are used. Also it tends to make diets unpalatable. For these reasons, I now recommend only moderate salt restriction (e.g. senior, "early cardiac" or renal diets); although, terminally, more extreme NaCl restriction (e.g. a cardiac diet) may be necessary. Exercise and sodium restriction are instituted in NYHA phase II. Diuretic therapy has long been the cornerstone in the management of congestive signs. We now know that extensive diuresis also activates the RAAS system. For this reason, I do not recommend diuresis as monotherapy and the dosage should be minimized to avoid RAAS activation, dehydration, azotemia, and hypokalemia. With angiotensin converting-enzyme inhibitors (ACE I), the diuretic dosage can typically be reduced by 50%. Terminally, increasing levels of diuresis may, however, be necessary. Furosemide (Lasix) is by far the most commonly used diuretic. It is the drug of choice for emergency management of pulmonary edema. In refractory cases and in cases complicated by hypokalemia, potassium sparing diuretics may provide an additive effect. Diuretics are employed in late phase II or III. The old diuretic, spirononlactone, has found new promise in heart failure, as an aldosterone receptor blocker. Conventional vasodilator therapy has been largely replaced with the advent of ACE I. Nevertheless, nitroglycerin is useful in emergency situations to reduce preload and pulmonary edema and may be used chronically in refractory cases, as well. Hydralazine can be used to rescue dogs failing despite polypharmacy, to reduce cough due to severe mitral regurgitation, and possibly, to reduce pulmonary hypertension in heart failure due to HWD or other causes. In general, conventional vasodilators are employed in late phase III or phase IV. ACE I have become a cornerstone in the chronic management of heart failure and may be employed early (phase II) for reasons outlined above. There is evidence that they slow progression of heart failure in people and animals and they prolong life, improve quality of life, reduce electrolyte abnormalities, and blunt pathological remodeling. As suggested above, diuretic doses can and should be reduced in the presence of concomitant ACE-inhibition. In the case of enalapril (Enacard), the dose can be doubled in refractory cases. New agents (or new uses for older agents) have targeted the neurohormonal abnormalities attendant to heart failure. These include beta blockers, such as carvedilol or metoprolol to blunt the sympathetic nervous system in heart failure; neutral endopeptidase inhibitors (e.g. ecadotril) which interfere with the breakdown of ANP, a hormone which has many effects opposite that of the RAAS; and angiotensin II receptor blockers (e.g. losartan) which have similar effects as ACE-I., but by blocking receptors, rather than formation of angiotensin II. Antioxidants and anti-cytokine therapies will see use in the future as well. Positive inotropes, other than digoxin, have fallen largely into disfavor because they do not prolong life, may worsen arrhythmias and/or increase heart rate, can be given only intravenously, and newer therapies have replaced them. Dobutamine, dopamine, and amrinone can be used intravenously in cases of myocardial failure to rescue phase IV dogs. Digoxin, on the other hand, has enjoyed increased popularity because it is the only positive (although only weakly so) inotrope that is orally available, slows heart rate, and normalizes baroreceptor function. In addition, the RADIANCE and DIG trials in humans showed patients in heart failure denied digoxin had worsening of signs, quality of life, exercise tolerance and hemodynamic status. Digoxin is exquisitely indicated in heart failure with myocardial failure and, especially, if accompanied by SVT. A sound theoretical argument for digoxin can be made in dogs with heart failure, normal sinus rhythm and maintained myocardial function, however discretion must be used in these dogs as other drugs will control signs with less danger of toxicity. Therefore in some dogs (e.g. 4 pound Pomeranian with mitral regurgitation), the owner, inherent appetite, renal function, and severity of signs must be considered. In general, digoxin should be instituted in late phase II with myocardial failure and phase III (at same time as diuretic) in dogs without myocardial failure. Miscellaneous agents such as oxygen, morphine, dobutamine, dopamine, epinephrine, calcium chloride, etc., have special uses in severe heart failure (phase IV) and/or CPR. Taurine and carnitine are nutritional additives that respectively have been advocated for heart failure in cats and dogs. Taurine has all but eliminated feline dilated cardiomyopathy. The jury is still out regarding the overall utility and specific indications for carnitine in dogs. Cocker spaniels with dilated cardiomyopathy have responded to taurine plus carnitine supplementation. Fish oils may improve appetite and blunt cardiac cachexia and Coenzyme Q10 has its advocates in the management of heart failure dilated cardiomyopathy. I reserve bronchodilators for dogs with known (or suspected) lower airway collapse or other respiratory disease, but these agents do not represent part of my routine protocol for the management of heart failure. Lastly, some centers now employ new surgical procedures or interventions, such as mitral valve reconstruction, balloon valvuloplasty of the pulmonic and aortic valves, and percutaneous balloon or thorascopic pericardiotomy for the treatment heart failure.  Figure 1. Overview of management of heart failure. * Beta blockers are theoretically indicated in both MR and DCM. However, this author uses them only in the latter. **Furosemide, spironolactone, or both. NG=nitroglycerin, Hydral = hydralazine, Amlod = amlodipine. Additionally, antiarrhythmic agents are added when needed and digoxin is instituted prior to heart failure in atrial fibrillation. Medical Management of Factors Contributing to Signs of Systolic Heart Failure in Dogs Adapted from Atkins, CE: Atrioventricular Valvular Insufficiency in Allen DG (ed): Small Animal Medicine, Lippincott, 1992
