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Background Genetic variation in catechol-O-methyltransferase ( COMT ), a key enzyme in estrogen and catecholamine metabolism, has plausible physiological links to cardiovascular disease (CVD) and its risk factors. In WHS (Women's Health Study), COMT variants rs4818 and rs4680 were associated with a lower risk of CVD among women receiving placebo but not aspirin, suggesting a possible role of COMT in thrombosis. Methods and Results To evaluate potential pathways linking COMT with CVD, and COMT effect modification of aspirin in prevention, we examined COMT association with CVD risk and subclinical measures, coronary artery calcium, and carotid intima-media thickness in MESA (Multi-Ethnic Study of Atherosclerosis). In 65 957 person-years of follow-up, during which 498 events occurred, COMT rs4818 was associated with lower CVD risk (hazard ratio, 0.85; 95% CI, 0.74-0.97 [ P =0.02]). This association remained virtually unchanged after adjusting for common CVD risk factors. Fibrinogen was the only risk factor associated with rs4818 (β, -3.65; SE, 1.35 mg/dL [ P =0.007]). Results were directionally similar but not significant for rs4680. Adjusted hazard ratios for COMT rs4818 CVD association were 0.79 (95% CI, 0.65-0.95; P =0.02) among individuals who used aspirin <3 days per week and 0.89 (95% CI, 0.71-1.13; P =0.34) among more frequent users ( P interaction =0.39). Neither intima-media thickness nor coronary artery calcium was associated with COMT . Conclusions In a multiethnic prospective cohort of men and women, the COMT rs4818G allele was associated with lower CVD risk and lower fibrinogen levels but not with radiographic measures of subclinical atherosclerosis. These results suggest a plausible role of COMT in the latter stages of CVD.

Background: Two coding variants in the apo L1 gene ( APOL1 ) are strongly associated with kidney disease in blacks. Kidney disease itself increases the risk of cardiovascular disease, but whether these variants have an independent direct effect on the risk of cardiovascular disease is unclear. Previous studies have had inconsistent results., Methods: We conducted a two-stage individual participant data meta-analysis to assess the association of APOL1 kidney-risk variants with adjudicated cardiovascular disease events and death, independent of kidney measures. The analysis included 21,305 blacks from eight large cohorts., Results: Over 8.9±5.0 years of follow-up, 2076 incident cardiovascular disease events occurred in the 16,216 participants who did not have cardiovascular disease at study enrollment. In fully-adjusted analyses, individuals possessing two APOL1 kidney-risk variants had similar risk of incident cardiovascular disease (coronary heart disease, myocardial infarction, stroke and heart failure; hazard ratio 1.11, 95% confidence interval, 0.96 to 1.28) compared to individuals with zero or one kidney-risk variant. The risk of coronary heart disease, myocardial infarction, stroke and heart failure considered individually was also comparable by APOL1 genotype. APOL1 genotype was also not associated with death. There was no difference in adjusted associations by level of kidney function, age, diabetes status, or body-mass index., Conclusions: In this large, two-stage individual participant data meta-analysis, APOL1 kidney-risk variants were not associated with incident cardiovascular disease or death independent of kidney measures., (Copyright © 2019 by the American Society of Nephrology.)

Background: A role for vitamin K in coronary artery calcification (CAC), a subclinical manifestation of cardiovascular disease (CVD), has been proposed because vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein (MGP), are present in vascular tissue. Observational studies found that low circulating phylloquinone (vitamin K-1) was associated with increased CAC progression, especially in persons treated for hypertension. It is unknown whether hypertension treatment modifies this putative role of vitamin K in clinical CVD risk. Objective: We determined the association between vitamin K status and incident clinical CVD in older adults in the Health ABC (Health, Aging, and Body Composition Study) and whether the association differed by hypertension treatment status. Methods: Plasma phylloquinone was measured in 1061 participants free of CVD (70-79 y of age, 58% women, 39% black). Plasma uncarboxylated MGP [(dp)ucMGP] was measured in a subset of 635 participants. Multivariate Cox models estimated the HR for incident CVD over 12.1 follow-up years. Effect modification by hypertension was tested with the use of interaction terms. Results: Neither low plasma phylloquinone (<0.2 nmol/L) nor elevated (dp)ucMGP (≥574 pmol/L) was significantly associated with incident CVD [respective HRs (95% CIs): 1.27 (0.75, 2.13) and 1.02 (0.72, 1.45)]. In participants treated for hypertension ( n = 489; 135 events), low plasma phylloquinone was associated with higher CVD risk overall (HR: 2.94; 95% CI: 1.41, 6.13). In those with untreated hypertension ( n = 153; 48 events) and without hypertension ( n = 418; 92 events), low plasma phylloquinone was not associated with incident CVD. The association between high (dp)ucMGP did not differ by hypertension treatment status ( P -interaction = 0.72). Conclusions: Vitamin K status was not significantly associated with CVD risk overall, but low plasma phylloquinone was associated with a higher CVD risk in older adults treated for hypertension. Additional evidence from larger clinical studies is needed to clarify the importance of vitamin K to CVD in persons treated for hypertension, a segment of the population at high risk of clinical CVD events., Competing Interests: 2: Author disclosures: MK Shea, SL Booth, DE Weiner, TE Brinkley, AM Kanaya, RA Murphy, EM Simonsick, CL Wassel, and SB Kritchevsky, no conflicts of interest. VitaK is a research and development organization owned by Maastricht University. At the time of this study, C Vermeer was an advisor to VitaK but had no financial interests in this organization., (© 2017 American Society for Nutrition.)

