Objective To investigate roles of inflammation and a cholesteryl ester transfer protein (CETP) polymorphism potentially related to recent findings demonstrating coronary risk with increasing HDL cholesterol (HDL-C). Methods and Results A novel graphical exploratory data analysis tool allowed examination of coronary risk in postinfarction patients relating to HDL-C and C-reactive protein (CRP). Results demonstrated a high-risk subgroup defined by high HDL-C and CRP exhibiting larger HDL particles and lower lipoprotein-associated phospholipaseA2 (Lp-PLA2) levels than lower-risk patients. Subgroup CETP-associated risk was probed using a functional CETP polymorphism (TaqIB, rs708272). Multivariable modeling revealed in the high-risk subgroup greater risk for B2 allele-carriers (less CETP activity) versus B1 homozygotes (hazard ratio 2.41, 95% CI 1.04-5.60, p=0.041). Within the high-risk subgroup, B2 allele-carriers had higher serum amyloid A levels than B1 homozygotes. Evidence is also presented demonstrating CETP genotypic differences in HDL subfraction distributions regarding nonHDL-C and Lp-PLA2 potentially relating to impaired HDL remodeling. Conclusions Postinfarction patients with high HDL-C and CRP levels demonstrate increased risk for recurrent events. Future studies should aim at characterizing altered HDL particles from such patients and elucidating mechanistic details related to inflammation and HDL particle remodeling. Such patients should be considered in drug trials involving raising HDL-C.

No abstract

Few studies are available in human populations investigating involvement of vascular inflammation and oxidative stress-related dysfunctional transformation of high-density lipoprotein (HDL) in establishing cardiovascular disease (CVD) risk. To this end, the current work investigated a subgroup of post-infarction patients at high-risk for recurrent events defined by high levels of HDL cholesterol (HDL-C) and concurrently high levels of C-reactive protein (CRP). Thrombospondin-4 (TSP-4), a matricellular protein of vessel walls associated with inflammation, was investigated in terms of CVD risk using multivariable modelling with a well-characterised functional genetic polymorphism of THBS4 (A387P, rs1866389) along with previously demonstrated risk-related functional genetic polymorphisms of CYBA (C242T, rs4673) and CETP (TaqIB, rs708272), and a set of blood markers. Results revealed risk-association for the gain-of-function P-allele of the THBS4 polymorphism (hazard ratio 2.00, 95% confidence interval 1.10-3.65, p=0.024). Additionally, von Willebrand factor was associated with D-dimer levels in the higher-risk P allele patients suggestive of a connection between endothelial dysfunction and thrombogenesis. In conclusion, TSP-4, a matricellular protein involved in regulating vascular inflammation, plays a role in establishing recurrent coronary risk in post-infarction patients with high levels of HDL-C and CRP. Further studies should focus on additional effects of vascular inflammatory processes on anti-atherogenic functionality of HDL particles.

Objective-Nonhyperlipidemic postinfarction patients are at high risk for recurrent coronary events by virtue of incident myocardial infarction (MI); however, few studies assess risk beyond incident MI. The aim of this study was to assess such risk as a function of 37 atherosclerosis-associated genetic polymorphisms and 17 blood marker variables. Methods and Results-Screening of polymorphisms in nonhyperlipidemic postinfarction patients revealed significant risk only for the 4G/5G insertion/deletion polymorphism in the promoter of the plasminogen-activator inhibitor-1 (PAI-1) gene. Outcome event mapping, an exploratory data analysis tool, was then applied to define a subgroup (182 patients from total study population of 846 nondiabetic patients) exhibiting maximal functional dependence of risk on the PAI-1 polymorphism. Cox multivariable regression analyses within the subgroup adjusted for significant clinical covariates and medication use as a function of the PAI-1 polymorphism and 17 atherosclerosis-associated blood markers revealed significant risk for patients homozygous for the 4G allele (hazard ratio 4.30, 95% CI 1.98 to 9.33, Pϭ0.00023), and lack of significant risk-association with any blood marker. Conclusions-In a subgroup of normolipidemic postinfarction patients, only the PAI-1 4G/5G polymorphism was associated with recurrent risk from a set of atherosclerosis-associated genetic polymorphisms and blood markers. A lthough hypercholesterolemic postinfarction patients are at high risk for recurrent coronary events, normocholesterolemic postinfarction patients suffer recurrent events as well. 1 Beyond incident myocardial infarction (MI), traditional and nontraditional risk factors play a role 2,3 although little specific information is available especially for normolipidemic postinfarction patients. 4 In a previous report on nondiabetic patients of the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) postinfarction study, when lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) was included in models, it resulted in replacement of apolipoprotein B (apoB) as the only risk factor of recurrent coronary events from a set of thrombogenic, inflammatory, and metabolic blood markers. 5 To determine predictors of risk for recurrent events in normolipidemic postinfarction patients, we studied nondiabetic THROMBO patients (nϭ846) as a function of a set of 37 genetic markers associated with cardiovascular disease (CVD) followed by studies with a set of 17 thrombogenic, inflammatory, and metabolic blood markers. 5 Preliminary screening of genetic markers in normolipidemic (cholesterol Ͻ5.17 mmol/L, triglycerides Ͻ1.69 mmol/L) study patients revealed most significant risk for the 4G/5G insertion/deletion polymorphism (4 or 5 sequential guanosines, respectively) of plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of fibrinolysis. The polymorphism is located in the gene promoter region (chromosome 7) and results in allele-specific responses to multiple agents. 6 Accordingly, studies have shown th...