Pathophysiology of Heart Failure

Heart failure (HF) is a progressive syndrome involving ventricles that leads to inadequate cardiac output. It can be classified based on location and output or ejection fraction. Ejection fraction (EF) is an essential measurement in the diagnosis and surveillance of HF. Reduced EF corresponds to systolic heart failure (HFrEF). However, HF with preserved ejection fraction (HFpEF) is becoming increasingly prevalent. Also known as diastolic HF, this form of HF is related to aging. The pathophysiology of HF involves four major interrelated systems: the heart, vasculature, kidney, and neurohumoral regulatory circuits. Myocardial overload, hypertension, valvular defects, or genetic cardiomyopathies cause insufficient cardiac output, leading to compensatory cardiac myocyte hypertrophy, metabolic reprogramming, and altered gene expression.

Increased fibroblast proliferation and extracellular matrix deposition result in fibrosis, disrupting cardiomyocyte communication and causing cell death via apoptosis or necrosis. Vascular stiffness stems from impaired crosstalk between luminal endothelial and underlying smooth muscle cells, involving receptors that increase intracellular Ca²⁺ levels. Endothelial dysfunction disrupts the balance between vasodilating NO and vasoconstricting reactive oxygen species (ROS), increasing afterload. The kidney regulates Na⁺ and H₂O levels, maintaining adequate GFR and diuresis through autoregulatory and neurohumoral mechanisms. If untreated, chronic activation of the sympathetic nervous system and RAAS leads to fatal cardiac tissue remodeling. Neurohumoral regulation creates a vicious cycle of vasoconstriction, increased afterload, volume overload, tachycardia, and positive inotropic actions. Common heart failure symptoms include tachycardia, decreased exercise tolerance, shortness of breath, maldigestion ascites, and peripheral and pulmonary edema. Heart failure ranges from Class I to IV. At the same time, the AHA and ACC extended this classification by adding stages A (preventable risk factors), B (asymptomatic stage requiring treatment), C (oscillations between symptoms in class II and III), and D (final stage requiring heart transplantation and left ventricular assist device implantation).