*In most instances of mitral insufficiency, positive inotropic support is unnecessary. 1Not commercially available at the time of this writing. 2Calcium channel (verapamil and diltiazem) and Beta blockers (propranolol, esmolol, atenolol) should be used with caution in patients in heart failure. s.i.d. = once daily; b.i.d. = twice daily; t.i.d. = three times daily; q.i.d. = four times daily; IM = intramuscularly; IV = intravenously; SC = subcutaneously; PO = per os; prn = as needed. Management Of Heart Failure:
Neurohumoral Modulation, Diuretics, And Salt Restriction Our understanding of the pathogenesis and management of heart failure has markedly changed over the last 20 years. During this time we have learned that the heart may fail due to diastolic dysfunction, as well as systolic dysfuncton; that hemodynamic alterations and their managment are less important than the body's own maladaptive neurohormonal response to a fall in cardiac output; that drugs which improve hemodynamics may actually result in long-term harm; and that the greatest clinical benefits result from therapies which blunt the body's neurohormonal response in heart failure. In addition, there have been a plethora of new procedures, drugs, and even drug classes introduced for the management of cardiac disease. Some of the most important clinical ramifications of heart failure, such as dyspnea (due to pulmonary edema or pleural effusion) and ascites, are directly attributable to sodium and fluid retention resulting from activation of the renin-angiotensin-aldosterone system (RAAS). Management of the signs of congestive heart failure (CHF) has relied upon the use of natriuretic diuretics (furosemide), restriction of dietary sodium, and more recently angiotensin converting-enzyme inhibitors (ACE-I) which, by blocking aldosterone production, combat sodium retention and congestion. In addition, as vasodilators, ACE-I unload the heart, improving cardiac output and exercise, normalize electrolyte abberations, and blunt the pathological cardiovascular remodeling produced by angiotensin II and aldosterone. While off-loading therapy with the aforementioned drug groups can be life-saving, their use can be associated with adverse side-effects. Most notable of these are hypotension, azotemia, renal failure, and arrhythmias. Certain complications are more apt to occur when combinations of drugs are used. Because of the potential for such side effects, these drugs are best employed in specific sequence and combinations. The following discussion relates to their use in the management of chronic heart failure. Angiotensin Converting-Enzyme Inhibitors In landmark veterinary studies of enalapril in NYHA phase III and IV heart disease (moderate to severe heart failure), due to mitral regurgitation (MR) and dilated cardiomyopathy (DCM), enalapril improved survival by >100% as well as reducing pulmonary edema and, improving quality of life scores.1-3 Exercise capacity is also improved in dogs with experimental mitral insufficiency.4 Benazepril has likewise been shown to improve survival.5 ACE-I have proven to provide additional benefits in human patients by blocking pathological remodeling, presumably slowing progression of heart disease and by normalizing serum electrolyte concentrations. Today, ACE-I represent the cornerstone in the chronic management of CHF. They are indicated in virtually all cases of systolic heart failure in which they are tolerated. There was early concern regarding the renal safety of these compounds 6-8 and all ACE-I, which have enjoyed extensive clinical use, have been associated with renal dysfunction, usually temporary.9 There has been speculation that, at very high doses (180x the clinical dosage), ACE-I have direct nephrotoxic effects but it is generally felt that the major impact of ACE-I on the kidney, with clinically relevant dosages, is through production of hypotension, with reduced renal perfusion pressure and resulting in worsening of azotemia.10 To date, veterinary clinicians have had experience with enalapril, captopril, benazepril, and lisinopril. Of these, only enalapril has been extensively studied and is licensed for use in management of heart failure in the United States, though benazepril has been marketed in Europe and Canada. The active metabolite of benazepril is reportedly excreted both in the bile and in the urine so that lower serum concentrations are evident in experimental renal disease.11 The clinical relevance of this is unclear. Over 10 years of veterinary clinical experience with ACE-I (mainly captopril and enalapril) have taught us that their impact on kidney function is minimal even in the face of severe heart failure. When azotemia is observed, ACE-I are almost always being used in conjunction with diuretics and sodium restriction and hypotension results. Typically, cessation of diuretic therapy or reduction in the dosage results in the reversal of azotemia.9 In studies of enalapril in NYHA phase III and IV heart disease (moderate to severe heart failure), due to MR and DCM, there was actually a lower incidence of azotemia in the enalapril-treated group than the placebo-treated group.1-3,12 Furthermore, in a study of enalapril's role in the delay or prevention of heart failure due to naturally-occuring MR, showed that enalapril at the standard dosage of 0.5 