This review provides background on the laboratory design for MESA (Multi-Ethnic Study of Atherosclerosis) as well as the approach used in MESA to select biomarkers for measurement. The research related to the multitude of circulating and urinary biomarkers of inflammation and other novel and emerging biological pathways in MESA is summarized by domain, or pathway, represented by the biomarker. The contributions of MESA biomarkers to our knowledge of these key pathways in the development and progression of atherosclerosis, cardiovascular disease, diabetes, kidney disease, and pulmonary disease are highlighted, as are the contributions of MESA to recommendations for clinical use of several of these biomarkers. In addition, contributions of MESA to multicohort genomics consortia and current collaborations in transomics and metabolomics are noted., (Copyright © 2016 World Heart Federation (Geneva). Published by Elsevier B.V. All rights reserved.)

Objective: At the cellular level, how excess adiposity promotes atherogenesis is not fully understood. One pathway involves secretion of adipokines that stimulate endothelial dysfunction through increased expression of adhesion molecules. However, the relationship of adiposity to adhesion molecules that promote atherosclerosis is largely unknown., Methods: Linear regression models were used to assess the sex-specific associations of soluble cellular adhesion molecules (sP- and sL-selectin, sICAM-1, sVCAM-1, and sHGF) and adiposity in 5,974 adults examined as part of the Multi-Ethnic Study of Atherosclerosis (MESA). Adiposity measures included body mass index (BMI), waist-to-hip-ratio (WHR), and computed tomography measures of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT)., Results: The mean age was 64 years and 52% were female. In multivariable models adjusting for traditional cardiovascular risk factors, sHGF was positively associated with BMI, WHR, and VAT in both males and females, and sP-selectin with WHR and VAT in males. sVCAM-1 was inversely associated with VAT in females only., Conclusions: Our results showed the relation of adiposity to soluble cellular adhesion proteins was similar across adiposity measures and for both sexes. However, the relationship between adiposity and sVCAM-1 and P-selectin may be modified by sex and the measure used to assess adiposity., (© 2015 The Obesity Society.)

Objective: Pericardial and intra-thoracic fat are associated with prevalent cardiovascular disease (CVD) and CVD risk factors. However, it is unclear if these fat depots predict incident CVD events and/or all-cause mortality. We examined prospective associations between areas of pericardial and intra-thoracic fat and incident CVD and mortality over a 12-year follow-up in a subset of participants without baseline clinical CVD from the Rancho Bernardo Study (RBS)., Methods: Participants were 343 community-dwelling older adults (mean baseline age = 67) who completed a clinic visit in 2001-02, including a computed tomography scan of the chest. Incident CVD and mortality were recorded through January 2013., Results: Over a 12.6-year median follow-up, there were 60 incident CVD events and 49 deaths. Pericardial fat was associated with all-cause mortality, such that each standard deviation increment predicted a 34% higher chance of death after adjusting for demographics, lifestyle factors, comorbidities, and visceral fat (95% CI = 1.01-1.78). When categorized by tertile, those in the middle tertile of pericardial fat showed no increased risk of mortality, while those in the highest tertile had 2.6 times the risk (95% CI = 1.10-5.97) compared to the lowest tertile. There was a marginal association between intra-thoracic fat and mortality (p = 0.06). Neither pericardial nor intra-thoracic fat was significantly associated with incident CVD. There were no significant interactions by sex., Conclusions: Higher pericardial, but not intra-thoracic, fat was associated with earlier all-cause mortality in older adults over a 12-year follow-up. This association was primarily driven by a higher mortality rate in those in the highest tertile of pericardial fat., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This study sought to determine an aggregate, pathway-specific risk score for enhanced prediction of death and myocardial infarction (MI)., Background: Activation of inflammatory, coagulation, and cellular stress pathways contribute to atherosclerotic plaque rupture. We hypothesized that an aggregate risk score comprised of biomarkers involved in these different pathways-high-sensitivity C-reactive protein (CRP), fibrin degradation products (FDP), and heat shock protein 70 (HSP70) levels-would be a powerful predictor of death and MI., Methods: Serum levels of CRP, FDP, and HSP70 were measured in 3,415 consecutive patients with suspected or confirmed coronary artery disease (CAD) undergoing cardiac catheterization. Survival analyses were performed with models adjusted for established risk factors., Results: Median follow-up was 2.3 years. Hazard ratios (HRs) for all-cause death and MI based on cutpoints were as follows: CRP ≥3.0 mg/l, HR: 1.61; HSP70 >0.625 ng/ml, HR; 2.26; and FDP ≥1.0 μg/ml, HR: 1.62 (p < 0.0001 for all). An aggregate biomarker score between 0 and 3 was calculated based on these cutpoints. Compared with the group with a 0 score, HRs for all-cause death and MI were 1.83, 3.46, and 4.99 for those with scores of 1, 2, and 3, respectively (p for each: <0.001). Annual event rates were 16.3% for the 4.2% of patients with a score of 3 compared with 2.4% in 36.4% of patients with a score of 0. The C statistic and net reclassification improved (p < 0.0001) with the addition of the biomarker score., Conclusions: An aggregate score based on serum levels of CRP, FDP, and HSP70 is a predictor of future risk of death and MI in patients with suspected or known CAD., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The presence and severity of coronary artery calcified plaque (CAC) differs markedly between individuals of African and European descent, suggesting that admixture mapping may be informative for identifying genetic variants associated with subclinical cardiovascular disease., Methods and Results: Admixture mapping of CAC was performed in 1040 unrelated African Americans with type 2 diabetes mellitus from the African American-Diabetes Heart Study, Multi-Ethnic Study of Atherosclerosis and Family Heart Study using the Illumina custom ancestry informative marker panel. All cohorts obtained computed tomography scanning of the coronary arteries using identical protocols. For each ancestry informative marker, the probability of inheriting 0, 1, and 2 copies of a European-derived allele was determined. Linkage analysis was performed by testing for association between each ancestry informative marker using these probabilities and CAC, accounting for global ancestry, age, sex, and study. Markers on 1p32.3 in the GLIS1 gene (rs6663966, logarithm of odds [LOD]=3.7), 1q32.1 near CHIT1 (rs7530895, LOD=3.1), 4q21.2 near PRKG2 (rs1212373, LOD=3.0), and 11q25 in the OPCML gene (rs6590705, LOD=3.4) had statistically significant LOD scores, whereas markers on 8q22.2 (rs6994682, LOD=2.7), 9p21.2 (rs439314, LOD=2.7), and 13p32.1 (rs7492028, LOD=2.8) manifested suggestive evidence of linkage. These regions were uniformly characterized by higher levels of European ancestry associating with higher levels or odds of CAC. Findings were replicated in 1350 African Americans without diabetes mellitus and 2497 diabetic European Americans from Multi-Ethnic Study of Atherosclerosis and the Diabetes Heart Study., Conclusions: Fine mapping these regions will likely identify novel genetic variants that contribute to CAC and clarify racial differences in susceptibility to subclinical cardiovascular disease.

