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Introduction
Heart failure with reduced ejection fraction (HFrEF), defined as heart failure with a left ventricular ejection fraction of 40% or less, is the common end point of many different injuries to the myocardium (Heidenreich et al., 2022). Its pathophysiology explains both why the condition progresses and why its treatment looks the way it does.
From injury to falling cardiac output
Myocardial infarction, long-standing hypertension, cardiomyopathies and valve disease all reduce the number or performance of working cardiomyocytes. Stroke volume falls, and the body reads the drop in cardiac output as a drop in circulating volume.
Compensation that becomes the problem
Two neurohormonal systems respond. The sympathetic nervous system raises heart rate and contractility, and the renin-angiotensin-aldosterone system (RAAS) causes vasoconstriction and sodium and water retention. In the short term, both maintain blood pressure and organ perfusion. Sustained activation, however, increases preload, afterload and myocardial oxygen demand. Angiotensin II and aldosterone promote myocardial fibrosis, and prolonged catecholamine exposure is directly toxic to cardiomyocytes. The natriuretic peptides released as the chambers stretch counter these effects through natriuresis and vasodilation, but they are gradually overwhelmed.
Ventricular remodeling
Over months, the left ventricle dilates and becomes more spherical, its walls thin and contraction becomes less efficient. As the mitral annulus stretches, functional mitral regurgitation adds volume load to an already failing ventricle, creating a self-reinforcing cycle.
Lifespan considerations
In older adults, arterial stiffening and reduced responsiveness to beta-adrenergic stimulation narrow cardiac reserve, so decompensation can follow minor stressors such as an infection. In children, HFrEF more often results from congenital heart disease or cardiomyopathy than from coronary disease, and it may present as feeding difficulty, sweating with feeds and poor weight gain rather than exertional dyspnea.
Why the mechanisms shape treatment
Guideline-directed medical therapy targets each mechanism (Heidenreich et al., 2022). An angiotensin receptor-neprilysin inhibitor (or an ACE inhibitor or ARB) and a mineralocorticoid receptor antagonist block RAAS effects, and neprilysin inhibition also preserves the protective natriuretic peptides. Evidence-based beta-blockers blunt sympathetic toxicity and allow reverse remodeling. SGLT2 inhibitors complete the four drug classes and reduce heart failure hospitalization and cardiovascular death.
Reference
Heidenreich, P. A., Bozkurt, B., Aguilar, D., Allen, L. A., Byun, J. J., Colvin, M. M., Deswal, A., Drazner, M. H., Dunlay, S. M., Evers, L. R., Fang, J. C., Fedson, S. E., Fonarow, G. C., Hayek, S. S., Hernandez, A. F., Khazanie, P., Kittleson, M. M., Lee, C. S., Link, M. S., . . . Yancy, C. W. (2022). 2022 AHA/ACC/HFSA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation, 145(18), e895–e1032. https://doi.org/10.1161/CIR.0000000000001063