mg/kg daily had no effect on serum creatinine concentrations, as compared to placebo.13 In fact, evidence is building to prove benefit when ACE-I are administered chronically to both human and veterinary patients with naturally-occurring and experimental renal failure.14-20 Mechanisms for this improvement are postulated to be the antihypertensive effect, reduction of angiotensin II-induced mesangial cell proliferation, and renal vasodilatory effects of ACE-I, the latter related to a fall in renal filtration pressure and proteinuria.14-16 Enalapril has recently been shown to reduce urine protein loss and reduce blood pressure in naturally-occurring canine glomerulonephritis.18 Likewise, benazepril reduced azotemia and proteinuria in a short-term study of experimental and naturally-occurring renal insufficiency in cats19 and lowered BUN and creatinine concentrations and blood pressure in cats with polycystic kidney disease.20 As mentioned above, ACE-I have the potential to produce symptomatic hypotension. This is due to the mixed vasodilatory effect of this group of drugs and is typically observed when ACE-I are used in conjunction with other off-loading therapies, such as vasodilators, diuretics, and sodium restriction. Hypotension is reversed by altering drug therapies but may be problematic in producing azotemia, inappetance, weakness, lassitude, and precipitating digitalis intoxication by reducing renal elimination. Beta-Blockers Beta-blockers, such as metoprolol and carvedilol have earned a place in the management of heart failure in human dilated cardiomyopathy.20a Their rationale is derived from the large body of evidence as to the harmful nature of the sympathetic nervous system (SNS) in the syndrome of CHF. Their use has been slowly accepted because of the negative inotropic effect and difficulties in titrating to an effective dose. Nevertheless, improved quality of life, exercise tolerance, and survival have all been experienced in multiple clinical trials with carvedilol and metoprolol. Carvedilol, a non-selective beta- and alpha-blocker also has oxygen radical scavenging capabilities and reduces endothelin release. Hence the drug, in addition to sparing the heart the effects of the SNS, is a vasodilator and antioxidant, reduces heart rate, and has antiarrhythmic properties.20b Carvedilol has 2 major drawbacks. First it is a negative inotrope so is difficult to use with severely symptomatic patients. Secondly, it is expensive. The first drawback is overcome by starting early in the disease process, avoiding its use in NYHA phase IV, and beginning at a very low dosage, titrating toward a target dose of 25 mg BID in a large breed dog. At NCSU, a Doberman pinscher would be started at 3.125 (or even 1.56) mg QD for 2 weeks, then BID x 2 weeks, then 6.25/3.125 mg for 2 weeks, etc, until a full dose of 25-50 mg daily, divided BID, is achieved or the patient shows signs of intolerance. If intolerance develops (usually lassitude, inappetance, and hypotension), the dosage is dropped to the last tolerated dosage for 2-4 weeks and then an attempt is made to increase as previously described. If the patient cannot tolerate increaseses in carvedilol, the last tolerated dosage is accepted as maximum. Human studies indicate that, while the benefit is lessened, sub-optimal dosages still provide benefits. The second drawback - cost - is overcome, if necessary, by using atenolol, a much less expensive, selective B1 receptor blocker. The compromise is the lack of vasodilatory and antioxidant properties and an inconvenient formulation for the early titration period. The dosage and titration schedule for atenolol approximates that of carvedilol, although fragmenting 25 mg tablets to 3.125 mg is challenging. There are not data on beta-blockers in naturally-acquired canine mitral regurgitation, though there are data in experimental models, indicating hemodynamic and remodeling benefit, using very high doses of atenolol. 20c Additionally, there are clear data indicating quality of life and survival benefit in humans with CHF, treated with beta-blockers. Unfortunately, dosing these agents is somewhat difficult in small dogs and this author has yet to routinely embrace this group of agents (carvedilol, atenolol, and metoprolol) in this setting, either before or after the onset of CHF. Aldosterone Receptor Blockers Spironolactone and eplerinone, aldosterone receptor blockers, used in the treatment of heart failure in humans, are thought to be effective by blocking the remodeling effects of aldosterone. It has been shown in people, but not dogs, that aldosterone and angiotensin II "escape" from ACE-inhibitor suppression weeks to months after institution of therapy.20d Spironolactone has been embraced by veterinary cardiologists for the treatment of CHF caused by dilated cardiomyopathy, mitral regurgitation, etc in dogs. As yet unpublished studies by Rausch and colleagues at NCSU demonstrated no risk for hyperkalemia in dogs treated concurrently with enalapril and spironolactone. The dosage used by this author for aldosterone receptor blockade is 0.5 mg/kg QD. The use of spironolactone as a diuretic is discussed below. Sodium Restriction The salt avidity that results from aldosterone secretion in heart failure has been well documented.21 Sodium restriction contributes to signs of congestion (pulmonary edema, ascites, pleural effusion) and hence reduction in salt intake is logical. There are little data on clinical outcomes with such strategy but stringent salt restriction with diuresis has been shown to reduce total body sodium stores while, paradoxically, blunting acute furosemide-induced diuresis.22 Roudebush demonstrated that neither moderate nor severe salt