A population-based cohort study has shown that patients with a higher serum cholesterol efflux capacity, the capacity of HDL particles to mediate cholesterol efflux from macrophages, have a marked decrease in all-cause mortality as compared to patients with a lower serum cholesterol efflux capacity.
The study results were published in the Journal of the American College of Cardiology (JACC) and included 1609 patients (Between January 2003 and April 2014) with confirmed ST-elevation myocardial infarction (STEMI) treated by primary percutaneous intervention (PCI) followed for a total of 1 to 6 years for all-cause mortality. The study cohort was a part of the ePARIS registry, a large prospective registry with extensive patient datasets. Serum cholesterol efflux capacity was measured using radiolabeled Hydrogen-cholesterol human macrophages. This assay is not routinely used in clinical practice but rather a research assay commonly used in studies of HDL function. The investigators were able to show that, when serum cholesterol efflux capacity was modeled either as a continuous variable or as quartiles, patients with a higher serum cholesterol efflux capacity had lower mortality and a step-wise inverse relationship between increasing quartiles of serum cholesterol efflux capacity and all-cause mortality at 6 years was observed (hazard ratio [HR] for the highest versus lowest quartile: 0.40; 95% confidence interval [CI]: 0.27 to 0.58). In addition, the investigators showed that serum cholesterol efflux capacity remained an independent biomarker of long-term survival in MI patients after adjusting for age and sex, cardiovascular risk factors (diabetes, hypertension, current smoking, obesity, LDL cholesterol levels, HDL cholesterol levels, log-transformed triglyceride levels, and status with regard to use of statins- adjusted HR: 0.54; 95% CI: 0.32 to 0.89). Additional analyses revealed that cholesterol efflux is an independent marker of not only short-term prognosis at 30 days after the MI (adjusted HR: 0.32; 95% CI: 0.13 to 0.78; p = 0.012) but also a marker of the long-term prognosis in MI survivors (adjusted HR: 0.51; 95% CI: 0.29 to 0.89; p = 0.018)
This study contributes to the changing paradigms in the HDL hypothesis. Findings from the Framingham Heart Study showed an inverse association of HDL levels with cardiovascular outcomes. However, the inability of CETP inhibitors, Niacin and Apo-A1 Milano to improve cardiovascular outcomes in large randomized trials has led researchers to seek alternative mechanisms to improve outcomes in STEMI patients. Reverse cholesterol transport plays a pivotal role in transfer of cholesterol from peripheral tissues to the liver for biliary secretion and significantly contributes to protection from atherosclerosis. Rather than simply improving the number of HDL molecules, this evolving hypothesis focuses on improving the function of the HDL molecules. Cholesterol efflux from lipid-laden macrophages is a critical step in reverse cholesterol transport. Novel therapies that aim to restore cholesterol efflux capacity in this high risk patient population are currently being studied to improve outcomes.
One such innovative therapy currently being studied is the infusion of high quality Apolipoprotein A-1 for improving cholesterol efflux capacity in STEMI patients. Currently being conducted under the academic leadership of Dr. C. Michael Gibson of the PERFUSE Group at Beth Israel Deaconess Medical Center, this randomized, controlled, multi-center trial plans to enroll 17,400 patients from 1000 sites in 46 countries worldwide in the AEGIS-II phase 3 study (Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome). Similar to the present population-based study conducted in France, multiple studies have shown cholesterol efflux capacity as an independent biomarker inversely related to cardiovascular events in high-risk populations and validate the hypothesis of the AEGIS-II trial. Indeed, the AEGIS-II trial will be a landmark study to demonstrate the significance of cholesterol efflux capacity in terms of improving cardiovascular outcomes in a randomized, controlled setting.
In terms of limitations, this registry-based study was limited by the modest number of subjects included in the cohort, however, this may have been compensated by the fact that the study subjects were on average 20 years older than previously conducted population-based cohort studies. Secondly, data on secondary cardiovascular events were not available in this study; however the investigators used all-cause mortality as an endpoint which included cardiovascular mortality. Finally, Apolipoprotein A-1 measurements were not recorded for correlation with cholesterol efflux capacity.
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