Cholesterol is an essential lipid molecule with vital functions in maintaining cellular integrity and hormone synthesis.

However, elevated levels of cholesterol in the bloodstream, particularly low-density lipoprotein cholesterol (LDL-C), exert complex and predominantly detrimental effects on heart health.

Cholesterol and Cardiac Metabolism

High circulating cholesterol alters the metabolic landscape of cardiac cells. Excess cholesterol and triglycerides accumulate in cardiac tissue, leading to lipid overload that disrupts normal myocardial energy homeostasis. This excess triggers oxidative stress, mitochondrial dysfunction, and proinflammatory signaling within heart muscle cells. In parallel, mitochondrial distress caused by cholesterol overload impairs adenosine triphosphate (ATP) production, directly limiting the energy supply essential for sustained cardiac contractions.

According to Dr. Lorenzo Da Dalt, a researcher in cardiac lipid metabolism, lipid accumulation — including sterols — in the myocardium drives mitochondrial dysfunction, oxidative stress, and shifts in substrate use, contributing to impaired cardiac contractile function and heart failure.

Hypercholesterolemia also affects gene regulation in the heart. Overexpression of peroxisome proliferator-activated receptor gamma (PPARγ), a key transcription factor involved in lipid metabolism, has been linked to excessive intracellular lipid storage and altered mitochondrial structure that promote myocardial dysfunction. This molecular disruption suggests that lipid dysregulation contributes to the development of cardiomyopathy independent of vascular complications.

Cholesterol’s Role in Cardiac Structural Changes

Besides functional impairments, elevated cholesterol induces structural remodeling of heart tissue. Chronic hypercholesterolemia promotes myocardial fibrosis through activation of mast cells and pro-fibrotic pathways including transforming growth factor-beta (TGF-β) signaling.

These fibrotic changes stiffen cardiac muscle, impairing its relaxation and filling during diastole, a condition often preceding overt heart failure. Additionally, cholesterol-related inflammation enhances apoptosis of endothelial and cardiac cells, further degrading cardiac architecture and facilitating progression toward myocardial injury and dysfunction.

Electrophysiological Impact and Arrhythmia Risk

Cholesterol-induced metabolic and structural changes extend to cardiac electrical activity. High cholesterol and associated obesity contribute to remodeling of cardiac ion channels and gap junction proteins essential for electrical conduction. This remodeling results in altered action potential duration and repolarization dispersion favorable to arrhythmogenesis.

Experimental models demonstrate that lipid overload increases susceptibility to arrhythmias by promoting oxidative stress-induced calcium leakage and disrupted ion currents in cardiac cells. These effects heighten the risk of potentially fatal ventricular arrhythmias in hypercholesterolemic patients.

Clinical Correlations and Reversibility

Clinical data corroborate these mechanistic insights. Familial hypercholesterolemia patients exhibit early impairment in myocardial strain and left ventricular function relative to lipid levels, indicating heart damage before ischemic events develop. Importantly, lowering serum cholesterol through diet or pharmacologic interventions partially reverses myocardial dysfunction and fibrosis, emphasizing the modifiable nature of cholesterol’s cardiac effects.

Dr. Yu Si Yao, Department of Cardiovascular Diseases, The First Affiliated Hospital of Guangdong Pharmaceutical University: "Hypercholesterolemia not only promotes atherosclerosis but directly impairs myocardial contractility and electrical stability through lipid accumulation and oxidative injury, necessitating early lipid management to protect cardiac function."

Cholesterol affects the heart through intricate biochemical and physiological mechanisms that extend beyond vascular disease. Excess cholesterol accumulation in myocardial cells disrupts metabolic processes, induces structural fibrosis, and alters electrophysiology, collectively impairing heart performance and increasing arrhythmia risk. Understanding the multifaceted impact of cholesterol on myocardial health deepens the approach toward reducing cardiovascular morbidity and mortality in hyperlipidemic populations.