restriction alone caused azotemia in aged, normal dogs, but when furosemide (3.2 mg/kg b.i.d.) was coupled with severe (but not moderate) salt restriction, serum creatinine rose by 63% - more than twice as much as in dogs receiving a diet with a standard sodium content.23 Furthermore, both moderate and severe salt restriction activated the renin-angiotensin-aldosterone system (RAAS) and when furosemide was added to the regimen, there was nearly a 6000-fold increase in serum aldosterone concentration with severe salt restriction. Finally, it is well established that salt restriction increases the likelihood of azotemia with ACE-I therapy.10 One can conclude that sodium restriction, while logical and likely useful in reducing total body sodium concentration and diuretic requirements, is not without a toll. This toll represents the tendency to increase azotemia with concurrent diuretic and ACE-I therapy and to activate the RAAS. Use of moderate salt restriction (e.g., a diet designed for renal patients with .22% sodium by dry weight) early in heart failure is advisable, with severe salt restriction (.10% sodium by dry weight) being reserved for patients refractory to therapy. Concurrent diuresis should be avoided as long as possible and ACE-I should accompany sodium restriction and diuretic therapy. Diuretics The most widely used diuretic is furosemide, a loop diuretic. It is potent and, while life-saving, it has the potential to produce azotemia, hypotension, and electrolyte disturbances, to lower cardiac output and to activate the RAAS.23,24 Fatal arrhythmias have been associated with "non-potassium sparing diuretics".25 Furosemide is not primarily nephrotoxic, though it can potentiate other nephrotoxic drugs. It produces prerenal azotemia by dehydration and hypotension and has a synergistic effect in diminishing renal function when used with either ACE-I or sodium restriction.10,23,24 Furosemide is the drug of choice for life-threatening pulmonary edema. Otherwise, it should be used only as needed to control signs of congestion. In other words, because it activates the RAAS, lowers blood pressure and cardiac output, causes azotemia and electrolyte disturbances, and potentiates adverse effects of other cardiac therapies, it should not be used as a monotherapy (i.e., with the exception of emergency therapy, furosemide therapy should always be accompanied by an ACE-I) and should be used at the lowest dosage compatible with good quality of life. If azotemia develops in a patient receiving polypharmacy, the first change should be the decrement or cessation of furosemide. The aldosterone antagonist, spironolactone, has received renewed interest with a report that survival was prolonged in humans with heart failure when spironolactone (~0.3 mg/kg QD) was administered concurrently with conventional therapy in NYHA phase IV patients.26 Because spironolactone is a weak diuretic, particularly at the modest dosage used in this study, the investigators concluded that benefits were due to blunting the adverse effects of aldosterone. This drug might logically be used early in heart failure for this reason, but there are no data for early or pre-heart failure states. As mentioned above, we have seen no increase in electrolyte abnormalities with concurrent ACE-inhibition and adlosterone blockade. It is meant to compensate for temporary or incomplete suppression of aldosterone secretion by ACE-I and should be used concurrently with ACE-I. It is also employed as an adjunctive diuretic at 1-2 mg/kg QD-BID with a loop diuretic, such as furosemide. Enhanced diuresis is enjoyed when 2 diuretics work synergistically in different parts of the nephron. Conclusion Of the therapeutic strategies discussed, loop-diuretic therapy has the greatest potential for adverse side-effects (hypotension, azotemia, activation of RAAS, electrolyte disturbances and fatal arrhythmias). Therefore, except in emergencies, furosemide should not be used as a monotherapy and should be used at the lowest dosage preventing signs of CHF. Salt restriction has similar, but lesser effects on RAAS activation, and potentiates diuretic- and ACE-I-induced tendencies toward azotemia.3,4 Therefore, moderate, rather than severe salt restriction, is indicated until signs of heart failure become refractory. Of the off-loading theapies under discussion, only ACE-I have been shown to benefit heart failure while blunting other pathophysiological processes (RAAS activation, electrolyte abnormalities, aldosterone- and angiotension II-induced cardiac remodeling, and renal dysfunction). Therefore, if either azotemia or hypotension is noted in a patient being managed for heart failure, the diuretic should first be discontinued or the dosage reduced, being reinstituted as necessary. Reduction or cessation of ACE-I is employed only if altering the diuretic dosage is ineffectual. Though ACE-I are generally safe, BUN and creatinine, as well as serum potassium concentration and systemic blood pressure should be monitored periodically, particularly if sodium restriction and/or diuretic therapy are utilized concurrently. Finally, when any of these agents are utilized, either alone or in combination, if caution is exercised and hypotension avoided, there is little risk of significant renal impairment. Beta-blockers are indicated in DCM (NYHA Phase I, II, and III). Although theoretically indicated, this author does not employ this therapy routinely for this modality in MR. Aldosternone receptor blockers are useful in CHF, but their exact role is yet to be defined. I use spironolactone to aid in RAAS-suppression and to enhance diuresis in refractory CHF. REFERENCES
Feline Hypertrophic Cardiomyopathy 2003 HOCM, Silent??
