Physicians' Academy for Cardiovascular Education

Reduced cholesterol efflux capacity in people with very high HDL-c and CAD

Literature - Agarwala AP et al., ATVB 2015

High-Density Lipoprotein (HDL) Phospholipid Content and Cholesterol Efflux Capacity Are Reduced in Patients With Very High HDL Cholesterol and Coronary Disease

Agarwala AP, Rodrigues A, Risman M, et al.
Arterioscler Thromb Vasc Biol. Originally published April 2, 2015. doi: 10.1161/ATVBAHA.115.305504


The HDL-c hypothesis that predicts that HDL-c levels are causally related to prevention of coronary artery disease (CAD), has been challenged. Common variants associated with small changes in HDL-c levels do not protect against coronary disease, while variants associated with LDL-c and triglyceride levels do [1,2]. Also clinical trials evaluating the effect of raising HDL-c failed to show clinical benefit [3,4]. Thus, a causal role of HDL-c in heart disease is topic of debate.
One of the properties of HDL that may protect against CAD is its role in promoting cholesterol efflux and reverse cholesterol transport [5]. HDL-c concentration, however, does not always reflect its functionality. Although extremely high HDL-c levels are generally associated with lower risk of CAD, a phenotype characterised by very high HDL-c with development of CAD in the absence of traditional risk factors also exists.
This study tests the hypothesis that individuals with this phenotype have altered composition and reduced function of their HDL that may predispose them to higher CAD risk. 55 cases with very high HDL-c and CAD were recruited, as well as 120 matched controls with high HDL-c without CAD.

Main results

  • HDL phospholipid (HDL-PL) concentrations were lower in cases (92+37 mg/dL) than in controls (109+43 mg/dL, P=0.0095), which fully accounted for the difference in total plasma PLs. No differences were seen in total HDL particle number or in either large, medium or small HDL particle numbers.
  • The capacity of HDL to promote cholesterol efflux from J774 macrophages was measured. After adjustment for age, sex and BMI, cases showed significantly lower efflux capacity than did controls (1.96+0.39 vs. 2.11+0.43, P=0.03, cAMP-inducible efflux: 0.60+0.24 vs. 0.71+0.32, P=0.025).
  • The ratio of cholesterol efflux/HDL-c was also lower in cases as compared with controls (0.023+0.005 vs. 0.025+0.006, age, sex and BMI-adjusted P: 0.006).
  • HDL-PL was a significant predictor of total cholesterol efflux capacity (slope: 0.0025, R2: 0.06, P=0.009). Cholesterol esterification rate or phospholipid transfer protein activity did not differ between cases and controls.


Individuals with the paradoxical phenotype of extremely high HDL-c and CAD, show reduced levels of HDL phospholipids and lower HDL cholesterol efflux capacity. These findings add to the accumulating evidence that HDL composition and function are linked to clinical CV disease, rather than HDL-c concentrations.
Find this article online at Arterioscler Thromb Vasc Biol.


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