Search

Objective— Vitamin K–dependent proteins (VKDPs), which require post-translational modification to achieve biological activity, seem to contribute to thrombus formation, vascular calcification, and vessel stiffness. Whether VKDP activity is prospectively associated with incident cardiovascular disease has not been studied. Approach and Results— VKDP activity was determined by measuring circulating des-γ-carboxy prothrombin concentrations in a random sample of 709 multiethnic adults free of cardiovascular disease drawn from the Multi-Ethnic Study of Atherosclerosis (MESA). Lower des-γ-carboxy prothrombin concentrations reflect greater VKDP activity. Subjects were followed up for the risk of ischemic cardiovascular disease (coronary heart disease, stroke, and fatal cardiovascular disease) for 11.0 years of follow-up. A total of 75 first ischemic CVD events occurred during follow-up. The incidence of ischemic cardiovascular disease increased progressively across des-γ-carboxy prothrombin quartiles, with event rates of 5.9 and 11.7 per 1000 person-years in the lowest and highest quartiles. In analyses adjusted for traditional cardiovascular risk factors and measures of vitamin K intake, a doubling of des-γ-carboxy prothrombin concentration was associated with a 1.53 (95% confidence interval, 1.09–2.13; P =0.008) higher risk of incident ischemic cardiovascular disease. The association was consistent across strata of participants with diabetes mellitus, hypertension, renal impairment, and low vitamin K nutritional intake. Conclusions— In this sample of middle-aged and older adults, VKDP activity was associated with incident ischemic cardiovascular events. Further studies to understand the role of this large class of proteins in cardiovascular disease are warranted.

Objective— CD14 is a glycosylphosphotidylinositol-anchored membrane glycoprotein expressed on neutrophils and monocytes/macrophages that also circulates as a soluble form (sCD14). Despite the well-recognized role of CD14 in inflammation, relatively little is known about the genetic determinants of sCD14 or the relationship of sCD14 to vascular- and aging-related phenotypes. Methods and Results— We measured baseline levels of sCD14 in >5000 European-American and black adults aged 65 years and older from the Cardiovascular Health Study, who were well characterized at baseline for atherosclerotic risk factors and subclinical cardiovascular disease, and who have been followed for clinical cardiovascular disease and mortality outcomes up to 20 years. At baseline, sCD14 generally showed strong positive correlations with traditional cardio-metabolic risk factors and with subclinical measures of vascular disease such as carotid wall thickness and ankle-brachial index (independently of traditional cardiovascular disease risk factors), and was also inversely correlated with body mass index. In genomewide association analyses of sCD14, we (1) confirmed the importance of the CD14 locus on chromosome 5q21 in European-American; (2) identified a novel African ancestry-specific allele of CD14 associated with lower sCD14 in blacks; and (3) identified a putative novel association in European-American of a nonsynonymous variant of PIGC , which encodes an enzyme required for the first step in glycosylphosphotidylinositol anchor biosynthesis. Finally, we show that, like other acute phase inflammatory biomarkers, sCD14 predicts incident cardiovascular disease, and strongly and independently predicts all-cause mortality in older adults. Conclusion— CD14 independently predicts risk mortality in older adults.

Objective— Although prior studies report a relationship between elevated lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) and incident cardiovascular disease, the prospective association of Lp-PLA 2 with incident peripheral arterial disease (PAD) has not been studied. We investigated the association between Lp-PLA 2 mass and activity and the risk of developing clinical PAD and low ankle–brachial index (ABI). Approach and Results— Among Cardiovascular Health Study participants, a population-based cohort of 5888 adults aged ≥65 years enrolled in 1989 to 1990, Lp-PLA 2 mass and activity were measured in 4537 individuals without baseline PAD. Clinical PAD, defined as leg artery revascularization or diagnosed claudication, was ascertained through 2011. Incident low ABI, defined as ABI 0.9 at baseline and a second ABI measurement 3 or 6 years later. Analyses were adjusted for demographics, cholesterol, smoking, comorbidities, and C-reactive protein. Each standard deviation increment in Lp-PLA 2 mass (117 ng/mL) was associated with a higher risk of developing clinical PAD (hazard ratio 1.28; 95% confidence interval 1.13, 1.45) and incident low ABI (odds ratio 1.16; 95% confidence interval 1.00, 1.33). Results per standard deviation increment in Lp-PLA 2 activity (13 nmol/min per mL) were similar for clinical PAD (hazard ratio 1.24; 95% confidence interval 1.07, 1.44) and low ABI (odds ratio 1.28; 95% confidence interval 1.09, 1.50). Conclusions— Higher Lp-PLA 2 mass and activity were associated with development of both incident clinical PAD and low ABI. Future studies are needed to determine whether pharmacological inhibition of Lp-PLA 2 reduces the incidence of PAD.