Objectives: The goal of this study was to evaluate the prospective association of fetuin-A levels with cardiovascular disease (CVD) mortality., Background: Fetuin-A is a circulating inhibitor of calcium deposition in the vasculature and of insulin action in muscle and fat, and may be involved in the pathogenesis of CVD., Methods: This is a population-based prospective study of 633 men and 1,025 women (median age = 73 years) who had fetuin-A levels and CVD risk factors evaluated in 1992 to 1996 and were followed for vital status through 2010., Results: Plasma fetuin-A (g/l ± SD) was highest in women using oral estrogens (0.55 ± 0.12), intermediate for women not using oral estrogens (0.51 ± 0.10), and lowest for men (0.50 ± 0.10), p < 0.001. Lower fetuin-A levels were associated with older age, but with lower levels of other CVD risk factors including adiposity, blood pressure, lipids, triglycerides, and insulin resistance (all p < 0.01). During the median 12-year follow-up, 273 deaths were attributed to CVD. The association of fetuin-A with CVD mortality differed by diabetes status (p for interaction = 0.003). Adjusting for age, sex, oral estrogens, and lifestyle, the hazard ratio for CVD mortality comparing the lowest fetuin-A quartile with all higher values was 1.76 (95% confidence interval [CI]: 1.34 to 2.31; p < 0.001) for participants without diabetes and 0.43 (95% CI: 0.19 to 0.98; p = 0.046) for participants with diabetes., Conclusions: Low fetuin-A levels predicted greater risk for CVD mortality in older adults without diabetes, but were associated with reduced risk of CVD death in those with diabetes. Fetuin-A may provide novel insight into mechanisms leading to CVD death in those with versus without diabetes., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to determine the association of fetuin-A with subclinical cardiovascular disease (CVD) in community-living individuals., Background: Fetuin-A is a hepatic secretory protein that inhibits arterial calcium deposition in vitro. Lower fetuin-A levels are associated with arterial calcification and death in end-stage renal disease populations. The association of fetuin-A with subclinical CVD in the general population is unknown., Methods: Among 1,375 community-living individuals without prevalent clinical CVD, we measured plasma fetuin-A concentrations. Peripheral arterial disease (PAD) was defined by ankle brachial index <0.90, coronary artery calcification (CAC) was measured by computed tomography, and common and internal intima-media thickness (cIMT) were measured by carotid ultrasound. PAD was measured concurrent with fetuin-A, and CAC and cIMT were measured 4.6 years (mean) later., Results: Mean age was 70 ± 11 years, and 64% were women. Fetuin-A levels were inversely associated with CAC severity. When evaluated as CAC categories (0, 1 to 100, 101 to 300, >300) with ordinal logistic regression, each SD higher fetuin-A was associated with 31% lower odds of CAC severity (proportional odds ratio: 0.69; 95% confidence interval: 0.46 to 0.92; p = 0.008) in models adjusted for demographic data, lifestyle factors, traditional CVD risk factors, and kidney function. In contrast, no association of fetuin-A was observed with PAD or high common or internal cIMT in adjusted models., Conclusions: Lower fetuin-A levels are independently associated with greater CAC severity but not PAD or cIMT. If confirmed, fetuin-A might mark calcium deposition within the vasculature but not atherosclerosis per se., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Several common genomic loci, involving various immunity- and metabolism-related genes, have been associated with plasma fibrinogen in European Americans (EAs). The genetic determinants of fibrinogen in African Americans (AAs) are poorly characterized. Using a vascular gene-centric array in 23,634 EA and 6657 AA participants from 6 studies comprising the Candidate Gene Association Resource project, we examined the association of 47,539 common and lower frequency variants with fibrinogen concentration. We identified a rare Pro265Leu variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene single nucleotide polymorphisms (FGB rs1800787 and FGG rs2066861) significantly associated with fibrinogen in EAs were prevalent in AAs and showed consistent associations. Several fibrinogen locus single nucleotide polymorphism associated with lower fibrinogen were exclusive to AAs; these include a newly reported association with FGA rs10050257. For IL6R, IL1RN, and NLRP3 inflammatory gene loci, associations with fibrinogen were concordant between EAs and AAs, but not at other loci (CPS1, PCCB, and SCL22A5-IRF1). The association of FGG rs2066861 with fibrinogen differed according to assay type used to measure fibrinogen. Further characterization of common and lower-frequency genetic variants that contribute to interpopulation differences in fibrinogen phenotype may help refine our understanding of the contribution of hemostasis and inflammation to atherothrombotic risk.

