María Trinidad Soria-Florido1,2, Olga Castañer1,3, Camille Lassale1, Ramon Estruch3,4,5, Jordi Salas-Salvadó3,6,7,8, Miguel Ángel Martínez-González3,9,10, Dolores Corella3,11, Emilio Ros3, Fernando Arós3,12, Roberto Elosua1,13, José Lapetra3,14, Miquel Fiol3,15, Angel Alonso-Gómez3,12, Enrique Gómez-Gracia3,16, Lluís Serra-Majem3,17, Xavier Pintó3,18, Mònica Bulló3,6,7,8, Miguel Ruiz-Canela3,9, Jose V Sorlí3,11, Álvaro Hernáez1,3,5, Montserrat Fitó1,3. 1. Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain (M.T.S.-F., O.C., C.L., R. Elosua, A.H., M.Fitó). 2. Universitat de Barcelona, Spain (M.T.S.-F.). 3. CIBER (Centro de Investigación Biomédica en Red) of Pathophysiology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain (O.C., R. Estruch, J.S.-S., M.Á.M.-G., D.C., E.R., F.A., J.L., M.Fiol, A.A.-G., E.G.-G., L.S.-M., X.P., M.B., M.R.-C., J.V.S., A.H., M.Fitó). 4. Hospital Clínic, Barcelona, Spain (R. Estruch, E.R.). 5. August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain (R. Estruch, A.H.). 6. Universitat Rovira i Virgili, Reus, Spain (J.S.-S., M.B.). 7. Hospital Universitari Sant Joan, Reus, Spain (J.S.-S., M.B.). 8. Pere Virgili Institute (IISPV), Reus, Spain (J.S.-S., M.B.). 9. Universidad de Navarra, Pamplona, Spain (M.Á.M.-G., M.R.-C.). 10. Harvard TH Chan School of Public Health, Boston, MA (M.Á.M.-G.). 11. Universidad de Valencia, Spain (D.C., J.V.S.). 12. Hospital Universitario de Álava, Vitoria, Spain (F.A., A.A.G.). 13. CIBER Cardiovascular Diseases (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain (R. Elosua). 14. Distrito Sanitario Atención Primaria Sevilla, Spain (J.L.). 15. Balearic Islands Health Research Institute, Hospital Son Espases, Palma de Mallorca, Spain (M.Fiol). 16. Universidad de Málaga, Spain (E.G.-G.). 17. Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain (L.S.-M.). 18. Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain (X.P.).
Abstract
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 (OR1SD, 0.58; 95% CI, 0.40-0.83) and low levels of sphingosine-1-phosphate (OR1SD, 0.70; 95% CI, 0.52-0.92) and apolipoprotein A-I (OR1SD, 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 (OR1SD, 1.27; 95% CI, 0.99-1.63). Low values of cholesterol efflux capacity (OR1SD, 0.33; 95% CI, 0.18-0.61), sphingosine-1-phosphate (OR1SD: 0.60; 95% CI: 0.40-0.89), and apolipoprotein A-I (OR1SD, 0.59; 95% CI, 0.37-0.93) were particularly linked to myocardial infarction, whereas high HDL oxidative-inflammatory index values (OR1SD, 1.53; 95% CI, 1.01-2.33) and low apolipoprotein A-I levels (OR1SD, 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.
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 (OR1SD, 0.58; 95% CI, 0.40-0.83) and low levels of sphingosine-1-phosphate (OR1SD, 0.70; 95% CI, 0.52-0.92) and apolipoprotein A-I (OR1SD, 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 (OR1SD, 1.27; 95% CI, 0.99-1.63). Low values of cholesterol efflux capacity (OR1SD, 0.33; 95% CI, 0.18-0.61), sphingosine-1-phosphate (OR1SD: 0.60; 95% CI: 0.40-0.89), and apolipoprotein A-I (OR1SD, 0.59; 95% CI, 0.37-0.93) were particularly linked to myocardial infarction, whereas high HDL oxidative-inflammatory index values (OR1SD, 1.53; 95% CI, 1.01-2.33) and low apolipoprotein A-I levels (OR1SD, 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.