Etiology and Pathophysiology Hypertrophic cardiomyopathy (HC/HCM) is the most prevalent feline cardiac disorder. It affects most commonly middle aged cats (average 6.5 years), but all ages are affected. There is a male predisposition (> 75%). In humans, there is an important hereditary predisposition for HCM in 55% of cases. In people, this disorder may be congenital or acquired, and probably represents a group of diseases. Although the etiology of feline HCM is unknown, the Persian and Maine coon cat have appeared to be predisposed in some case series, suggesting a genetic influence. A case-controlled study in our laboratory, which showed a trend toward a predisposition for Maine coon cats, was validated by work of Meurs, et al. which has shown that HCM in Maine coon cats is heritable as an autosomal dominant trait. Interesting work by Kittleson and associates suggested a potential etiologic role for excessive growth hormone secretion in some cases. As is the case with systemic hypertension, hyperthyroidism, and aortic stenosis, HCM is associated with marked left ventricular hypertrophy, but in this instance, no underlying cause can be identified. Cardiac lesions are typified by severe left ventricular concentric hypertrophy and secondary left atrial dilatation. Asymmetric septal hypertrophy (ASH), present in the majority of dogs and humans with HC, is present in only 30% of cats with HC. Histological cardiac myofiber disarray is reported in 27% of affected cats and only in those with asymmetric septal hypertrophy. Other histological features of feline HC include myocardial and endocardial fibrosis and narrowed coronary arteries. Dynamic aortic outflow obstruction, secondary mitral insufficiency, myocardial ischemia, and systemic arterial embolism (SAE) may complicate this syndrome. The left heart is predominately affected and clinical signs manifested as sudden death or, more commonly, acute left heart failure due to diastolic dysfunction. Pleural effusion is occasionally associated with HC. Systolic function is usually adequate or enhanced. Tilley and Lord demonstrated an elevated resting left ventricular end diastolic pressure (LVEDP) in feline HC. With the administration of isoproterenol, mimicking endogenous, stress related sympathoadrenal activity, the LVEDP pressure doubled. Left ventricular end diastolic pressure is indicative of pressures in the left atrium and pulmonary veins, which reflect the tendency for the development of pulmonary edema. In addition, during stressful situations, acceleration of the heart rate reduces cardiac filling time and myocardial perfusion. The former further diminishes cardiac volume and the latter results in relative myocardial ischemia in a rapidly beating heart with high oxygen needs, thereby, aggravating diastolic dysfunction. Stressful incidents, such as a car ride, restraint for an ECG, confrontation with a dog, or an embolic event may precipitate in left heart failure and pulmonary edema. Clinical Signs With the aid of ECG, thoracic radiographs, and echocardiography, a high percentage of cases of HC are diagnosed prior to the onset of symptomatology. Suspicion is raised in such instances when the attending clinician discovers a murmur, gallop, or arrhythmia. At the other end of the spectrum, cats may die unexpectedly with no prior signs. The most common clinical sign is the sudden onset of dyspnea, with or without evidence of SAE (the prevalence of which has ranged from 16 to 48%, in clinical and autopsy studies, respectively). Physical examination typically reveals a well fleshed, dyspneic cat with audible pulmonary crackles, murmur (50% of cases) typically loudest at the left apex, gallop (40%, usually S4), and/or arrhythmia (25 to 40% of cases). Heart sounds may be muffled. The oral mucosa is ashen, the pulses normal, weak, or absent (SAE), the apex beat may be hyperdynamic, and the liver may rarely be palpably enlarged. Cats with HC are generally not hypothermic, providing information useful in differentiation from DC. Diagnosis Diagnosis of HC is not difficult, but does require special testing to confirm clinical suspicions. Without the aid of echocardiography, dilated and restrictive (RC) cardiomyopathies can be difficult to distinguish from HC. This distinction is especially important in the case of DC, because it requires an entirely different therapeutic approach and prognosis. Other disorders that produce left ventricular and septal hypertrophy, such as hyperthyroidism, systemic hypertension, and aortic stenosis, must also be ruled out. The ECG is abnormal in 35 to 70% of cases and can provide useful diagnostic information. Many ECG findings are not specific, but left axis deviation and left anterior fascicular block are strongly suggestive of HC, but also may be recognized in RC, hyperkalemia, hyperthyroidism, and, rarely, DC. Other ECG abnormalities include P mitrale and P pulmonale (10% and 20%, respectively), tall R waves (40%), wide QRS complexes (35%), conduction disturbances (50%, including left axis deviation in 25% and left anterior fascicular block in 15%), and arrhythmias (55%, usually ventricular in origin). Thoracic radiographic findings suggestive of HC include cardiomegaly with a prominent left ventricle and atrium, and pulmonary congestion and/or edema. In