The impact of metabolic stress on ventricular remodelling, myocardial substrate metabolism, and lipotoxicity in pressure overload-induced cardiomyopathy.

Heart failure is a growing public health problem, the leading cause of hospitalization, and a major cause of mortality. Epidemiological studies support a strong association between metabolic cardiovascular risk factors and heart failure incidence. In Framingham Heart Study participants free of coronary heart disease at baseline, high non-high density lipoprotein (non-HDL) cholesterol levels and low HDL cholesterol levels are independently associated with heart failure incidence after adjustment for interim myocardial infarction and clinical covariates. Furthermore, higher plasma levels of saturated fatty acids (SFA) are independently associated with incident heart failure. Metabolic intermediates in glucose and/or lipid metabolism may act in a signalling manner (e.g. by the accumulation of specific bioactive lipids) to affect cardiac remodelling in response to increased load. The different work packages of this project converge to the investigation of the postulated detrimental self-perpetuating cycle cardiac dysfunction→altered cardiac metabolism→cardiac dysfunction and provide gene therapeutic tools (adeno-associated viral vectors for hepatocyte-specific and cardiomyocyte-specific gene transfer) to beneficially affect cardiac structure, function, and metabolism. The role of SFA, non-HDL lipoproteins, and HDL lipoproteins in the development of pressure overload-induced cardiac hypertrophy and heart failure induced by transverse aortic constriction will be investigated.