Therapeutic Challenge to Adiposity of the Heart

Abstract

See related article, pages 1208–1217 The recent increase in the prevalence of obesity is one possible explanation for the adverse trends in cardiovascular morbidity and mortality. Hospitalizations for congestive heart failure have increased, and the decline in death because of coronary heart disease has leveled off. In parallel with these aspects, there is emerging evidence that inherited and acquired cardiomyopathies are associated with marked intracellular lipid accumulation in the heart.1–5 Three types of mismatches between uptake and utilization of long chain fatty acid (LCFA) lead to abnormally high intracellular LCFA concentrations in the heart, resulting in lipotoxic cardiomyopathy. First, inborn errors in myocardial β-oxidation are associated with heart failure, arrhythmias, sudden death, and pathologic lipid accumulation with a 3-fold increase in phospholipids and 100-fold increase in triglycerides in the myocardium.1 Second, myocardial metabolism switches from utilization of LCFA to utilization of glucose during the development of cardiac hypertrophy and in the ischemic and failing heart. Although this metabolic switch initially serves an adaptive function, accumulation of intracellular LCFA in these acquired conditions contributes to contractile dysfunction and the generation of cardiac arrhythmias.2 Third, several-fold increased cardiac myocyte triglyceride stores are observed in animal models of obesity and diabetes, in which high serum free fatty acid levels promote LCFA uptake in excess of tissue capacity for utilization.3,4 This lipid accumulation contributes to cardiac myocyte apoptosis by nonoxidative metabolic pathways, such as ceramide synthesis, and to congestive heart failure (Figure). Even in humans, myocardial lipid content has been recently reported to increase with the degree of adiposity and contribute to the adverse structural and functional cardiac adaptations, suggesting that myocardial lipid content is a biomarker and putative therapeutic target for cardiac disease in obese patients.5 Indeed, one trial of the medium-chain triglyceride-enriched diet rescued the baseline …