HDL therapy for the acute treatment of atherosclerosis.
Although pharmacologic intervention to treat atherosclerosis originally focused on lowering LDL-cholesterol levels as a therapeutic target, a number of intervention trials have also highlighted the powerful effect of elevating HDL-cholesterol levels to reduce cardiovascular morbidity and mortality. Although the mechanism(s) by which HDL beneficially alters the atherosclerotic disease process is (are) still unknown, it is presumed that high levels of HDL facilitate the efflux of cholesterol from the arterial wall, thereby enhancing the transport of cholesterol and other lipids from arteries back to the liver for biliary excretion as fecal sterols and bile acids. It has therefore been hypothesized that through a rapid facilitation of HDL mediated cholesterol efflux from arteries by infusion of synthetic apolipoprotein A-I (apoA-I)/phospholipid (A-I/PL) complexes, HDL therapy could have an acute therapeutic application to treat cardiovascular disease at the site of action, namely the vulnerable, unstable atherosclerotic plaque. Single high dose infusions and repeated injections of lower doses of apoA-I variants or mimetics complexed to phospholipids have produced remarkable effects on the progression and regression of atherosclerosis in animal models. The positive results of these preclinical experiments have compelled researchers to perform exploratory studies in human subjects in which reconstituted HDL and synthetic A-I/PL complexes are infused through a peripheral vein. These clinical studies are testing the hypothesis and the potential use of synthetic HDL as a new treatment modality for acute coronary syndromes. Given that there is an unmet medical need for new and more effective therapies to elevate HDL-cholesterol levels and improve HDL function, a historical review, update and discussion of the preclinical and clinical studies which support the use of HDL therapy for reducing cardiovascular morbidity and mortality is warranted.
Newton
Roger S
RS
Esperion Therapeutics, Inc, 3621 South State Street, 695 KMS Place, Ann Arbor, MI 48108, USA. rnewton@esperion.com
Krause
Brian R
BR
D000818:Animals; D016632:Apolipoprotein A-I / Q000502:physiology / Q000627:therapeutic use; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000503:physiopathology*; D006801:Humans; D008075:Lipoproteins, HDL / Q000502:physiology* / Q000627:therapeutic use*
D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL