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Principles of Therapy of Cardiovascular Disease

By Suzanne M. Cunningham, DVM, DACVIM (Cardiology), Department of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University ; Kursten V. Roderick, DVM, Tufts University

Although therapy is disease-specific, there are some general goals of therapy for heart disease: 1) Chronic stretch on myocardial fibers should be minimized, because chronic stretch injures and irritates fibers, causes them to consume excess quantities of oxygen, and leads to their death and replacement by fibrous connective tissue (remodeling). 2) Edema fluid should be removed because it makes the lungs wet, heavy, and stiff and causes ventilation-perfusion inequalities, impairs oxygen diffusion, and fatigues muscles of ventilation. 3) Cardiac output should be improved, and the amount of regurgitation (most often mitral regurgitation) decreased. Improved cardiac output enhances blood flow to important organs, and reducing mitral regurgitation decreases stretch and reduces pressures in the left atrium and pulmonary veins, thus reducing pulmonary capillary pressure and edema formation. 4) Heart rate and rhythm should be regulated. A heart beating too slowly fails to eject enough blood, whereas a heart beating too rapidly does not have time to fill adequately and consumes too much oxygen at a time when there is too little coronary blood flow. A heart beating too irregularly may deteriorate into ventricular fibrillation and sudden death. 5) Oxygenation of the blood should be improved. Inadequate oxygenation leads to inadequate energy to fuel both contraction and relaxation of the myocardium. Inadequate oxygenation of the myocardium may also lead to myocardial fibrosis and arrhythmia. 6) The likelihood of thromboembolism should be minimized. Cats with hypertrophic cardiomyopathy may shed emboli from the enlarged left atrium, which may block major arterial branches and lead to ischemia and death. 7) Mature heartworms and microfilariae should be killed. Mature heartworms may initiate severe changes in the pulmonary arteries that ultimately impede blood flow through the lungs.

The ultimate goals of therapy for cardiovascular disease are achieved when treatment resolves the presenting clinical signs, the respiratory and heart rates are not increased at rest, and quality of life is good for both pet and owner.

Common Therapeutic Agents

Furosemide is a loop diuretic that decreases resorption of sodium, chloride, and potassium in the thick ascending limb of the loop of Henle. It is also a venodilator when used IV. It is the most important and effective means to remove edema fluid from animals with heart failure and frequently is lifesaving in the short term. Diuresis with furosemide may be augmented by using thiazide diuretics (eg, hydrochlorothiazide). Thiazides suppress resorption of sodium and water at the distal renal tubules. When using a loop diuretic and a diuretic that works at the distal tubules, the ability of the kidneys to conserve water is reduced dramatically, so dehydration and hypokalemia may develop. This may be signaled by worsening azotemia, and renal values must be monitored closely in animals on multiple diuretics. Torsemide is a loop diuretic that is 10 times more potent than furosemide; it is reserved for refractory CHF or in cases of suspected diuretic resistance to furosemide.

Spironolactone is a potassium-sparing diuretic that blocks the effects of aldosterone. Like thiazides, it exerts its effect principally at the distal convoluted tubule. Although spironolactone effectively maintains potassium levels, data suggest that it does not induce a significant diuretic effect. However, spironolactone minimizes remodeling of both blood vessels and the heart, and like angiotensin-converting enzyme (ACE) inhibitors and β-blockers, has been shown to decrease symptoms and to prolong the lives of people and perhaps dogs with heart failure. Aldactazide, a combination diuretic consisting of spironolactone and hydrochlorothiazide, may be used in cases of refractory CHF. Renal values should be monitored closely because of the risk of worsening azotemia and renal failure with aldactazide therapy. Amiloride and triamterene are also potassium-sparing diuretics; however, these drugs are not typically used in veterinary medicine.

Digitalis glycosides exert their effects by inhibiting membrane Na+/K+-ATPase. This increases intracellular sodium, which activates the sodium-calcium pump that increases intracellular calcium. Digoxin increases the force of myocardial contraction (to a minor degree), slows the heart rate, and improves baroreceptor function. Digoxin has a narrow therapeutic index; thus, serum levels should be monitored, and animals should be watched for signs of toxicosis (vomiting, diarrhea, inappetance, arrhythmogenesis).

