Featured Commentary

Issue No. 1: February 11, 2011

The importance of HDL functionality to cardiovascular risk

The first in a series of regular Commentaries highlighting topical issues relevant to EAS activities.

The link between HDL and cardiovascular disease risk is far more complex than originally thought. Although extensive epidemiological evidence is clearly supportive of an independent association between plasma levels of HDL cholesterol and cardiovascular disease risk,¹ data from genetic and clinical intervention studies are inconsistent.

This apparent conundrum may relate to the inherent heterogeneity of HDL particles, in terms of composition, structure and biological function. Indeed, HDL function may be compromised in certain disease states.² Emerging evidence suggests that in individuals with atherogenic dyslipidemia associated with low HDL-C plasma levels, HDL, in particular small, dense protein-rich HDL₃ particles, are less capable of protecting LDL against oxidative modification.³ This has led some to propose that the functionality of HDL may be as relevant as plasma levels of HDL cholesterol to cardiovascular risk assessment. A new study reported in the New England Journal of Medicine⁴ lends support to this proposal.

The authors hypothesed that the capacity of HDL to promote cholesterol efflux, i.e., the ability of HDL to accept cholesterol from macrophage foam cells, which reflects the role of HDL in atheroprotection – might be predictive of atherosclerotic burden independent of plasma levels of HDL cholesterol. Ex vivo cholesterol efflux capacity was measured from blood samples obtained from healthy volunteers (n=203) and patients with or without angiographic evidence of coronary artery disease (>50% stenosis) (442 cases and 351 controls). Carotid intima-media thickness (CIMT) was also measured in the healthy volunteer cohort.

In healthy volunteers there was a significant inverse association between cholesterol efflux capacity and CIMT, even after adjustment for plasma levels of HDL cholesterol (p=0.003) and apoliprotein A-I (p=0.005). In contrast, there was no association between plasma HDL cholesterol concentration and CIMT.

Compared with controls, patients with coronary artery disease not only had significantly lower levels of HDL cholesterol and apolipoprotein A-I, but also lower cholesterol efflux capacity (p<0.001 for each comparison). Logistic regression analysis showed that increased efflux capacity was independently predictive of a decrease in risk of coronary artery disease. Each 1-SD increase in cholesterol efflux capacity was associated with 30% decrease (95% CI 17-41%) in coronary disease risk (p<0.001). This association remained robust even when HDL cholesterol level was included as a covariate in the model (p=0.002) (Figure).

 

 

In supplementary studies, cholesterol efflux capacity was increased in patients with metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in statin-treated hypercholesterolemic patients. Indeed, in another study reported in the Journal of the American College of Cardiology⁵, atheroma progression was delayed after pioglitazone treatment in diabetic patients with low HDL cholesterol plasma levels. This may relate to the effects of treatment on both HDL function and level.

In an accompanying editorial⁶, Dr Jay Heinecke suggests that these findings support the relevance of cholesterol efflux capacity, as a measure of HDL function, to the pathophysiology of atherosclerosis. Although much remains to be done to delineate HDL metabolism it is plausible that other measures of HDL function, such as assessment of oxidative or anti-inflammatory properties, might be relevant in this context. From a clinical perspective, normalising anti-atherogenic function associated with defective HDL, as well as raising HDL cholesterol levels, might represent a promising and complementary therapeutic strategy.

References

1. The Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993-2000.
2. Kontush A, Chapman MJ. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidaemia, inflammation, and atherosclerosis. Pharmacol Rev 2006;58:342-74.
3. Kontush A, Chapman MJ. Antiatherogenic function of HDL particle subpopulations: focus on antioxidative activities. Curr Opin Lipidol 2010;21:312-8.
4. Khera AV, Cuchel M, de la Llera-Moya M et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011;364:127-35.
5. Nicholls SJ, Tuzcu EM, Wolski K et al. Lowering the triglyceride/high-density lipoprotein cholesterol ratio is associated with the beneficial impact of pioglitazone on progression of coronary atherosclerosis in diabetic patients. J Am Coll Cardiol 2011;57:153-9.
6. Heinecke J. HDL and cardiovascular disease risk – time for a new approach? N Engl J Med 2011 364:170-1.

Article written by Jane Stock, freelance medical writer and journalist. January 2011