Circulating adiponectin is involved in the atherosclerotic process and has been associated with cardiovascular disease as well as obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. The adiponectin gene (ADIPOQ) encodes the circulating protein adiponectin and affects its expression. Only a small proportion of all known ADIPOQ polymorphisms have been investigated in relation to circulating adiponectin concentrations. Using data from 3,355 African-American and white men and women aged 33-45 at the year 15 examination from the Coronary Artery Development in Young Adults (CARDIA) Study the association between 10 single-nucleotide polymorphisms (SNPs) within ADIPOQ and serum adiponectin was examined using linear regression. SNPs were chosen based on a tagSNP approach. Models were stratified by self-reported race to control for population stratification, and Bonferroni corrected for multiple comparisons. ADIPOQ SNPs rs17300539 (P < 0.0001), rs182052 (P = 0.0013), rs822393 (P = 0.0005), rs9882205 (P = 0.0001), and rs3774261 (P = 0.0001) were strongly associated with serum adiponectin concentrations in whites. In general, there was a dose-response relationship of adjusted mean adiponectin concentrations across genotypes. Only one SNP, rs17300539 was marginally associated with serum adiponectin concentrations (P = 0.0087) in African Americans. Significant interactions were found between waist and rs182052 (P = 0.0029) and between rs9882505 and smoking (P = 0.001) in whites. Many ADIPOQ SNPs have not yet been examined, and additional studies are needed to determine whether these may be functional variants.

Background: Whether novel biomarkers improve risk prediction of mortality beyond standard cardiovascular disease (CVD) risk markers in peripheral arterial disease (PAD) patients, and whether any such prediction differs with length of follow-up, remains controversial. Our objective was to determine in patients with PAD whether novel biomarkers improve prediction of CVD mortality and total mortality., Methods: A cohort of 397 patients who were referred to a vascular lab had PAD diagnosed by noninvasive testing. Fifty-eight percent also had coronary or cerebrovascular disease at baseline. Predictors of total, CVD, and non-CVD mortality were assessed with Cox proportional hazards models, and the incremental value of predictors was evaluated with both the C-statistic and the integrated discrimination improvement (IDI) index., Results: Total mortality was 11% at 2-year follow-up and 65% at an average of 6.6-year of follow-up (maximum, 11.4 years). At 2 years, hs-CRP was a strong and significant predictor of mortality, with a hazard ratio (HR) of 1.56 per standard deviation (P = .006). However, at full follow up, standard CVD risk markers were significant (age, gender, ankle-brachial index, other CVD, and hypertension), but hs-CRP no longer showed a significant relationship (HR 1.12; P = .11). None of the other biomarkers studied showed a significant independent association with mortality. Hs-CRP improved the C-statistic and the IDI beyond standard risk markers at 2 years, but not at full follow-up., Conclusions: hs-CRP was a strong predictor of short-term mortality in this cohort of PAD patients, while standard risk markers were better at predicting longer-term mortality., (Copyright (c) 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Differences in cardiovascular disease (CVD) burden exist among racial/ethnic groups in the United States, with African-Americans having the highest prevalence. Subclinical CVD measures have also been shown to differ by race or ethnicity. In the United States, there has been a significant intermixing among racial/ethnic groups creating admixed populations. Very little research exists on the relationship of genetic ancestry and subclinical CVD measures., Methods and Results: These associations were investigated in 712 black and 705 Hispanic participants from the Multi-Ethnic Study of Atherosclerosis candidate gene substudy. Individual ancestry was estimated from 199 genetic markers using STRUCTURE. Associations of ancestry and coronary artery calcium (CAC) and common and internal carotid intima media thickness were evaluated using log-binomial and linear regression models. Splines indicated linear associations of ancestry with subclinical CVD measures in African-Americans but presence of threshold effects in Hispanics. Among African-Americans, each SD increase in European ancestry was associated with an 8% (95% CI, 1.02 to 1.15; P=0.01) higher CAC prevalence. Each SD increase in European ancestry was also associated with a 2% (95% CI -3.4% to -0.5%, P=0.008) lower common carotid intima media thickness in African-Americans. Among Hispanics, the highest tertile of European ancestry was associated with a 34% higher CAC prevalence (P=0.02) when compared with the lowest tertile., Conclusions: The linear association of ancestry and subclinical CVD suggests that genetic effects may be important in determining CAC and carotid intima media thickness among African-Americans. Our results also suggest that CAC and common carotid intima media thickness may be important phenotypes for further study with admixture mapping.

Large arteries commonly become stiff in kidney failure, but few studies have investigated arterial stiffness in earlier stages of kidney disease. We evaluated the association between kidney function and aortic pulse wave velocity (aPWV) and its potential modification by race, diabetes, or coronary heart disease in older adults. We measured aPWV in 2468 participants in the Health Aging and Body Composition (Health ABC) study; mean age was 73.7 yr, 40% were black, and 24% had diabetes. After categorizing kidney function into three groups on the basis of cystatin C level, multivariable analysis revealed that the medium and high cystatin C groups associated with a 5.3% (95% confidence interval 0.8 to 10.0%) and 8.0% (95% confidence interval 2.2 to 14.1%) higher aPWV than the low cystatin C group; however, chronic kidney disease, as defined by estimated GFR <60 ml/min per 1.73 m(2), did not significantly associate with aPWV. We did not identify interactions between cystatin C and race, diabetes, or coronary heart disease. In conclusion, stiffness of large arteries, a major risk factor for cardiovascular disease, may partially mediate the association between cystatin C and cardiovascular risk in older adults.

Background and aimsHepatocyte growth factor (HGF) has previously been associated with risk of stroke, coronary heart disease, and atherosclerosis. We hypothesized that higher circulating HGF is associated with greater progression of measures of atherosclerosis: coronary artery calcium (CAC) and carotid plaque.MethodsParticipants aged 45-84 years from the prospective cohort study Multi-Ethnic Study of Atherosclerosis had HGF measured at baseline (between 2000 and 2002) and were followed for progression of atherosclerosis for up to 12 years. CAC was measured at all five exams using the Agatston method. Mixed-effects models were used to examine the association of HGF and CAC progression among 6695 participants with available data. Relative risk regression was used to assess the association between HGF and new or additional carotid plaque between exams 1 and 5 in 3400 participants with available data. All point estimates were adjusted for potential confounding variables.ResultsEach standard deviation higher HGF at baseline was associated with 2.9 Agatston units/year greater CAC progression (95% CI: 1.6-4.2, p

