Dysfunctional High-Density Lipoproteins Are Associated with a Greater Incidence of Acute Coronary Syndrome in a Population at High Cardiovascular Risk: A Nested Case-Control Study

Background: Studies have failed to establish a clear link between high-density lipoprotein (HDL) cholesterol and cardiovascular disease, leading to the hypothesis that the atheroprotective role of HDL lies in its biological activity rather than in its cholesterol content. However, to date, the association between HDL functional characteristics and acute coronary syndrome has not been investigated comprehensively. Methods: We conducted a case-control study nested within the PREDIMED (Prevención con Dieta Mediterránea) cohort, originally a randomized trial in which participants followed a Mediterranean or low-fat diet. Incident acute coronary syndrome cases (N=167) were individually matched (1:2) to control patients by sex, age, intervention group, body mass index, and follow-up time. We investigated 2 individual manifestations (myocardial infarction, unstable angina) as secondary outcomes. We measured the following functional characteristics: HDL cholesterol concentration (in plasma); cholesterol efflux capacity; antioxidant ability, measured by the HDL oxidative-inflammatory index; phospholipase A2 activity; and sphingosine-1-phosphate, apolipoproteins A-I and A-IV, serum amyloid A, and complement 3 protein (in apolipoprotein B-depleted plasma). We used conditional logistic regression models adjusted for HDL cholesterol levels and cardiovascular risk factors to estimate odds ratios (ORs) between 1-SD increments in HDL functional characteristics and clinical outcomes. Results: Low values of cholesterol efflux capacity (OR_1SD, 0.58; 95% CI, 0.40-0.83) and low levels of sphingosine-1-phosphate (OR_1SD, 0.70; 95% CI, 0.52-0.92) and apolipoprotein A-I (OR_1SD, 0.58; 95% CI, 0.42-0.79) were associated with higher odds of acute coronary syndrome. Higher HDL oxidative inflammatory index values were marginally linked to acute coronary syndrome risk (OR_1SD, 1.27; 95% CI, 0.99-1.63). Low values of cholesterol efflux capacity (OR_1SD, 0.33; 95% CI, 0.18-0.61), sphingosine-1-phosphate (OR_1SD: 0.60; 95% CI: 0.40-0.89), and apolipoprotein A-I (OR_1SD, 0.59; 95% CI, 0.37-0.93) were particularly linked to myocardial infarction, whereas high HDL oxidative-inflammatory index values (OR_1SD, 1.53; 95% CI, 1.01-2.33) and low apolipoprotein A-I levels (OR_1SD, 0.52; 95% CI, 0.31-0.88) were associated with unstable angina. Conclusions: Low cholesterol efflux capacity values, pro-oxidant/proinflammatory HDL particles, and low HDL levels of sphingosine-1-phosphate and apolipoprotein A-I were associated with increased odds of acute coronary syndrome and its manifestations in individuals at high cardiovascular risk. Clinical Trial Registration: URL: https://www.controlled-Trials.com/ISRCTN35739639. Unique identifier: ISRCTN35739639.