HDL Is Not Dead Yet

Abstract

High-density lipoprotein cholesterol (HDL-C) levels are inversely correlated with coronary heart disease (CHD) in multiple epidemiological studies, but whether HDL is causal or merely associated with CHD is unclear. Recent trials for HDL-raising drugs were either not effective in reducing CHD events or, if beneficial in reducing CHD events, were not conclusive as the findings could be attributed to the drugs’ LDL-reducing activity. Furthermore, the first large Mendelian randomization study did not causally relate HDL-C levels to decreased CHD. Thus, the hypothesis that HDL is protective against CHD has been rightfully challenged. However, subsequent Mendelian randomization studies found HDL characteristics that are causally related to decreased CHD. Many aspects of HDL structure and function, especially in reverse cholesterol transport, may be better indicators of HDL’s protective activity than simply measuring HDL-C. Cholesterol efflux capacity is associated with lower levels of prevalent and incident CHD, even after adjustment for HDL-C and apolipoprotein A-1 levels. Also, subjects with very high levels of HDL-C, including those with rare mutations that disrupt hepatic HDL uptake and reverse cholesterol transport, may be at higher risk for CHD than those with moderate levels. We describe here several cell-based and cell-free in vitro assays of HDL structure and function that may be used in clinical studies to determine which of HDL’s functions are best associated with protection against CHD. We conclude that the HDL hypothesis may need revision based on studies of HDL structure and function, but that the HDL hypothesis is not dead yet.

CSL112 Infusion Rapidly Increases APOA1 Exchange Rate via Specific Serum Amyloid-Poor HDL Subpopulations When Administered to Patients Post–Myocardial Infarction

“…[10][11][12][13] However, recent genetic and clinical trial data suggest that the simple quantity of HDL-C may not be causal in preventing atherosclerosis nor reflect HDL functionality. 14 Many authors have observed that the functional activity of HDL in plasma samples from patients with cardiovascular disease may be substantially lower than predictions based on HDL-C or APOA1 levels [15][16][17][18][19] and the term "dysfunctional HDL" describes the phenomenon. Notably, HDL particles from cardiovascular disease patients are enriched in proteins involved in the acute-phase response, such as members of the SAA (serum amyloid A) family.…”

Porphyromonas gingivalis Virulence Factors and Clinical Significance in Periodontal Disease and Coronary Artery Diseases

“…Thus, P. gingivalis LPS has a potential role in inducing macrophages to modify native LDL [ 171 ]. Likewise, P. gingivalis can initiate the oxidation of high-density lipoprotein (HDL), reverse the cholesterol transport pathway, remove cholesterol from macrophages, and thus contribute to atherosclerosis [ 172 , 173 ]. In addition, it can lead to an imbalance of proatherogenic and atheroprotective cytokines by disturbing the balance of Th17 and Treg [ 174 ].…”

Glycosylation of HDL-Associated Proteins and Its Implications in Cardiovascular Disease Diagnosis, Metabolism and Function

“…One of the problems with HDL particle analysis for diagnostic purposes has been the extreme complexity of these particles and the lack of resolution of older measurement tools. For example, although high HDL-cholesterol (HDL-C) concentrations have been found to be protective against CVD, several large recent studies demonstrated that the relationship between HDL-C concentration and adverse health outcomes tends to follow a U-shaped curve, with both low HDL-C and very high HDL-C being associated with increased cardiovascular (CV) events (21)(22)(23). Clearly, it is not simply the measurement of the total amount of cholesterol carried within HDL that is diagnostic, but rather some other aspect of HDL that is critical, whether it be compositional, structural, or functional.…”