BACKGROUND:APOL1 genetic variants confer an increased risk for kidney disease. Their associations with cardiovascular disease (CVD) are less certain. We aimed to compare the prevalence of subclinical CVD and incidence of atherosclerotic CVD and heart failure by APOL1 genotypes among self-identified black participants of MESA (Multi-Ethnic Study of Atherosclerosis). METHODS AND RESULTS:Cross-sectional associations of APOL1 genotypes (high-risk=2 alleles; low-risk=0 or 1 allele) with coronary artery calcification, carotid-intimal media thickness, and left ventricular mass were evaluated using logistic and linear regression. Longitudinal associations of APOL1 genotypes with incident myocardial infarction, stroke, coronary heart disease, and congestive heart failure were examined using Cox regression. We adjusted for African ancestry, age, and sex. We also evaluated whether hypertension or kidney function markers explained the observed associations. Among 1746 participants with APOL1 genotyping (mean age 62 years, 55% women, mean cystatin C-based estimated glomerular filtration rate 89 mL/min per 1.73 m2, 12% with albuminuria), 12% had the high-risk genotypes. We found no difference in prevalence or severity of coronary artery calcification, carotid-intimal media thickness, or left ventricular mass by APOL1 genotypes. The APOL1 high-risk group was 82% more likely to develop incident heart failure compared with the low-risk group (95% confidence interval, 1.01-3.28). Adjusting for hypertension (hazard ratio, 1.80; 95% confidence interval, 1.00-3.24) but not markers of kidney function (hazard ratio, 1.86; 95% confidence interval, 1.03-3.35) slightly attenuated this association. The APOL1 high-risk genotypes were not significantly associated with other clinical CVD outcomes. CONCLUSIONS:Among blacks without baseline CVD, the APOL1 high-risk variants may be associated with increased risk for incident heart failure but not subclinical CVD or incident clinical atherosclerotic CVD.

Coronary artery calcification (CAC) by the Agatston method predicts cardiovascular disease (CVD), but requires cardiac gated computed tomography (CT) scans, a procedure not covered by most insurance providers. An ordinal CAC score (scored 0-12 based on artery number and extent of calcification involvement) can be measured on standard chest CTs. However, the correlation of ordinal and Agatston CAC scores and their relative association with CVD mortality is uncertain, which we sought to determine. Nested case-control study. Community-living individuals undergoing "whole body" CT scans for preventive medicine. 4,544 consecutive patients with CT scans, were followed from 2000 to 2009. We selected cases who died of CVD (n = 57) and age, sex, and CT slice-thickness matched each case to three controls (N = 171). Cardiac gated 3 mm chest CTs and non-gated 6 mm standard chest CTs. CVD death over 9 years follow-up. The intra- and inter-reader kappa for the ordinal CAC score was 0.90 and 0.76 respectively. The correlation of Agatston and ordinal CAC scores was 0.72 (p

The cellular adhesion pathway is critical in the pathophysiology of atherosclerosis, and genetic factors contributing to regulation of circulating levels of related proteins may be relevant to risk prediction of cardiovascular disease. In contrast to conducting separate genome-wide protein quantitative trait loci (pQTL) mapping analyses of each individual protein, joint genetic association analyses of multiple quantitative traits can leverage cross-trait co-variation and identify simultaneous regulatory effects on protein levels across the pathway. We conducted a multi-pQTL (mpQTL) analysis of 15 proteins related to cellular adhesion assayed on 2313 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). We applied the MQFAM multivariate association analysis method in PLINK on normalized protein level residuals derived from univariate linear regression, adjusting for age, sex, and principal components of ancestry. Race/ethnicity-stratified analyses identified nine genome-wide significant ( P < 5e−08) loci associated with co-variation of protein levels. Although the majority of these SNPs were in proximity to structural genes of the assayed proteins, we discovered multiple loci demonstrating co-association with the circulation of at least two proteins. Of these, two significant loci specific to non-Hispanic white participants, rs17074898 at ALOX5AP ( P = 1.78E−08) and rs7521237 at KIAA1614 ( P = 2.2E−08), would not have met statistical significance using univariate analyses. Moreover, common patterns of multi-protein associations were discovered at the ABO locus across race/ethnicity. These results indicate the biological relevance of blood group antigens on regulation of circulating cellular adhesion pathway proteins while also demonstrating race/ethnicity-specific co-regulatory effects. [ABSTRACT FROM AUTHOR]

Subclinical cardiovascular disease (CVD) may be associated with both adipose and skeletal muscle tissues in the abdomen. Accordingly, we examined whether subcutaneous, intermuscular, and visceral adipose tissue, as well as abdominal lean muscle, were associated with the presence and extent of vascular calcification in multiple vascular beds. Three hundred and ninety four patients (58.1% men) underwent electron beam computed tomography (EBCT) scans as part of routine health maintenance screening. The coronary and carotid calcium scores were analyzed at the time of the scan, whereas the other calcium scores, as well as the body composition analyses, were analyzed retrospectively. Mean age was 55.2 ± 11.1 years and BMI was 26.9 ± 4.2. The prevalence of any calcification in the carotids, coronaries, thoracic aorta, abdominal aorta, and iliacs was 30.1, 60.1, 39.8, 55.7, and 56.8%, respectively. Compared to those with calcification in different vascular beds, those without vascular calcification generally had significantly more lean muscle and less adipose tissue. In separate multivariable logistic models, a 1 s.d. increment in the ratio of abdominal and visceral fat to total area of each corresponding compartments was significantly associated with an increased odds for the presence of thoracic aortic calcium (odds ratio (OR) = 1.6, 1.5, respectively; P = 0.01 for both). Conversely, increases in abdominal lean muscle were associated with significantly decreased odds of thoracic aortic calcification (OR = 0.34; P ≤ 0.01). A similar pattern of associations existed among the other vascular beds. Also, the association between lean muscle and vascular calcification was independent of visceral adipose tissue. In conclusion, adipose tissue was positively and lean body mass inversely associated with prevalent aortic calcification. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to determine the association of family history of peripheral artery disease (PAD) with PAD prevalence and severity. Background: PAD is a significant public health problem. Shared genetic and environmental factors may play an important role in the development of PAD. However, family history of PAD has not been investigated adequately. Methods: The San Diego Population Study enrolled 2,404 ethnically diverse men and women 29 to 91 years of age who attended a baseline visit from 1994 through 1998 to assess PAD and venous disease. Ankle brachial index measurement was performed at the baseline clinic examination, and family history of PAD was obtained via questionnaire. Family history of PAD was defined primarily as having any first-degree relative with PAD. Prevalent PAD was defined as ankle brachial index ≤0.90, and severe prevalent PAD was defined as ankle brachial index ≤0.70, with both definitions also including any previous leg revascularization. Logistic regression was used to evaluate the association of family history of PAD with prevalent PAD. Results: The mean age was 59 ± 11 years, 66% were women, and 58% were Caucasian, with 42% representing other racial or ethnic groups. Prevalence of PAD was 3.6%, and severe prevalent PAD was 1.9%. In fully adjusted models, family history of PAD was associated with a 1.83-fold higher odds of PAD (95% confidence interval: 1.03 to 3.26, p = 0.04), an association that was stronger for severe prevalent PAD (odds ratio: 2.42, 95% confidence interval: 1.13 to 5.23, p = 0.02). Conclusions: Family history of PAD is independently strongly associated with PAD prevalence and severity. This indicates a role for genetic factors or other shared environmental factors, or both, contributing to PAD. [Copyright &y& Elsevier]

