Strategies to promote HDL-C: an emerging therapeutic target.

Hydroxy-methyl glutaryl coenzyme A reductase inhibitors (statins) have accumulated an extraordinary record of successful randomized clinical trials, transforming the practice of preventive cardiology. However, most placebo-controlled statin trials have reported not more than 25–35% reduction in morbidity/mortality during 5 year follow-up. Thus, despite their established benefits in primary and secondary prevention, statin drugs fail to prevent the majority of clinical events. In acute coronary syndromes (ACS), despite aggressive use of statins, the prognosis is even less favourable. In a recent trial of lipid lowering in ACS, the 2 year event rate was still 22% in the most aggressively treated patients. These findings highlight the need to develop new strategies to compliment statins in reducing cardiovascular risk. Emerging therapeutic targets include C-reactive protein, recently shown to have a strong link to outcomes during statin administration. However, few therapies other than statins have been shown to reduce C-reactive protein. A particularly inviting therapeutic target is highdensity lipoprotein cholesterol (HDL-C), a lipoprotein with well-established protective properties in epidemiological studies. Olsson et al. present data from the MIRACL study describing the ability of plasma lipoproteins to predict recurrent clinical events. Surprisingly, the incidence of clinical events could not be predicted by the plasma LDL-C concentration at baseline. Further, the reduction in clinical events with high dose atorvastatin did not correlate with the degree of LDL-C lowering. This finding adds further evidence to support the concept that the benefit of commencing statins early in the setting of ACS may result from their pleiotropic properties. A pivotal finding of this analysis was the association of plasma concentration of HDL-C at baseline with the incidence of subsequent clinical events. These observations provide important support for the concept that HDL-C is atheroprotective. It has been .50 years since the initial report that patients with a history of myocardial infarction had lower plasma levels of HDL-C. However, it took several decades for the concept of the protective properties of HDL-C to gain popularity. The key observation was the finding in large population studies that the plasma HDL-C concentration was inversely correlated with the incidence of cardiovascular disease (CVD). HDL was the strongest biochemical predictor of CVD in the Framingham cohort. It was further demonstrated that elevating plasma HDL by either the transgenic expression of apolipoprotein A-I (apoA-I) or the infusion of native HDL, reconstituted HDL (rHDL), or lipid-free apoA-I reduced lesion size in animal models of atherosclerosis. These findings have stimulated considerable interest to further understand the mechanisms underlying these beneficial properties. The best characterized functional property of HDL-C is its role in the promotion of reverse cholesterol transport. A key factor in this process involves the interaction between lipid deplete apoA-I and the transmembrane protein ABCA1, which results in cellular cholesterol efflux. However, it has become apparent that HDL-C possesses other functional properties that may contribute to its beneficial impact on the arterial wall. HDL-C exerts a favourable impact on vascular reactivity, via the promotion of nitric oxide bioavailability. HDL-C exerts antioxidant effects, inhibiting LDL-C oxidation and improving the balance of nitric oxide to superoxide.