Enalapril, benazepril, lisinopril, and ramipril are ACE inhibitors commonly used in heart failure management in dogs. They are all equally effective at blocking the conversion of angiotensin I to angiotensin II. They minimize remodeling of both blood vessels and myocardium. They are part of the mainstay treatment regimen for advanced cardiac disease and heart failure.

Amrinone and milrinone, analogues of theophylline that deactivate other forms of phosphodiesterase, are potent IV inodilators. That is, they are both positive inotropes and vasodilators. However, they have been associated with worse outcomes in people with CHF and are not commonly used. Pimobendan, a calcium-sensitizing agent and phosphodiesterase inhibitor, is another inodilator shown to improve the quality of life and improve survival in dogs with CHF. Pimobendan is not approved for use in cats but may be beneficial in cats with heart failure (that do not have evidence of outflow tract obstruction). Sildenafil is a potent phosphodiesterase inhibitor used to treat moderate to severe pulmonary hypertension in dogs. Sildenafil has been shown to improve exercise intolerance and quality of life in people and dogs with pulmonary hypertension via pulmonary arterial vasodilation. There may also be additional beneficial effects on vascular remodeling and cardiac function.

Both procainamide and quinidine, class IA antiarrhythmics used formerly to manage ventricular arrhythmias, have been superseded by the class III antiarrhythmics sotalol and amiodarone, and the class IB antiarrhythmic mexiletine for treatment of malignant ventricular arrhythmias. Sotalol is used to treat both supraventricular and ventricular tachyarrhythmias, and it is particularly effective in treatment of Boxers with arrhythmogenic right ventricular dysplasia, either alone or in combination with mexiletine. Amiodarone is useful to manage all forms of arrhythmias, including ventricular arrhythmias, and rate control or conversion of atrial fibrillation. Increased liver enzymes and hepatotoxicity are potential adverse effects of amiodarone; thus, liver enzymes and serum amiodarone levels should be monitored periodically throughout therapy. Lidocaine, a class IB antiarrhythmic, is used only IV for emergency ventricular arrhythmias such as sustained ventricular tachycardia or R-on-T morphology.

Atenolol, propranolol, and metoprolol are oral β-blockers, and esmolol is an IV β-blocker, that slow the heart rate, suppress arrhythmias, and up-regulate adrenergic receptors. Carvedilol is a β- and α-adrenergic blocker that scavenges oxygen-free radicals. Like ACE inhibitors and spironolactone, carvedilol has been shown to both prolong life and decrease symptoms in people with heart failure; however, β-blockers are not generally advised for use in animals with active CHF. β-blockers are often used to treat dogs with subaortic stenosis, and for dynamic outflow obstruction in cats with hypertrophic cardiomyopathy.

Diltiazem is a calcium-channel blocker used to slow ventricular rate in animals with atrial fibrillation or supraventricular tachycardia. It is also used occasionally in cats with hypertrophic cardiomyopathy and outflow tract obstruction.

Atropine and glycopyrrolate block the effects of the vagus nerve on the SA node. Because the vagus nerve slows discharge of the SA node and heart rate, these compounds speed heart rate and may be useful when the heart beats too slowly. Nitroglycerin is a venodilator usually applied in a paste form to the skin inside the earflap or the mucous membranes; venodilation causes blood to pool in the dilated peripheral veins and splanchnic organs, decreasing left ventricular preload and pulmonary edema. Sodium nitroprusside is another nitrate that is a veno- and arterial dilator. Nitroprusside can be administered IV to treat acute fulminant CHF. These two medications should never be given simultaneously. Aspirin, clopidogrel, dalteparin, enoxaparin, and coumadin are antithrombotics that may prevent thromboembolism in cats with cardiomyopathy. Rivaroxaban is an oral factor Xa inhibitor that may prove useful for thromboprophylaxis in cats and dogs, although further studies are needed to evaluate its dosing and safety. Taurine and l-carnitine are amino acids used to prevent dilated cardiomyopathy in cats and in a limited number of dogs, respectively. Melarsomine is used to kill mature heartworms; ivermectin, milbemycin, and selamectin are used to kill microfilariae. Doxycycline should be administered to target Wolbachia, an intracellular bacteria that has a symbiotic relationship with heartworms.

Pimobendan and ACE inhibitors have been proved to be safe and effective to treat dogs with heart failure. Furosemide and digoxin are approved but without data proving either safety or efficacy. Use of other agents to manage heart failure or rhythm disturbances is based on anecdotal evidence or unblinded, uncontrolled reports and clinical experience.