HDL Cholesterol: Form Versus Function

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Science Translational Medicine  07 Jan 2015:
Vol. 7, Issue 269, pp. 269ec1
DOI: 10.1126/scitranslmed.aaa3468

The lipid concentrations in your blood can help determine whether you’re at risk for atherosclerotic cardiovascular disease (ASCVD); not enough high density lipoprotein (HDL) cholesterol, a lipid species that promotes reverse cholesterol transport, and you’re considered at elevated risk. However, several drugs that raise plasma HDL levels fail to improve cardiovascular outcomes, and genetic variations associated with HDL concentration are not associated with ASCVD. Therefore, how plasma HDL is linked to atheroprotection in humans remains unclear.

Rohatgi et al. hypothesized that HDL function, rather than concentration, would be a more relevant measurement. The authors decided to test cholesterol efflux capacity—the ability of HDL to accept cholesterol from macrophages, a critical initial step in reverse cholesterol transport—in a large cohort of adults without baseline cardiovascular disease (2924 participants enrolled in the Dallas Heart Study). The primary endpoint was a composite ASCVD outcome defined by first nonfatal heart attack, nonfatal stroke, coronary artery revascularization procedure, or death from cardiovascular causes. Cholesterol efflux capacity was assessed by measuring the efflux of fluorescently labeled cholesterol from a murine macrophage cell line to apolipoprotein B-depleted plasma from study participants. The investigators found that higher cholesterol efflux capacity at baseline was strongly associated with lower rates of future cardiovascular events, with a 67% reduction in risk between the highest versus lowest quartiles of cholesterol efflux capacity. Furthermore, adding cholesterol efflux capacity to a traditional ASCVD risk factor panel significantly improved risk prediction.

This study demonstrates that measuring HDL function rather than absolute concentration can be used to enhance current clinical risk prediction strategies for ASCVD. Deeper insight into the relationship between HDL function and ASCVD can substantially advance our understanding of human atherogenesis and provide novel opportunities for its prevention and treatment.

A. Rohatgi et al., HDL cholesterol efflux capacity and incident cardiovascular events. N. Eng. J. Med. 371, 2383–2393 (2014). [Summary]

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