HDL in Atherosclerotic Cardiovascular Disease: In Search of a Role

Abstract

For a long time, high-density lipoprotein cholesterol (HDL-C) has been regarded as a cardiovascular disease (CVD) protective factor. Recently, several epidemiological studies, while confirming low plasma levels of HDL-C as an established predictive biomarker for atherosclerotic CVD, indicated that not only people at the lowest levels but also those with high HDL-C levels are at increased risk of cardiovascular (CV) mortality. This “U-shaped” association has further fueled the discussion on the pathophysiological role of HDL in CVD. In fact, genetic studies, Mendelian randomization approaches, and clinical trials have challenged the notion of HDL-C levels being causally linked to CVD protection, independent of the cholesterol content in low-density lipoproteins (LDL-C). These findings have prompted a reconsideration of the biological functions of HDL that can be summarized with the word “HDL functionality”, a term that embraces the many reported biological activities beyond the so-called reverse cholesterol transport, to explain this lack of correlation between HDL levels and CVD. All these aspects are summarized and critically discussed in this review, in an attempt to provide a background scenario for the “HDL story”, a lipoprotein still in search of a role.

Serum Cholesterol Levels and Risk of Cardiovascular Death: A Systematic Review and a Dose-Response Meta-Analysis of Prospective Cohort Studies

“…A worldwide study demonstrated that among all modifiable risk factors of CV disease, abnormal serum levels of cholesterol were associated with the highest attributable risk for the occurrence of CVD, especially ischemic heart disease [ 3 , 4 ].…”

Atherogenic index of plasma for non-diabetic, coronary artery disease patients after percutaneous coronary intervention: a prospective study of the long-term outcomes in China

“…An explanation for this may be the effect of HDL-C, as has been described. Previous studies have also found a U-shaped association which has further fueled the discussion on the pathophysiological role of HDL in cardiovascular diseases [ 36 ]. This may mean that a single assessment method for CVD risk using HDL-C is unsuitable.…”

Clinical characteristics of cardiovascular patients with extremely low levels of high-density lipoprotein cholesterol

“…HDL-C level has been challenged time and time again for its association with cardiovascular diseases. Instead, the HDL function may be the real link with cardiovascular diseases [ 29 ]. Since the role of HDL in prevention and progression of cardiovascular diseases remains to be further clarified, we assume, in the current study, that extremely low level of HDL-C is only a marker, which reflects a comprehensive result of multiple adverse concomitant factors, and the high cardiovascular mortality is probably due to the presence of severe conditions.…”