Progression Of Heart Failure

By | 2011-12-12

Traditionally heart failure has been perceived as a hemodynamic disorder that promotes weakness, the development of debilitating congestive signs, deterioration of cardiac function, and ultimately death. Although the initial cardiac insult varies, it was historically rationalized that ventricular remodeling and disease progression occur as consequences of the compensatory mechanisms that promote vasoconstriction and fluid retention. It was recognized that diseased hearts operate on a depressed and flattened Frank-Starling curve, such that volume retention and vasoconstriction, rather than promoting cardiac output, merely exacerbated congestive heart failure. The symptoms of heart failure developed as venous pressures breached the lymphatics’ ability to remove edema or as blood flow to exercising muscles was severely limited.

If disease progression were solely mediated by hemodynamic alterations, it was hypothesized, drugs capable of “unloading” the heart (e.g., vasodilators and positive inotropes) would retard this progression and improve survival. In the first Veterans Affairs Heart Failure Trial (V-HeFT) completed in 1985, prazosin or a combination of hydralazine and isosorbide dinitrate was used to decrease preload and afterload. Although prazosin was more effective at reducing blood pressure, only the hydralazine/isosorbide dinitrate combination reduced mortality compared with placebo. The discordance between the hemodynamic and prognostic findings could not be explained by the traditional perception of heart failure. Support for the hemodynamic hypothesis was further undermined by the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial completed in December of 1994, which found that administration of amlodipine to patients with severe chronic heart failure had no significant effect on mortality.

Similar to the use of vasodilators to decrease ventricular wall stress and increase cardiac output, potent inotropic drugs capable of increasing cyclic adenosine monophosphate levels were developed with the intent to improve survival. If poor pump performance were responsible for the progressive nature of heart failure, it was hypothesized, these positive inotropes should alter the natural course of cardiovascular disease. The phosphodiesterase inhibitor milrinone, which has potent inotropic and vasodilative properties, in fact was found to alter the course of heart failure but in a fashion opposite that expected. In October of 1990, the Prospective Randomized Milrinone Survival Evaluation (PROMISE) trial was stopped 5 months prior to its scheduled completion date because administration of oral milrinone was found to increase all-cause mortality by 28%. Patients with the severest symptoms (i.e., New York Heart Association (NYHA] class IV), who therefore would be the most likely to receive additional medical therapy, showed a 53% increase in mortality. Administration of the partial beta-agonist xamoterol also failed to improve survival in a study of 516 patients.

These drug trial failures were accompanied in the late 1980s and early 1990s by an evolution in the understanding of the traditional hemodynamic model of heart failure. It still was recognized that hemodynamic alterations accounted for the symptomatic manifestations of cardiac disease, but a new understanding of the condition resulted in the conclusion that the body’s compensatory neurohormonal mechanisms contributed to the dilemma of disease progression. Activation of the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS) was found to promote both adverse hemodynamic consequences and direct toxic effects on the myocardium. Cultured mammalian cardiomyocytes exposed to norepinephrine displayed a concentration-dependent decrease in viability that was attenuated significandy by beta-receptor blockade. In addition, norepinephrine was implicated in the provocation of ventricular arrhythmias and the impairment of sodium excretion by the kidneys. Pathophysiologic levels of angiotensin II were found to promote myocytolysis with subsequent fibroblast proliferation, and aldosterone was implicated in the process of myocardial extracellular matrix remodeling. These findings established a connection between hemodynamic mechanisms and neurohormonal consequences, which mutually promote a cycle of disease progression. The initial cardiac insult is followed by activation of neurohormonal compensatory mechanisms that produce further hemodynamic alterations and myocardial fibrosis. Cardiac output continues to decline, the compensatory mechanisms continue to be activated, and the disease process proceeds unabated.

