High density lipoprotein: When to rethink too much of a good thing.

High density lipoprotein cholesterol (HDL-C) is a known contributor to atherosclerotic cardiovascular disease (ASCVD) risk when HDL-C <40 mg/dL in men and <50 mg/dL in women. There has been much interest in the potential cardioprotective properties of HDL-C, as it removes cholesterol from the periphery to the liver for exertion and holds inherent anti-thrombotic and anti-inflammatory properties. However, clinical trials raising HDL-C pharmacologically have not shown to improve cardiovascular outcomes. In fact, observational studies have demonstrated an increased risk of non-cardiovascular mortality and infection when HDL-C >90 mg/dL and >70 mg/dL in women and men, respectively. The ability for the HDL particle to effectively transport cholesterol from the periphery for excretion in bile is more complex than illustrated on a standard cholesterol panel. There is variability in its function, size, density, subclass, reverse cholesterol transport, and cholesterol efflux capacity, which impact the particles ability to effectively reduce cardiovascular disease (CVD) risk. Research has shown that HDL particles are prone to have a reduction in its efficacy in response to infection, auto-immune disease, menopause and cardiometabolic conditions during pregnancy. Additionally, recent studies have shown that low HDL-C may not adequately influence ASCVD risk in Black adults. The purpose of this contemporary review is to highlight the utility of using HDL-C in assessing CVD risk.