BackgroundDisorders in mineral metabolism are associated with risk for cardiovascular disease (CVD) events in patients with kidney disease as well as in the general population. This risk is thought to be mediated, in part, through the mechanism of stiffening of the arteries.MethodsThe objective of this study was to evaluate the relationships between serum calcium, phosphorus, intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D levels and arterial pulse wave velocity (aPWV) among 2,229 community-dwelling elderly persons participating in the Health Aging and Body Composition (Health ABC) study.ResultsThe mean age of the participants was 72 years; 52% were woman, 39% were black, and 17% had chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2). In parallel unadjusted analyses, the following associations were observed: 2.86% greater aPWV per 12 ng/ml (s.d.) lower 25-hydroxyvitamin D (95% confidence interval −4.38%, −1.31%), 3.04% greater aPWV per 28 pg/ml (s.d.) higher iPTH (95% confidence interval 1.42−4.68%), and 2.37% lower aPWV per 0.5 mg/dl (s.d.) higher phosphorus (95% confidence interval −3.90% to - 0.81%). Except for phosphorus, these associations were attenuated and rendered no longer statistically significant after adjustment for demographic risk factors, clinical site, season, medications and other CVD risk factors. The results were similar in men and women and were not dependent on the presence of CKD.ConclusionsAmong well-functioning community-dwelling elderly persons, only serum phosphorus was associated with aPWV; and this association was in the opposite direction of the one hypothesized. Factors other than vascular stiffening may mediate the relationship between disordered mineral metabolism and CVD events in community-living elders.American Journal of Hypertension (2011). doi:10.1038/ajh.2011.43 [ABSTRACT FROM AUTHOR]

Circulating adiponectin is associated with both clinical and subclinical cardiovascular disease (CVD). Variants of the adiponectin gene (ADIPOQ) are associated with clinical CVD, but little is known about associations with subclinical CVD. We studied the association of 11 ADIPOQ single-nucleotide polymorphisms (SNPs) with common and internal carotid intima media thickness (cIMT), presence of coronary artery calcification (CAC), and CAC scores (in those with CAC) in 2,847 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were white (n = 712), African American (n = 712), Chinese (n = 718), and Hispanic (n = 705). All models were adjusted for age, sex, and field site, and stratified by race/ethnic group. African Americans with genotypes AG/GG of rs2241767 had 36% greater (95% confidence interval (CI; 16%, 59%), P = 0.0001) CAC prevalence; they also had a larger common cIMT (P = 0.0043). Also in African Americans, genotypes AG/AA of rs1063537 were associated with a 35% (95% CI (14%, 59%), P = 0.0005) greater CAC prevalence. Hispanics with the AA genotype of rs11711353 had a 37% (95% CI (14%, 66%), P = 0.0011), greater CAC prevalence compared to those with the GG genotype. Additional adjustment for ancestry in African-American and Hispanic participants did not change the results. No single SNP was associated with subclinical CVD phenotypes in Chinese or white participants. There appears to be an association between ADIPOQ SNPs and subclinical CVD in African Americans and Hispanics. Replication as well as assessment of other ADIPOQ SNPs is warranted. [ABSTRACT FROM AUTHOR]

A higher serum phosphorus level is associated with cardiovascular disease (CVD) events among community-living populations. Mechanisms are unknown. The ankle-brachial index (ABI) provides information on both atherosclerosis and arterial stiffness. In this cross-sectional study (2000–2002), the authors evaluated the association of serum phosphorus levels with low (<0.90) and high (≥1.40 or incompressible) ABI as compared with intermediate ABI in 5,330 older US men, among whom the mean serum phosphorus level was 3.2 mg/dL (standard deviation, 0.4), 6% had a low ABI, and 5% had a high ABI. Each 1-mg/dL increase in serum phosphorus level was associated with a 1.6-fold greater prevalence of low ABI (95% confidence interval (CI): 1.2, 2.1; P < 0.001) and a 1.4-fold greater prevalence of high ABI (95% CI: 1.0, 1.9; P = 0.03) in models adjusted for demographic factors, traditional CVD risk factors, and kidney function. However, the association of phosphorus with high ABI differed by chronic kidney disease (CKD) status (in persons with CKD, prevalence ratio = 2.96, 95% CI: 1.61, 5.45; in persons without CKD, prevalence ratio = 1.14, 95% CI: 0.81, 1.61; interaction P = 0.04). In conclusion, among community-living older men, higher phosphorus levels are associated with low ABI and are also associated with high ABI in persons with CKD. These associations may explain the link between serum phosphorus levels and CVD events. [ABSTRACT FROM PUBLISHER]

