Therapeutic potential of high-density lipoproteins in heart failure with reduced ejection fraction

Plasma high-density lipoprotein (HDL) cholesterol levels and plasma levels of its major apolipoprotein (apo), apo A-I, are inversely correlated with the incidence of coronary heart disease. The potential protection conferred by HDL against ischemic cardiovascular diseases has been most often attributed to its role in reverse cholesterol transport. However, HDLs exert divergent functions that include actions mediated by signalling via scavenger receptor class B, type I (SR-BI), and/or receptor activation by HDL cargo molecules. These pleiotropic properties offer perspectives for new therapeutic areas for HDL-targeted interventions. The therapeutic area that is considered in this PhD is heart failure with reduced ejection fraction (HFrEF). Heart failure is a growing public health problem, the leading cause of hospitalization, and a major cause of mortality. This syndrome is the pathophysiological state in which cardiac dysfunction is responsible for failure of the heart to pump blood at a rate commensurate with the requirements of metabolising tissues. It is characterised by symptoms and signs of increased tissue and organ water, and of decreased tissue and organ perfusion. Epidemiological studies support a strong association between HDL cholesterol levels and heart failure incidence. In Framingham Heart Study participants free of coronary heart disease at baseline, low HDL cholesterol levels were independently associated with heart failure incidence after adjustment for interim myocardial infarction and clinical covariates. The general hypothesis that will be investigated in the course of this PhD thesis is whether HDL exerts direct effects on the myocardium and beneficially affects cardiac function in a model of pressure overload-induced cardiomyopathy. Transverse aortic constriction (TAC) is a commonly used model for pressure overload-induced cardiac hypertrophy and heart failure. TAC initially leads to compensatory hypertrophy of the heart, but over time, the response to chronic hemodynamic overload becomes maladaptive and results in cardiac dilatation and HFrEF. Targeted HDL therapies that will be evaluated in murine models are administration of recombinant HDL and hepatocyte-directed adeno-associated viral (AAV) serotype 8-mediated human apo A-I gene transfer. The hypothesis that HDL has an impact on cardiac structure and function will also be investigated in a model of dysfunctional HDL, scavenger receptor class B, type I (SR-BI) deficient mice.nrpages: 107status: publishe