Obesity, Diabetes, and Cardiovascular Diseases Compendium Lipid Use and Misuse by the Heart

1736 T he heart uses large amounts of fatty acids (FAs) as energy-providing substrates. More than 70% of all substrates used for ATP generation are derived from FAs, with the remaining sources being glucose, lactate, ketone bodies, and amino acids. The relatively tight coupling between lipid uptake and oxidation prevents accumulation of excess lipids in the cardiomyocyte. Several processes that affect heart function, including ischemia, sepsis, and heart failure, are associated with a reduction in FA oxidation (FAO) with a relative increase in anaerobic glycolysis and, in some cases, accumulation of nonoxidized FA derivatives in the form of lipids. In addition, excess circulating FA levels in type 2 diabetes mellitus and its precursor, the metabolic syndrome, also cause cardiac lipid accumulation. There is increasing evidence that many of these lipids worsen heart function and lead to structural myocardial damage, including cardiac fibrosis, myocyte apoptosis, and reduced contractility, which is often thought to be caused by mitochondrial dysfunction. However, the reversibility of this dysfunction along with several key steps of oxidative and glycolytic metabolism after the correction of cardiac stress and failure suggest that mitochondrial dysfunction is a reversible adaptation and is secondary to the altered metabolic pathways. 1 Several altered metabolic pathways lead to lipid accumulation. Experimental and clinical data provide evidence that lipid accumulation causes or exacerbates heart dysfunction, a process termed cardiac lipotoxicity. In support of this hypothesis, several recent studies have shown that reduction of toxic lipids is associated with improved metabolism and function of the heart. Abstract: The heart utilizes large amounts of fatty acids as energy providing substrates. The physiological balance of lipid uptake and oxidation prevents accumulation of excess lipids. Several processes that affect cardiac function, including ischemia, obesity, diabetes mellitus, sepsis, and most forms of heart failure lead to altered fatty acid oxidation and often also to the accumulation of lipids. There is now mounting evidence associating certain species of these lipids with cardiac lipotoxicity and subsequent myocardial dysfunction. Experimental and clinical data are discussed and paths to reduction of toxic lipids as a means to improve cardiac function are suggested.