Objective: Few population-based studies report cardiovascular disease (CVD) risk factor prevalence for South Asians in the United States. We examined CVD risk for South Asians in California.Design/setting/participants: We used data from two population-based surveys with South Asian participants in California, the California Health Interview Survey (CHIS) and the Cardiovascular Health among Asian Indian (CHAI) survey. The CHIS 2001 was conducted in English; 769 South Asians aged 25-83 years participated as one of many ethnic groups. The CHAI survey was population-based but focused on ethnicity-specific characteristics in 304 South Asians aged 25-80 years in English and Punjabi in 2001-2002.Main Outcome Measures: A CVD risk score included smoking, hypertension, hypercholesterolemia, diabetes, myocardial infarction, and angina. Separate logistic regression models examined the association of sociodemographics, lifestyle, medical risk, acculturation, and "any CVD risk."Results: In CHAI, hypertension (20%), hypercholesterolemia (24%), and diabetes (10%) were high; smoking was low (12%). In CHIS, prevalence of these conditions was lower, except smoking (21%). Approximately 35% of participants in each survey had any CVD risk. Male sex, age, higher body mass index, education less than a bachelor's degree, and alcohol use were associated with CVD risk in both studies. The CHAI subjects interviewed in English had higher odds of any CVD risk than those interviewed in Punjabi (odds ratio 10.3, 95% confidence interval 2.9-36.7).Conclusions: Data from multiple sources add crucial information about heterogeneity of risk within ethnic populations. South Asians in the CHIS had higher rates of smoking, but lower CVD risk scores than participants in the CHAI study. In CHAI, English language use was associated with increased CVD risk score. Additional research should examine if acculturation increases CVD risk. [ABSTRACT FROM AUTHOR]

Lower extremity peripheral artery disease (PAD) burden differs by race/ethnicity. Although familial aggregation and heritability studies suggest a genetic basis, little is known about the genetic susceptibility to PAD, especially in non-European descent populations. Genome-wide association studies (GWAS) of the ankle brachial index (ABI) and PAD (defined as an ABI < 0.90) have not been conducted in Hispanics/Latinos. We performed a GWAS of PAD and the ABI in 7,589 participants aged >45 years from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We also performed GWAS for ABI stratified by Hispanic/Latino ethnic subgroups: Central American, Mexican, and South American (Mainland group), and Cuban, Dominican, and Puerto Rican (Caribbean group). We detected two genome-wide significant associations for the ABI in COMMD10 in Puerto Ricans, and at SYBU in the Caribbean group. The lead SNP rs4466200 in the COMMD10 gene had a replication p = 0.02 for the ABI in Multi-Ethnic Study of Atherosclerosis (MESA) African Americans, but it did not replicate in African Americans from the Cardiovascular Health Study (CHS). In a regional look-up, a nearby SNP rs12520838 had Bonferroni adjusted p = 0.05 (unadjusted p = 7.5 × 10−5) for PAD in MESA Hispanics. Among three suggestive associations (p < 10−7) in subgroup-specific analyses, DMD on chromosome X, identified in Central Americans, replicated in MESA Hispanics (p = 2.2 × 10−4). None of the previously reported ABI and PAD associations in whites generalized to Hispanics/Latinos. [ABSTRACT FROM AUTHOR]

Background and aims Adipokines are known to predict cardiovascular events, yet their association with coronary artery calcium (CAC), a surrogate marker of coronary atherosclerosis and risk factor for cardiovascular disease (CVD), is unclear. We aimed at assessing the association between adipokines and the severity and progression of CAC in healthy older adults, and at exploring potential modification by gender. Methods 409 men and women from the Rancho Bernardo Study with no known CVD underwent a chest computed tomography scan to determine baseline CAC severity; 329 returned 4.5 years later for a repeat scan to evaluate CAC progression. Adipokines (IL-6, adiponectin, leptin, and TNF-α) were measured from baseline blood samples. Ordinal linear and logistic regression models were used to determine the association of each adipokine with baseline severity and future progression of CAC. Results Adjusting for age and sex, IL-6 and leptin were associated with greater odds of increasing CAC severity (OR = 1.63, 95% CI 1.22–2.19; OR = 1.19, 95% CI 0.99–1.43, respectively, per SD). The association with IL-6 remained significant in models further adjusted for lifestyle, body size, CVD risk factors, and body fat distribution. Adiponectin was associated with CAC progression (OR = 0.68, 95% CI 0.51–0.92 in fully adjusted models). This was modified by sex, with protective effects seen for men (OR = 0.57, 95% CI 0.38–0.85), but not for women (OR = 0.93, 95% CI 0.67–1.32; p -for-interaction = 0.04). Conclusions IL-6 and leptin predicted greater CAC severity while adiponectin predicted lower odds of CAC progression. More research is needed to explore biological mechanisms, including differences by sex. [ABSTRACT FROM AUTHOR]

Background and aims There is strong evidence that fat accumulating in non-adipose sites, “ectopic fat”, is associated with cardiovascular disease (CVD), including vascular calcification. Most previous studies of this association have assessed only a single ectopic fat depot. Therefore, our aim was to assess the association of total, regional, and ectopic fat with abdominal aorto-illiac calcification (AAC) and coronary artery calcification (CAC) in 798 African ancestry men. Methods Participants (mean age 62) were from the Tobago Bone Health Study cohort. Adiposity was assessed via clinical examination, dual x-ray absorptiometry, and computed tomography (CT). Ectopic fat depots included: abdominal visceral adipose tissue (VAT), liver attenuation, and calf intermuscular adipose tissue (IMAT). Vascular calcification was assessed by CT and quantified as present versus absent. Associations were tested using multiple logistic regression adjusted for traditional cardiovascular risk factors. Models of ectopic fat were additionally adjusted for total body fat and standing height. Results All adiposity measures, except VAT, were associated with AAC. Lower liver attenuation or greater calf IMAT was associated with 1.2–1.3-fold increased odds of AAC ( p < 0.03 for both), though calf IMAT was a stronger predictor than liver attenuation ( p < 0.001) when entered in a single model. No ectopic fat measure was associated with CAC. Conclusions Greater adiposity in the skeletal muscle and liver, but not in the visceral compartment, was associated with increased odds of AAC in African ancestry men. These results highlight the potential importance of both quantity and location of adiposity accumulation throughout the body. [ABSTRACT FROM AUTHOR]

