Fatty Acids and Their Roles in Cardiac Physiology and Pathology: Mechanistic and Interventional Studies

Fatty acids are central to cardiac physiology, serving as both primary energy substrates and precursors for bioactive lipid mediators that shape myocardial structure and function. Essential n-3 and n-6 polyunsaturated fatty acids (PUFAs) are of particular interest because they give rise to prostaglandins, leukotrienes, and a diverse oxylipin network that regulates coronary tone, inflammation, thrombosis, and tissue remodeling in the heart. In parallel, non essential saturated, monounsaturated, and trans fatty acids modulate cardiomyocyte metabolism, membrane organization, and receptor microdomains, thereby influencing how these mediator pathways are engaged in health and disease. Clinically, n--3 long chain PUFAs such as eicosapentaenoic acid and docosahexaenoic acid have been associated with reduced cardiovascular mortality and more favorable post-ischemic remodeling, yet high-dose supplementation has also been linked to a modestly increased risk of atrial fibrillation. Conversely, diets enriched in industrial trans fats and excessive long-chain saturated fats promote dyslipidemia, endothelial dysfunction, and pro arrhythmic remodeling, and are consistently associated with higher rates of coronary artery disease, heart failure, and sudden cardiac death. At the mechanistic level, cardiac fatty acid handling is governed by coordinated uptake via CD36 and fatty acid transport proteins, mitochondrial β oxidation pathways, and nuclear receptor signaling through peroxisome proliferator-activated receptors, which together determine substrate preference, mitochondrial function, and oxidative stress. Superimposed on these core metabolic processes, cyclooxygenase, lipoxygenase, and cytochrome P450 epoxygenase pathways convert arachidonic acid and n 3 PUFAs into distinct repertoires of prostanoids, leukotrienes, hydroxyeicosatetraenoic acids, epoxyeicosatrienoic acids, and specialized pro resolving mediators that critically influence myocardial inflammation, fibrosis, electrophysiology, and repair. This review synthesizes experimental and clinical evidence on how specific fatty acid species and their oxylipin derivatives contribute to cardiac physiology and pathology, with emphasis on lipotoxic cardiomyopathy, heart failure phenotypes, ischemia–reperfusion injury, and arrhythmogenesis. We also evaluate interventional strategies—including dietary patterns, essential fatty acid supplementation, and pharmacological modulation of fatty acid uptake or oxidation—to optimize cardiac fatty acid and oxylipin metabolism. By framing fatty acids primarily through the lens of essential fatty acid biology and addresses key gaps in linking mechanistic lipid mediator pathways to cardiac outcomes.