Related Experiment Videos
HDL therapy for the acute treatment of atherosclerosis
Roger S Newton1, Brian R Krause
1Esperion Therapeutics, Inc, 3621 South State Street, 695 KMS Place, Ann Arbor, MI 48108, USA. rnewton@esperion.com
Insights
Elevating high-density lipoprotein (HDL) cholesterol shows promise in reducing cardiovascular disease. HDL therapy using synthetic apolipoprotein A-I (apoA-I)/phospholipid complexes is being explored for acute treatment of atherosclerosis.
Area of Science:
- Cardiovascular Medicine
- Biochemistry
- Pharmacology
Background:
- Pharmacologic treatment for atherosclerosis initially focused on lowering LDL-cholesterol.
- Elevating HDL-cholesterol levels has demonstrated significant potential in reducing cardiovascular morbidity and mortality.
- The precise mechanisms of HDL's beneficial effects on atherosclerosis are still under investigation, but are thought to involve reverse cholesterol transport.
Purpose of the Study:
- To review and discuss preclinical and clinical studies on HDL therapy for cardiovascular disease.
- To explore the potential of synthetic HDL, specifically apolipoprotein A-I (apoA-I)/phospholipid (A-I/PL) complexes, as an acute therapeutic intervention.
- To address the unmet need for novel therapies that enhance HDL levels and function.
Main Methods:
- Review of historical data and recent preclinical studies involving apoA-I/phospholipid complexes in animal models.
- Analysis of exploratory clinical studies investigating the infusion of reconstituted HDL and synthetic A-I/PL complexes in human subjects.
- Examination of the therapeutic potential of HDL therapy for acute coronary syndromes.
Main Results:
- Preclinical studies in animal models showed significant effects of apoA-I/phospholipid complexes on atherosclerosis progression and regression.
- Exploratory human studies are evaluating the safety and efficacy of infusing synthetic HDL.
- These studies aim to validate HDL therapy as a novel treatment modality.
Conclusions:
- HDL therapy, particularly using synthetic apoA-I/phospholipid complexes, shows promise for treating cardiovascular disease.
- The potential for acute therapeutic application in vulnerable atherosclerotic plaques is being investigated.
- Further research and clinical studies are warranted to establish HDL therapy as an effective treatment for cardiovascular conditions.
Abstract:
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.