Role and predictive value of the HDL function for cardiovascular disease in a high risk population. HDL function-linked markers and mechanisms

Abstract

Cardiovascular disease remains the first cause of death worldwide. Pharmacological trials and Mendelian randomization studies have failed to unequivocally prove an inverse association between HDL-C levels and the risk of cardiac outcomes. Interest is now focused on the atheroprotective functions of the HDL particle. The aim of the present thesis was to evaluate the predictive role for cardiovascular diseases of a battery of HDL properties and components. Moreover, we evaluated the relationships among major CVD risk factors, 10-year CVD risk, and HDL-functionality and low-density lipoprotein (LDL) atherogenicity. We conducted a meta-analysis to obtain an updated record of the available published literature in this field. To assess the prognostic value for CVD of a set of novel surrogates of HDL-functionality and composition, we analyzed cholesterol efflux capacity (CEC), HDL oxidative-inflammatory index (HOII), platelet activating factor acetylhydrolase (PAF-AH) activity bound to HDL, and the concentrations of apolipoprotein (Apo) A-I and ApoA-IV, serum amyloid A (SAA), component Complement C3, and sphingosine-1-phosphate (S1P) in ApoB depleted plasmain a nested case-control study with volunteers at high cardiovascular risk from the PreDiMed Study (Effects of Mediterranean Diet on the Primary Prevention of Cardiovascular Disease). Samples were matched in a 1:2 fashion by age, sex, body mass index, intervention group, and follow-up time in the study at event occurrence. Finally, we analyzed the relationships among HDL function, LDL atherogenicity, and the risk for cardiovascular disease and classical risk factors. We used data from two representative subsamples of volunteers from the PreDiMed trial. Meta-analysis of data from the 25 studies revealed an inverse association for cholesterol efflux and antioxidant/anti-inflammatory capacities with the risk of major adverse cardiac outcomes. The association was confirmed for the risk of all-cause mortality and cholesterol efflux and antioxidant capacity. Findings from the case-control study display HDL-related function and its main protein, ApoA-I, as promising biomarkers of cardiovascular outcomes. Higher CEC, HOII, and ApoA-I levels are strong, independent surrogates of acute coronary syndrome (ACS). Moreover, S1P almost reached statistical significance, with a p-value=0.056, in the model including HDL-C as confounder. CEC and ApoA-I were both associated with a greater risk for acute myocardial infarction (AMI) independent of classical cardiovascular risk factors. Finally, higher HOII and lower ApoA-I (irrespective of type 2 diabetes mellitus, hypercholesterolemia, hypertension, and smoking habit) increased the risk of unstable angina (UA). High cardiovascular risk was related to low HLD-C and ApoA-I, poor CEC, and a dysfunctional HDL profile (higher content in triglyceride, more oxidized and smaller in size) and with high levels of ApoB and pro-atherogenic LDL (smaller and less resistant to oxidation). Volunteers with type-2 diabetes had low levels of HDL-C, ApoA-I, low-density lipoprotein cholesterol (LDL-C), and ApoB, and smaller, more oxidized LDL. Systemic hypercholesterolemia was related to greater HDL-C, LDL-C, ApoA-I, and ApoB levels and to small HDL size, higher CETP activity, and lower HDL capacity to esterify cholesterol. Each increase of 1 kg/m2 in body mass index was associated with low HDL-C, lower size of both HDL and LDL, and decreased HDL capacity to esterify cholesterol. Finally, men presented lower HDL-C and ApoA-I levels, greater HDL oxidation and HDL impaired vasodilatory capacity, and higher cholesterol content in LDL particles. Age was related to greater triglyceride content in the HDL core. In summary, the meta-analysis study showed that CEC, and the anti-inflammatory and antioxidant capacities of HDL, are inverse predictors of CVD. The association persisted with CEC and antioxidant capacity for all-cause mortality risk. These results were further confirmed in the case-cohort study, in which CEC at baseline showed a strong and independent inverse association with the risk of ACS and AMI. ApoA-I had the ability to predict ACS, AMI, and US. HOII proved to be a predictive index for ACS and UA. Finally, high cardiovascular risk scores and classical risk factors for cardiovascular disease were associated with impaired HDL regarding its components, particle size, and function, and with a more pro-atherogenic LDL.