High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events

Abstract

Background: The role of high-density lipoprotein (HDL) function in cardiovascular disease represents an important emerging concept. The present study investigated whether HDL anti-inflammatory capacity is prospectively associated with first cardiovascular events in the general population. Methods: HDL anti-inflammatory capacity was determined as its ability to suppress TNFα (tumor necrosis factor α)–induced VCAM-1 (vascular cell adhesion molecule-1) mRNA expression in endothelial cells in vitro (results expressed as achieved percent reduction by individual HDL related to the maximum TNFα effect with no HDL present). In a nested case-control design of the PREVEND (Prevention of Renal and Vascular End Stage Disease) study, 369 cases experiencing a first cardiovascular event (combined end point of death from cardiovascular causes, ischemic heart disease, nonfatal myocardial infarction, and coronary revascularization) during a median of 10.5 years of follow-up were identified and individually matched to 369 controls with respect to age, sex, smoking status, and HDL cholesterol. Baseline samples were available in 340 cases and 340 matched controls. Results: HDL anti-inflammatory capacity was not correlated with HDL cholesterol or hsCRP (high-sensitivity C-reactive protein). HDL anti-inflammatory capacity was significantly lower in cases compared with controls (31.6% [15.7–44.2] versus 27.0% [7.4–36.1]; P <0.001) and was inversely associated with incident CVD in a fully adjusted model (odds ratio [OR] per 1 SD, 0.74 [CI, 0.61–0.90]; P =0.002). Furthermore, this association was approximately similar with all individual components of the cardiovascular disease end point. The HDL anti-inflammatory was not correlated with cholesterol efflux capacity ( r =−0.02; P >0.05). When combining these 2 HDL function metrics in 1 model, both were significantly and independently associated with incident cardiovascular disease in a fully adjusted model (efflux: OR per 1 SD, 0.74; P =0.002; anti-inflammatory capacity: OR per 1 SD, 0.66; P <0.001). Adding HDL anti-inflammatory capacity improved risk prediction by the Framingham risk score, with a model likelihood-ratio statistic increase from 10.50 to 20.40 ( P =0.002). Conclusions: The HDL anti-inflammatory capacity, reflecting vascular protection against key steps in atherogenesis, was inversely associated with incident cardiovascular events in a general population cohort, independent of HDL cholesterol and HDL cholesterol efflux capacity. Adding HDL anti-inflammatory capacity to the Framingham risk score improves risk prediction.

The Endothelium Is Both a Target and a Barrier of HDL’s Protective Functions

“…Glycation of HDL induces the loss of its ability to counteract the inhibitory effect of oxidized LDL on endothelium-dependent vasorelaxation [ 128 ]. Glycated HDL particles induce endothelial cell apoptosis and increase oxidative stress [ 110 ]. Glycation of apoA-I interferes with its ability to inhibit the expression of VCAM1 and ICAM1 as well as neutrophil adhesion in rabbits and in cell culture [ 129 ].…”

HDL in Atherosclerotic Cardiovascular Disease: In Search of a Role

“…The first clinical trial with recombinant apoA-I Milano [113] produced a rapid regression of coronary atherosclerosis in patients following an acute coronary syndrome. However, subsequent studies failed to demonstrate incremental regression in statin-treated patients (Table 3) [114][115][116]: although this approach led to improved cholesterol efflux, its overall effect on preventing atherosclerotic disease and adverse cardiovascular events remains unclear [17,109,117]. Another strategy aiming at upregulating apoA-I has been tested with selective bromodomain and extra-terminal (BET) inhibitors, such as apabetalone, able to increase the endogenous synthesis of apoA-I by transcriptional regulation [120].…”

High-Density Lipoproteins in Kidney Disease

“…Several studies have shown that the cholesterol efflux capacity of HDL (a measure of the first step in reverse cholesterol transport) is an independent predictor of atherosclerosis and atherosclerotic cardiovascular events [ 9 , 10 , 11 ]. More recent studies have demonstrated that the HDL inflammatory index is an inverse predictor of cardiovascular events that is independent of both HDL-C levels and HDL efflux capacity [ 12 , 13 ]. These observations have provided strong support for the concept that metrics other than HDL-C levels, such as HDL functionality and composition, may better capture HDL cardiovascular protection.…”

“…Critically, reduction in CEC is not necessarily synchronized with dysfunction of other HDL functionalities. Indeed, as noted in the introduction, HDL inflammatory index appears to be an inverse predictor of cardiovascular events that is independent of efflux capacity and HDL-C [ 12 , 13 ]. We and others have shown that children with CKD or ESRD requiring dialysis who do not have long-standing comorbidities or risk factors characteristic of adults with CKD (e.g., diabetes, obesity, pre-existing cardiovascular disease) have HDL with reduced functionality including profound impairment in anti-inflammatory, anti-oxidative, and endothelial protection functions without CEC impairment [ 44 , 45 , 53 ].…”