Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins: an idea whose time for testing is coming, part I.

Vaso-occlusive disease resulting from atherosclerosis and thrombosis is the leading cause of death and morbidity in the United States and other industrialized nations. Although the precise cause of atherosclerosis is unclear, an emerging paradigm suggests that atherosclerosis involves multiple pathways in which lipoprotein entry and retention, injury to the vessel wall from diverse stimuli, and an associated long-term inflammatory and immune response seem to play a key role.1–4 Dyslipidemia characterized predominantly by elevated levels of one or more circulating non-HDL cholesterol lipoproteins [LDL, VLDL, lipoprotein(a), triglycerides] and/or reduced HDL cholesterol is one of the key risk factors for atherosclerosis and cardiovascular disease.5–16 Over the past several years, a number of large, prospective, randomized, controlled clinical trials have demonstrated both angiographic and clinical benefits of lipidlowering therapy, with a significant reduction in fatal and nonfatal cardiovascular events.17–23 These studies have primarily targeted LDL cholesterol through pharmacotherapy (mostly statins), with or without dietary counseling, lifestyle modification, or surgery (intestinal bypass in Program on the Surgical Control of the Hyperlipidemias [POSCH] trial). Overall, a significant and clinically worthwhile relative risk reduction ranging from 20% to 40% in major cardiovascular events has been achieved with these strategies, without significant adverse effects or increased noncardiovascular mortality. These remarkable results prompted Brown and Goldstein24 to predict that heart attacks will be gone with the century. This clearly reflects an overoptimistic point of view, because 60% to 70% of adverse cardiovascular events continue to occur despite LDL-lowering therapy. Potential reasons why cardiovascular events may continue to occur despite low LDL levels or despite LDL-lowering therapy include the following: (1) we may not be lowering LDL cholesterol to optimal levels, because optimal levels are not clearly defined, and (2) there may be other risk factors that are more important in certain patients than simply elevated LDL cholesterol. These observations underscore a need for additional preventive and therapeutic interventions exploiting new targets to compliment and augment the results of LDL lowering. One such potential target is HDL and its apolipoproteins. There is a large body of experimental evidence to suggest that augmenting HDL and/or its apolipoproteins can have major vascular protective effects ranging from prevention to stabilization and regression, independent of total or non-HDL cholesterol levels. Therefore, we think that the time is ripe for the development and clinical testing of this new frontier in antiatherogenic strategy.