HDL: Beyond Atheroprotection.

Decades of epidemiologic studies have firmly established the inverse relationship between HDL-cholesterol (HDL-C) levels and cardiovascular events.1 However, the resulting hypothesis that raising HDL-C levels should reduce cardiovascular disease (CVD)has been called into questionby the failure of recent trials designed to decrease CVD events, despite raising HDL-C levels with cholesteryl ester transfer protein inhibitors or extended release niacin. The failure of these trials to show a reduction in cardiovascular events has, in turn, stimulated interest in the concept that measures of HDL composition, HDL particle number, or HDL functions may be better predictors of cardiovascular risk than HDL-C levels. Among the antiatherogenic functions of HDL, reverse cholesterol transport, which refers to the ability of HDL to pick up cholesterol in the tissues and deliver it to the liver, has been considered themost important. Cholesterol efflux capacity (CEC) measures the ability of HDL to accept cholesterol from macrophages, which is the first step of reverse cholesterol transport. A number of recent studies has examined the ability of measures of HDL-C efflux capacity to detect radiographic prevalence of atherosclerosis and predict cardiovascular events. In the first human study to examine CEC as a marker for atherosclerosis, Khera et al.2 showed that CEC of apoBdepleted serum (a surrogate for HDL) was inversely associated with measures of carotid and coronary atherosclerosis, independent of HDL-C levels. A case control study of subjects recruited from the cardiac catheterization laboratory also found an inverse relationship between CEC and the presence of coronary atherosclerosis.3 Surprisingly, CEC in this setting was directly associated with subsequent incident cardiovascular events. Differences in the patient populations, study design, and/or methods for assessing CEC may have been responsible for this unexpected result. Subsequently, two larger prospective trials reported that CEC was inversely associated with cardiovascular events. In contrast to the other studies, which used radiolabeled cholesterol to track efflux, Rohatgi et al.4 used fluorescence-labeled cholesterol to measure CEC in subjects from the Dallas Heart Study who were free of coronary heart disease at baseline and found an inverse association with incident atherosclerotic CVD independent of HDL-C levels. More recently, CEC was found to be inversely associated with incident coronary heart disease events in a nested case control sample from the very large prospective European Prospective Investigation into Cancer and Nutrition-Norfolk Study.5 Comparing the top and bottom tertiles of CEC in subjects with incident coronary heart disease and controls, the study found that CEC was inversely associated with incident coronary heart disease events independent of HDL-C and ApoAI levels.5 Collectively, these prospective population studies support the hypothesis that measures of HDL function serve as a marker for atherosclerosis and risk of cardiovascular events independent of HDL-C levels. CKD is associated with low levels of HDL and increased risk of CVD. We and others have shown that functionality of HDL is altered by kidney dysfunction, including in recipients of renal transplant.6–8 Thus, the concept that impaired HDL function may contribute to the pathogenesis and risk for CVD in CKD is particularly attractive. Cardiovascular events are the main cause of death in recipients of renal transplant, with ischemic heart disease being the main culprit.9 Although renal transplantation improves long-term survival of patients with ESRD on dialysis, renal transplantation is associated with an accelerated form of atherosclerosis.9 In this issue of JASN, Annema et al.10 address the interesting possibility that CEC can predict adverse cardiovascular and renal events in recipients of renal transplants. This prospective study examined whether CEC at baseline is associated with future cardiovascular mortality, all-cause mortality, and graft failure. Baseline CEC did not predict cardiovascular mortality or all-cause mortality. However, there was a strong inverse association between graft failure and efflux capacity. Both the negative association between CEC and cardiovascular consequences as well as the positive association between CEC and graft survival are surprising and the subject of this commentary. The lack of association of baseline CEC with cardiovascular mortality may seem to conflict with the studies showing that CEC is inversely correlated with cardiovascular events,4,5 but there is a number of differences between these studies that may contribute to the apparent difference in their results, such as (1) patient population, (2) disease process, (3) size of the cohort, (4) cardiovascular end points, and (5) method for determining CEC. The accelerated atherosclerosis in subjects with renal transplants has a complex pathogenesis involving both immunologic and nonimmunologic processes.9 Therefore, the ability of CEC and other measures of HDL function to predict mortality caused by cardiovascular Published online ahead of print. Publication date available at www.jasn.org.