the ventrodorsal projection, the heart may appear "valentine shaped," reflecting the concentric ventricular hypertrophy and enlarged left auricle. Additionally, the apex is often shifted to the right. On the lateral view, the heart is enlarged with increased sternal contact, left atrial prominence, left ventricular convexity, and a prominent caudal cardiac waist. Pleural effusion may be noted in 25 to 33% of cases in heart failure, but is usually of much less volume than that noted in DC. Nonselective angiography is of less risk in HC than in DC. This procedure typically reveals normal or enhanced circulation, pulmonary venous tortuosity, left atrial enlargement, small left ventricular lumen, thickening of the left ventricular wall, and papillary muscle enlargement. The diagnosis of SAE (usually located at the aortic trifuracton: saddle thrombus) can be confirmed by the finding of an abrupt termination of the dye column in the aorta at its trifurcation. Echocardiography is extremely useful for distinguishing HC from DC, but, because of overlap of echocardiographic reference values, differentiation of normal from asymptomatic HC and HC from RC may be difficult. Concentric left ventricular hypertrophy and left atrial enlargement are features useful in confirming the diagnosis of HC. Cardiac function is normal to exaggerated, due to diminished afterload and possibly hypercontractility. Systolic anterior mitral valve motion may be evident, suggesting dynamic aortic outflow obstruction. If present, ASH, left atrial thrombi, pleural effusion, and/or pericardial effusion may be evident. In the case of sudden death, the diagnosis is made at necropsy by disclosure of typical gross and histologic cardiac pathology. Other laboratory findings, with the exception of hypotaurinemia, are similar to that described for feline DC. Differential diagnoses are also similar with the addition of restrictive pericarditis and emphasis of systemic hypertensive and hypertrophic thyrotoxic heart disease. Therapy The treatment of HCM is different than that of DCM (systolic myocardial failure) and entails the goals of reducing LVEDP, abolishing sinus tachycardia and other arrhythmias, improving myocardial oxygenation, and alleviating and preventing pulmonary edema. Positive inotropic agents are not needed and generally contraindicated because they may increase LVEDP and aggravate outflow obstruction. The latter precaution should be exercised in the use of arterial vasodilators and, to a lesser degree, preload reducing agents (diuretics and mixed or venodilators). Diuretic therapy is indicated to eliminate pulmonary edema. Furosemide is the diuretic of choice in emergencies because it reduces LVEDP and, hence, left atrial, and pulmonary venous pressures through diuresis and venodilation. In the emergency situation, treatment with parenteral furosemide (2 4 mg/kg IV or IM) is accompanied by the use of topical nitroglycerin (1/8 1/4 inch tid qid for first 24 hours, then "8 hours on, 8 off" only if necessary) and oxygen supplementation (40%). Although furosemide diuresis is usually successful, the addition of enalapril (.25-.5 mg/kg sid) is indicated in refractory cases or when biventricular failure (pleural effusion) ensues. It should be kept in mind that drugs which reduce preload (and afterload) may worsen outflow obstruction in hypertrophic obstructive cardiomyopathy (HOCM). Drugs that enhance ventricular relaxation and slow the heart include the beta adrenergic (atenolol), and calcium channel (diltiazem) blockers. Such therapy is indicated in treatment of the diastolic failure of HCM. Beta blockers improve diastolic performance only indirectly, enhancing ventricular filling by reducing heart rate and improving myocardial perfusion. Traditionally, beta-blockers have been administered orally after stabilization (24 to 36 hours after institution of diuretic therapy) to reduce and prevent elevations in LVEDP, to lower systolic pressure gradients and myocardial oxygen requirements, to prevent stress induced tachycardia and reduce resting heart rate, and for its antiarrhythmic effects. When arrhythmias are present, this drug may be initiated earlier in the disease course. This is the author's treatment of choice for asymptomatic HCM, for cats with documented outflow obstruction (HOCM), and when tachycardia persists. Calcium channel blocking agents have been effective in human HCM by reducing heart rate, myocardial oxygen consumption, and diastolic dysfunction. In addition to directly enhancing myocardial relaxation, these drugs dilate peripheral and coronary arteries. Bright has demonstrated the utility of diltiazem (3-7.5 mg po tid) in the treatment feline HCM, including those cases refractory to the beta-blocker, propranolol. Unfortunately, current packaging for human use, makes accurate feline dosing of diltiazem difficult. Long-acting diltiazem may be substituted and includes Cardizem CD (45 PO sid; requires disassembling capsules) or Dilacor (30 mg PO bid; requires disassembling capsules). Combining a calcium channel blocker and a beta blocker has theoretical advantages and is often done, using a long-acting form of each drug, one in the morning and one in the evening. There is no role for amlodipine in the normotensive cat with HCM as it has no theoretical or