Background Progression of coronary artery calcium (CAC) is associated with increased risk of coronary heart disease (CHD) and is reported to be greater in whites than blacks, Hispanics, and Chinese in the US. Our objective was to compare progression of CAC between Japanese Americans and whites. Methods Population-based sample of 303 Japanese American men and 310 white men aged 40–49 years, free of clinical cardiovascular disease at baseline, were examined for CAC at baseline (2004-2007) and follow-up (2008–2013). Progression of CAC was defined as change in coronary calcium scores (CCS) in participants with baseline CCS > 0 and incident CAC in participants with baseline CCS = 0. Multiple linear regression and relative risk regression were used to compare change in CCS scores and incident CAC between the two races, respectively. Results Japanese American men had significantly greater annual change in CCS than white men (median [interquartile range]: 11.3 Agatston units [1.4, 24.9] vs 2.5 [− 0.22, 14.5]) in the unadjusted analyses. After adjusting for cardiovascular risk factors and follow-up time, change in CCS (beta ± CI) and incidence rate ratio of CAC was similar in Japanese American men and white men: − 0.12 (− 0.34, 0.15) and (0.87 [95% CI: 0.20, 3.9]), respectively. Conclusions In contrast to previously reported greater progression of CAC in whites than other races, we found a similar progression of CAC in Japanese American men as white men. Our study identifies Japanese American men as a target group for prevention of CHD. Large prospective studies are warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

Background and aims ABO blood type is associated with cardiovascular disease, although the underlying mechanisms are presumed to be complex. While the relationship between non-O blood types and von Willebrand Factor (vWF) is well-established, associations with cellular adhesion molecules (CAMs) across diverse populations are understudied. Methods We genetically inferred ABO alleles for N = 6202 participants from the Multi-Ethnic Study of Atherosclerosis. Linear regression was used to evaluate associations between major ABO allele dosages and log-transformed measurements of vWF (N = 924), soluble E-selectin (sE-selectin, N = 925), soluble P-selectin (sP-selectin, N = 2392), and soluble ICAM-1 (sICAM-1, N = 2236) by race/ethnicity. Results For the selectins, the A1 allele was associated with significantly lower levels for all races/ethnicities, with each additional allele resulting in a 28–39% decrease in sE-selectin and 10–18% decrease in sP-selectin relative to Type O subjects. However, the A2 allele demonstrated effect heterogeneity across race/ethnicity for sE-selectin, with lower levels for non-Hispanic whites ( p = 0.0011) but higher levels for Hispanics ( p = 0.0021). We also identified elevated sP-selectin levels for B-allele carriers solely in Hispanic participants ( p = 1.0E-04). ABO-by-race/ethnicity interactions were significant for both selectins ( p < 0.0125). More modest associations were observed between A1 allele dosage and levels of sICAM-1, with ABO alleles explaining 0.8–1.1% of the total phenotypic variation within race/ethnicity. ABO associations with vWF activity were consistent across race/ethnicity, with B allele carriers corresponding to the highest vWF activity levels. Conclusions ABO blood type demonstrates complex associations with endothelial markers that are largely generalizable across diverse populations. [ABSTRACT FROM AUTHOR]

Introduction: Microvascular abnormalities delay the access of glucose and insulin to target tissues, which may lead to insulin resistance, a major mechanism underlying type 2 diabetes (DM). C2, derived from the radial artery pulse wave is a measure designed to estimate the global arterial function of the more distal part of the arterial circulation. C2 is inversely associated with visceral fat, incident hypertension and cardiovascular disease (CVD) events (i.e., lower C2 suggests pathology). We studied the association of C2 with new onset of diabetes in subjects free of overt CVD. Methods: 5214 multi-ethnic participants, initially aged 45- 84 years, with no DM at baseline underwent radial artery pulse wave applanation tonometry. C2 was derived from radial artery pulse contour analysis. Incident DM was diagnosed by fasting glucose ≥126 mg/dl or antidiabetic medicine in any of 4 clinic visits over 10 years. The associations of C2 were estimated using proportional hazards regression in model 1 adjusted for demographics (age, sex, and race/ethnicity), while model 2 additionally adjusted for baseline values of height, heart rate, BMI, resting blood pressure and antihypertensive medication, lipids and lipid-lowering medication, renal function, and 5 inflammatory biomarkers Results: Mean C2 at baseline was 4.58 ± 2.85 mL/mm Hgх100. Incident DM occurred in 651 participants during 10 years of follow-up. After adjustment for demographics, the Hazard ratio (HR) for incident DM, per standard deviation of C2, was 0.90 (95% CI: 0.82, 0.99, P = 0.03). After additional adjustment for CV risk factors and inflammatory markers, the corresponding HR was 0.88 (95% CI: 0.80 - 0.98, p = 0.02). For the lowest vs highest C2 quartile, the HR was 1.35 (1.03 - 1.79). No race/ethnic interaction with C2 was observed. Conclusions: In a multi-ethnic population free of overt CVD, C2, a derivative of the radial artery pulse contour, predicted incident DM beyond demographics, CVD risk factors and inflammatory markers. Changes in arterial pulse wave morphology may already manifest a long-term risk trajectory for type 2 diabetes independently of the classical risk factors. [ABSTRACT FROM AUTHOR]