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Distinctive phenotypes of presentation with diverse management targets exemplify the extensive syndrome of heart failure. These range from chronic heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF), acute decompensated heart failure (ADHF), and advanced heart failure. Early management evolved from symptom control to disease-modifying therapy in HFrEF with the advent of renin-angiotensin-aldosterone system (RAAS)–directed therapy, beta receptor antagonists, mineralocorticoid receptor antagonists, cardiac resynchronization therapy, and implantable cardio-defibrillators. However, similar advances have been elusive in the syndromes of HFpEF and ADHF, which have remained devoid of convincing therapeutic advances to alter their natural history. In advanced heart failure, a stage of disease typically encountered in HFrEF, the patient remains markedly symptomatic with demonstrated refractoriness or inability to tolerate full-dose neurohormonal antagonism, often requires escalating doses of diuretics, and exhibits persistent hyponatremia and renal insufficiency with frequent episodes of heart failure decompensation requiring recurrent hospitalizations. Such individuals are at the highest risk of sudden or progressive pump failure–related deaths (Chap. 255). In contrast, early-stage asymptomatic left ventricular dysfunction is amenable to preventive care, and its natural history is modifiable by neurohormonal antagonism (not further discussed).



Therapeutic targets in HFpEF include control of congestion, stabilization of heart rate and blood pressure, and efforts at improving exercise tolerance. Addressing surrogate targets, such as regression of ventricular hypertrophy in hypertensive heart disease, and use of lusitropic agents, such as calcium channel blockers and beta receptor antagonists, have been disappointing. Experience has demonstrated that lowering blood pressure alleviates symptoms more effectively than targeted therapy with specific agents.


The Candesartan in Heart Failure—Assessment of Mortality and Morbidity (CHARM) Preserved study showed a statistically significant reduction in hospitalizations but no difference in all-cause mortality in patients with HFpEF who were treated with the angiotensin receptor blocker (ARB), candesartan. Similarly, the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial demonstrated no differences in meaningful endpoints in such patients treated with irbesartan. An earlier analysis of a subset of the Digitalis Investigation Group (DIG) trial found no role for digoxin in the treatment of HFpEF. In the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS) trial of nebivolol, a vasodilating beta blocker, the subgroup of elderly patients with prior hospitalization and HFpEF did not appear to benefit in terms of all-cause or cardiovascular mortality. Much smaller mechanistic studies in the elderly with the angiotensin-converting enzyme inhibitor (ACEI) enalapril showed no effect on peak exercise oxygen consumption, 6-min walk distance, aortic distensibility, left ventricular mass, or peripheral neurohormone expression.


A small trial demonstrated that the phosphodiesterase-5 inhibitor sildenafil improved filling pressures and right ventricular function in a cohort of HFpEF ...

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