This more complete understanding of the neurohormonal systems led to the development and use of drugs designed to antagonize the RAS. A breakthrough in the management of cardiovascular disease came with the utilization of angiotensin-converting enzyme (ACE) inhibitors in the mid to late 1980’s. Angiotensin-converting enzyme is capable of degrading vasodilative bradykinin and is responsible for cleaving relatively inactive angiotensin I to the potent vasoconstrictor angiotensin II (AT II). Indirectly angiotensin-converting enzyme is responsible for aldosterone production, because AT II is a primary stimulus for adrenal gland production of mineralocorticoids. Given angiotensin-converting enzyme’s critical position in the RAS, it was proposed that angiotensin-converting enzyme inhibition may promote beneficial hemodynamic and neurohormonal antagonistic and antifibrotic actions.

The angiotensin-converting enzyme inhibitor enalapril has been extensively studied in humans with varying stages of heart failure. In three studies, compared with placebo or the combination of hydralazine and isosorbide dinitrate, enalapril reduced all-cause mortality in humans with a reduced ejection fraction and heart failure.

In another study, compared with placebo, enalapril did not reduce the mortality rate in asymptomatic patients with reduced ejection fraction, although it delayed the onset of heart failure. Because angiotensin-converting enzyme inhibitors have been shown to alleviate symptoms, improve patients’ clinical status, and decrease mortality, the current recommendation is that all humans with heart failure due to left ventricular systolic dysfunction receive an angiotensin-converting enzyme inhibitor. The mortality reductions associated with administration of angiotensin-converting enzyme inhibitors lends support to the theory that disease progression is mediated by factors other than hemodynamics alone.

Management of Stable Compensated Congestive Heart Failure

Deficiencies of the Triple Drug Regimen

Potential therapeutic strategies

Management of Refractory Congestive Heart Failure

Management of Heart Failure Secondary to Diastolic Dysfunction

Maintenance Therapy

After stabilization, furosemide is switched to oral administration and the dose is decreased (6.25 mg given twice daily) to prevent excessive preload reduction, dehydration, and hypokalemia. In cases of hypertrophic cardiomyopathy, additional drugs may be instituted to reduce the heart rate and improve diastolic filling. Drugs frequently used in the management of HCM include the beta blocker atenolol and the calcium channel blocker diltiazem. Calcium channel Mockers theoretically can exert a beneficial effect in the management of HCM by modestly reducing the heart rate and contractility, thereby diminishing myocardial oxygen demand. Diltiazem may promote a direct positive lusitropic effect, and verapamil may partially reduce coronary endothelial dysfunction compared with propranolol. Atenolol (6.25 to 12.5 mg given orally every 12 to 24 hours) appears to exert better rate control and more consistently alleviates left ventricular outflow tract obstruction compared with diltiazem. Beta-adrenergic blockade may also prevent myocardial fibrosis by inhibiting catecholamine-induced cardiotoxicity and ยป may combat ventricular arrhythmias by decreasing myocardial oxygen consumption. One theoretical disadvantage of the use of beta blockers in the management of diastolic dysfunction is that phospholamban is an inhibitory protein that controls the rate of diastolic calcium uptake into the sarcoplasmic reticulum. Beta-adrenergic stimulation phosphorylates phospholamban and removes this inhibitory effect. Beta blockade may prevent this phosphorylation (and therefore decrease diastolic calcium uptake) and further impair the active process of ventricular relaxation.

Similar to beta blockers, with their proposed neurohormonal benefits, angiotensin-converting enzyme inhibitors likely are beneficial in the management of feline HCM. The authors have seen cats with symptomatic cardiomyopathy show marked neurohormonal activation. With this finding, and with the frequent requirement for furosemide to control pulmonary edema, it appears prudent to use enalapril (1.25 to 2.5 mg given orally every 12 to 24 hours) in the management of diastolic dysfunction. Although there is concern that afterload reduction may precipitate dynamic left ventricular outflow tract obstruction, recent data suggest that angiotensin-converting enzyme inhibitors can be used safely in cats with systolic anterior motion of the mitral valve.