Antiatherosclerotic Effects of CSL112 Mediated by Enhanced Cholesterol Efflux Capacity.

Abstract

Approximately 12% of patients with acute myocardial infarction (AMI) experience a recurrent major adverse cardiovascular event within 1 year of their primary event, with most occurring within the first 90 days. Thus, there is a need for new therapeutic approaches that address this 90-day post-AMI high-risk period. The formation and eventual rupture of atherosclerotic plaque that leads to AMI is elicited by the accumulation of cholesterol within the arterial intima. Cholesterol efflux, a mechanism by which cholesterol is removed from plaque, is predominantly mediated by apolipoprotein A-I, which is rapidly lipidated to form high-density lipoprotein in the circulation and has atheroprotective properties. In this review, we outline how cholesterol efflux dysfunction leads to atherosclerosis and vulnerable plaque formation, including inflammatory cell recruitment, foam cell formation, the development of a lipid/necrotic core, and degradation of the fibrous cap. CSL112, a human plasma-derived apolipoprotein A-I, is in phase 3 of clinical development and aims to reduce the risk of recurrent cardiovascular events in patients with AMI in the first 90 days after the index event by increasing cholesterol efflux. We summarize evidence from preclinical and clinical studies suggesting that restoration of cholesterol efflux by CSL112 can stabilize plaque by several anti-inflammatory/immune-regulatory processes. These effects occur rapidly and could stabilize vulnerable plaques in patients who have recently experienced an AMI, thereby reducing the risk of recurrent major adverse cardiovascular events in the high-risk early post-AMI period.

• Authors: Bronwyn A Kingwell, Stephen J Nicholls, Elena Velkoska, Svetlana A Didichenko, Danielle Duffy, Serge Korjian, C Michael Gibson
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 11 Issue 8 Pg. e024754 (04 19 2022) ISSN: 2047-9980 [Electronic] England
• PMID: 35411789 (Publication Type: Journal Article, Review, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoprotein A-I
• CSL112
• Lipoproteins, HDL
• Cholesterol

Topics

• Apolipoprotein A-I
• Cholesterol (metabolism)
• Humans
• Lipoproteins, HDL (therapeutic use)
• Myocardial Infarction (drug therapy)
• Plaque, Atherosclerotic (drug therapy)