proven benefit and it may precipitate hypotension. A report by Rush, et al. demonstrated a reduction in wall thickness with the administration of enalapril to cats with HCM. This suggests a potential role for ACE-inhibitors in the treatment of HCM. These drugs are generally safe and do play a role in cases which are refractory or in which pleural effusion is present. In asymptomatic patients, it is logical that the renin-angiotensin-aldosterone system is not pathologically activated, and hence ACE-inhibitors might not be useful. Rush's data argue that they may play a role, however. Further studies are being planned. Enalapril is used at .5 mg/kg daily. Drugs other than those described above should be used sparingly and with caution Digoxin, while generally contraindicated in HCM, may be used when supraventricular arrhythmias are refractory to calcium channel and beta adrenergic blocking agents. Other therapies, including oxygen, aspirin or low molecular weight heparin, home confinement, and moderate salt restriction should be instituted as needed. Taurine supplementation is not indicated in the treatment of HCM. In asymptomatic cats with HCM, the author advises home confinement, moderate salt restriction, Beta- and/or calcium channel blockade, and aspirin indefinitely. Patient Monitoring Cats with asymptomatic HCM should be evaluated at 12 month intervals, while those with symptoms should ideally be seen more frequently until stabilized for a period of time. The prognosis for asymptomatic HCM is guarded to good, with a median survival of over 5 years. Cats presented in heart failure survive a median of approximately 3 months (though 20% live longer than 3 years; recent work by Rush and associates show that current therapeutic strategies have improved survival in heart failure due to HCM), while cats with emboli survive a median of approximately 2 months. Cardiovascular Formulary for Cats
*Selected name brands; some available as generic. **Most appropriate formulations for cats - other sizes available for many drug Feline Hypertension: Risks and Management Recognition and therapy of systemic hypertension in cats is an important aspect of small animal geriatric medicine. Target organs of hypertension include the heart and vessels, the brain, the kidney, and probably most importantly, the eye.1 Our experience has shown that hypertensive cats have associated disease, in order of prevalence, of the eye, kidney, heart, and central nervous system.1 The etiology and pathogenesis of hypertension in cats is largely unknown, but associations with hyperthyroidism, hyperaldosteronism, and renal failure have been recognized. A recent report on 69 cases seen at North Carolina State University (NCSU) for ocular disease revealed that at least 17%, and possibly as many as 50%, of cats have no identifiable cause of systemic hypertension (primary or essential hypertension).1 The renin-angiotensin-aldosterone system (RAAS) is probably abnormally activated in many or, perhaps, most cats with systemic hypertension and certainly is activated after therapy with such drugs as loop diuretics and vasodilators.2,3 Therapies for feline hypertension have varied and have not often been systematically evaluated. Therapies that have been employed and reported upon include diuretics (furosemide and spironolactone), angiotensin-converting enzyme inhibitors (ACE-I; captopril, enalapril, and benazepril), beta-blockers (propranolol and atenolol), and calcium channel blockers (diltiazem and amlodipine). Littman, retrospectively evaluated 24 cats with chronic renal failure (CRF), found that the most effective antihypertensive therapy was the combination of a beta-blocker and an ACE-I and that there was a poor response to furosemide.4 Jensen prospectively studied 12 similarly affected cats and found that the response to an ACE-I or beta-blocker alone was poor.5 Another retrospective study of 12 hypertensive cats with CRF and unresponsive to other therapy showed amlodipine to lower blood pressure by >20% in 11.6 Snyder demonstrated blood pressure control in a randomized, blinded, placebo-controlled study of amlodipine in hypertensive cats, as well.7 Finally, the NCSU study retrospectively found amlodipine to lower blood pressure >20% in 30 of 32 hypertensive cats with 28 becoming normotensive.1 Diltiazem and beta-blockers alone or with ACE-I also lowered blood pressure in the majority of cats so treated. The literature and clinical experience would, nevertheless, lead one to appropriately conclude that amlodipine is the single best agent for the management of feline systemichypertension. This said, beta-blockers have a specific role in slowing heart rate and blocking the cardiovascular effects of T3 in hyperthyroidism; ACE-I in combating drug-induced or spontaneous activation of the RAAS, for preserving renal function8,9, and for proven effects in lowering blood pressure10,11; spironolactone for its aldosterone-antagonistic effects12; and furosemide (possibly with nitroglycerin) for use in heart failure accompanying hypertension (See Table). Other therapeutic considerations include: whether there is activation of the RAAS, the role of the sympathetic nervous system, renal function and the effects of hypertension on renal function, salt intake, presence of heart failure (uncommon), and the presence of reversible causes of hypertension (e.g. hyperthyroidism, diabetes mellitus, pheochromocytoma). Additionally, I try to limit the number of pills to 1 (or 2) daily to reduce strain on the human-animal bond. In deciding on a therapeutic approach (See Fig), the author divides cats as follows: reversible cause - yes or no; with or without presumed RAAS activation (renal failure, heart failure, or treatment with vasodilators or loop diuretics); and by presence or absence of tachycardia (>200 bpm). The only common treatable cause of feline hypertension is hyperthyroidism, which is treated with methimazole, surgery, or 131I. In these cats, because of the effects of T3 on beta receptors, I employ a beta-blocker, such as atenolol (6.25-12.5 mg PO daily), to reverse the cardiovascular effects of hyperthyroidism prior to or until more definitive therapy is efficacious. If unsuccessful, I add enalapril at 0.5 mg/kg/day PO. In all cases, I employ a moderately salt-restricted diet (one designed for kidney patients) to lessen total body sodium without worsening renal function or severely activating the RAAS. In the euthyroid, non-tachycardic cat with hypertension, the somewhat complex algorithm described below can be avoided by merely administering amlodipine and enalapril each day. I advise 1 tablet in the AM and 1 in the PM, if the owners' schedule allows. If this is not successful, see the material below. RAAS Not Activated If the RAAS is not thought to be activated (this may be an erroneous assumption) and tachycardia is not problematic, the approach is as follows: amlodipine (0.625 mg to 1.25 mg PO daily, or even higher if unresponsive) plus a moderately salt-restricted diet and enalapril. The ACE-I is used to counteract activation of the RAAS, produced by the vasodilator effect of amlodipine.3 If unsuccessful, I first double the dosage of amlodipine, then sequentially add atenolol and finally diuretics (furosemide at 6.25-12.5 mg daily or spironolactone at 1-2 mg/kg daily PO), if needed. It should be pointed out that, in cats unresponsive to amlodipine plus a second drug, owner compliance should be evaluated. If tachycardia is present (without RAAS activation), I begin with moderate salt restriction and atenolol. With atenolol monotherapy, even though heart rate typically falls, blood pressure control is often inadequate. In that circumstance, I, sequentially add amlodipine plus enalapril, then, if needed, double the amlodipine dosage, and finally add a diuretic. On the other hand, if heart rate control is not initially successful, the atenolol dose is first increased. If this does not bring the exam room heart rate to <160 or the at home heart rate to <140, I would substitute diltiazem (DilacorR at 30 mg PO bid) for amlodipine to better control heart rate and then follow the same sequence. RAAS Abnormally Activated When conditions (heart failure, renal failure, or drug therapy) indicate the RAAS is inappropriately activated, I begin therapy with amlodipine, a moderately salt-restricted diet and enalapril (See Fig). If a normotensive state does not result, I add, sequentially, atenolol and finally diuretics (furosemide or spironolactone). Alternatively, if tachycardia is a concern, moderate salt restriction, atenolol, and enalapril would be used initially. If unsuccessful control of hypertension results, amlodipine would be added, and followed sequentially, as needed, by a doubling of the amlodipine dosage, and finally diuretic therapy if needed. If after initial therapy, heart rate control is inadequate, the atenolol dose is first increased. If this does not adequately control heart rate, I would substitute long-acting diltiazem (DilacorR at 30 mg PO bid) for amlodipine to better control heart rate and then follow the step-wise sequence mentioned above for blood pressure control, if needed. Heart failure secondary to hypertension is rare and will not be discussed except to say that diuretics will likely be necessary in such patients to control signs and that enalapril is indicated. Lastly, if renal failure or significant renal disease is present, the etiology should be sought (at least by urinalysis and culture) in the hopes of finding a reversible cause. Otherwise, treatment of renal disease is standard and beyond the scope of this manuscript. It is wise to consider the routes of excretion of the drugs being used in deciding dosage and dosing interval in the face of renal insufficiency. Lastly, hypotension may infrequently occur as a result of over-exuberant anti-hypertensive therapy. This should be avoided as it may further compromise renal function. The prognosis, overall, for hypertension is guarded but not grave. Vision lost rarely returns but survival averages have ranged from 18-21 months from the date of diagnosis.1,3 REFERENCES
 Figure An algorithmic approach to treating hypertension in cats. See text for details. *If a loop-diuretic is used, always administer and ACE-Inhibitor. Diuretic therapy might alternatively include an aldoterone-receptor-blocker (spironolactone). NaCl-x = sodium restricted diet. Amlod = amlodipine. Cardiovascular Formulary for Hypertensive Cats
*Selected name brands; some available as generic. **Most appropriate formulations for cats - other sizes available for many drugs. |
