Pleiotropic Effects of HDL: Towards New Therapeutic Areas for HDL-Targeted Interventions
B. De Geest.
Plasma levels of high density lipoprotein (HDL) cholesterol levels and of apolipoprotein A-I are
inversely correlated with the incidence of coronary heart disease. According to the HDL hypothesis, raising
HDL cholesterol is expected to lead to a decrease of coronary heart disease risk. The stringent requirement for
proving or refuting this hypothesis is that the causal pathway between the therapeutic intervention and a hard
clinical end-point obligatory passes through HDL. The lack of positive clinical results in several recent HDL
trials should be interpreted in light of the poor HDL specificity of the drugs that were investigated in these trials.
Nevertheless, the results of Mendelian randomization studies further raise the possibility that the
epidemiological relationship between HDL cholesterol and coronary artery disease might reflect residual
HDL are circulating multimolecular platforms that exert divergent functions: reverse cholesterol transport, antiinflammatory
effects, anti-oxidative effects, immunomodulatory effects, improved endothelial function,
increased endothelial progenitor cell number and function, antithrombotic effects, and potentiation of insulin
secretion and improvement of insulin sensitivity. Pleiotropic effects of HDL might be translated in clinically
significant effects in strategically selected therapeutic areas that are not directly related to native coronary
artery disease. In this review, four new therapeutic areas for HDL-targeted diseases are presented: critical
illness, allograft vasculopathy and vein graft atherosclerosis, type 2 diabetes mellitus, and heart failure. The
strategic selection of these therapeutic areas is not only based on specific functional properties of HDL but also
on significant pre-clinical and clinical data that support this choice.
Keywords: Apolipoprotein A-I, atherosclerosis, drug development, high density lipoproteins, ischemic
cardiovascular diseases, pleiotropic effects, reverse cholesterol transport.
Rights & PermissionsPrintExport