Objective— A common haplotype of the upstream transcription factor 1 gene ( USF1 ) has been associated with decreased susceptibility to familial combined hyperlipidemia (FCHL) and, paradoxically, with increased risk of cardiovascular disease (CVD) and all-cause mortality. Methods and Results— We assessed associations between USF1 tagSNPs, CVD risk factors, and aging-related phenotypes using data from 2 large population-based cohorts, Coronary Artery Risk Development in Young Adults (CARDIA) and the Cardiovascular Health Study (CHS), comprising younger and older adults, respectively. In CARDIA, each additional copy of the FCHL low-risk allele was associated with 2.4 mg/dL lower levels of LDL cholesterol ( P =0.01) and decreased risk of subclinical atherosclerosis as assessed by coronary artery calcium (odds ratio 0.79; 95%CI 0.63 to 0.98). Whereas there was little association between USF1 genotype and metabolic or CVD traits in older adults from CHS, the USF1 low-risk dyslipidemia allele was associated with higher plasma C-reactive protein and interleukin (IL)-6 levels and with increased risk of mortality, particularly attributable to noncardiovascular causes. Conclusions— There appears to be a complex and possibly age-dependent relationship between USF1 genotype, atherosclerosis phenotypes, and CVD risk. USF1 may influence mortality through pathways distinct from atherosclerosis. Alternatively, linkage disequilibrium with neighboring polymorphisms in other genes such as F11R may be responsible for the observed USF1 genotype–phenotype associations in older adults.

Inflammation is clearly recognized as a central component in the development and progression of cardiovascular disease (CVD). What is not clear, however, is how to best identify and monitor pathophysiologic inflammatory processes leading to acute coronary events. Many studies have focused on the potential of circulating biomarkers of inflammation to define risk of incident CVD events and morbidity and mortality following events. See pages 2517 and 2523 Lipoprotein-associated phospholipase A2 (Lp-PLA2) holds promise as a biomarker specifically associated with several key aspects of atherogenesis. Lp-PLA2, also known as platelet-activating factor acetylhydrolase (PAF-AH), is an enzyme produced primarily by macrophages and lymphocytes.1 Although Lp-PLA2 has been reported to exhibit both pro- and antiinflammatory activities, its primary role appears to be proatherogenic. In this context, Lp-PLA2 hydrolyzes oxidized phospholipids such as those within oxidized LDL, generating proinflammatory moieties lysophosphatidylcholine and oxidized fatty acids.1 In addition, approximately 80% of circulating Lp-PLA2 is sequestered on LDL particles which serve to modulate enzyme activity.1 Enzyme activity is reported to be increased when Lp-PLA2 bound to more atherogenic small dense LDL versus larger particles.2 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Kolodgie and colleagues3 and Gerber and colleagues4 provide important new evidence on the role of Lp-PLA2 in atherosclerosis development and prognostic value of this novel biomarker after myocardial infarction (MI). In an immunohistochemical study of …

Objective— Interleukin (IL)-6–mediated inflammation is involved in cardiovascular disease (CVD). We assessed IL-6 levels and the −174G>C genotype in a case-control study of men and women (average age 73 years) within the Cardiovascular Health Study. Methods and Results— Cases included incident angina, myocardial infarction (MI), and stroke (5-year follow-up), prevalent MI, and MRI-detectable infarcts. A control group and a group free of subclinical CVD were used for comparison. The −174C allele was associated with higher C-reactive protein (11% higher, P =0.02), fibrinogen (3% higher, P =0.02), and IL-6 (5% higher; P =0.16). IL-6 was associated with increased atherosclerosis when the control group was compared with the group free of subclinical CVD. No further association with CVD events was found when case groups were compared with the control group. Compared with its absence, presence of the −174C allele was associated with risk of MRI infarcts (odds ratio 1.5). Conclusions— IL-6 levels differentiated those with subclinical CVD from those without. Although the −174C allele was not associated with incident events, associations of the genotype with inflammation and MRI infarcts, combined with the plasma IL-6 results, suggest that IL-6 may chronically predispose an individual to develop atherosclerosis.