HDL: A Novel Target or Marker for Cardiovascular Risk

Abstract

HDL has become a potential therapeutic target to reduce the residual cardiovascular (CV) risk in statin treated patients. Over the last several years it has been established that HDL is heterogeneous and contains several discrete lipoproteins particles with different lipid compositions and separate anti-atherosclerotic functions. These functions include increasing ABCA1 and ABCG1 mediated cholesterol efflux from cholesterol loaded macrophages, and decreasing inflammation, LDL oxidation, and thrombosis. Epidemiological data, animal models and initial imaging and pilot trials have shown promise, however proof that increasing HDL-C levels will reduce CV clinical events independent of changes in plasma levels of LDL-C and triglycerides has been elusive. HDL cholesterol is now recognized as an ineffective biomarker for accessing HDL mediated changes in CV events since HDL-C is a static measurement with no information on the dynamic flux through the HDL-C pathway, the variability of the cholesterol content in the different HDL particles, and the recognition that >90% of HDL-C is derived from the liver and intestine with <2% coming from the cholesterol loaded peripheral vascular tissue macrophages. The focus of the elucidation of the role of HDL in CV disease has now shifted from the quantitation of HDL-C to a systematic analysis of HDL particle number, HDL proteome, HDL lipidome and functions of the individual HDL particles. Low HDL due to genetic mutations in apoA-I, the structural protein of HDL, is causative in the pathway of increased vascular disease. In contrast HDL can also be a marker of a generalized dyslipoproteinemia as is present in the metabolic syndrome and diabetes Thus; HDL can be both a player in the development of CV disease as well as a marker of CV disease risk. Novel therapeutic agents that may substantiate the potential importance of HDL as a therapeutic target under development include niacin/laropiprant, CETP inhibitors and HDL infusions in acute coronary syndrome patients. The outcome of clinical trials with these new therapeutic modalities will provide definitive data on the future of HDL as an importance approach to decreasing CV events in high risk patients with cardiovascular disease.