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1.  A Cross-sectional Study of the Association Between Chronic Hepatitis C Virus Infection and Subclinical Coronary Atherosclerosis Among Participants in the Multicenter AIDS Cohort Study 
The Journal of Infectious Diseases  2015;213(2):257-265.
Background. Hepatitis C virus (HCV) infection may increase the risk of cardiovascular disease (CVD). We evaluated the association of chronic HCV infection and coronary atherosclerosis among participants in the Multicenter AIDS Cohort Study.
Methods. We assessed 994 men with or without human immunodeficiency virus (HIV) infection (87 of whom had chronic HCV infection) for coronary plaque, using noncontrast coronary computed tomography (CT); 755 also underwent CT angiography. We then evaluated the associations of chronic HCV infection and HIV infection with measures of plaque prevalence, extent, and stenosis.
Results. After adjustment for demographic characteristics, HIV serostatus, behaviors, and CVD risk factors, chronic HCV infection was significantly associated with a higher prevalence of coronary artery calcium (prevalence ratio, 1.29; 95% confidence interval [CI], 1.02–1.63), any plaque (prevalence ratio, 1.26; 95% CI, 1.09–1.45), and noncalcified plaque (prevalence ratio, 1.42; 95% CI, 1.16–1.75). Chronic HCV infection and HIV infection were independently associated with the prevalence of any plaque and of noncalcified plaque, but there was no evidence of a synergistic effect due to HIV/HCV coinfection. The prevalences of coronary artery calcium, any plaque, noncalcified plaque, a mixture of noncalcified and calcified plaque, and calcified plaque were significantly higher among men with an HCV RNA load of ≥2 × 106 IU/mL, compared with findings among men without chronic HCV infection.
Conclusions. Chronic HCV infection is associated with subclinical CVD, suggesting that vigilant assessments of cardiovascular risk are warranted for HCV-infected individuals. Future research should determine whether HCV infection duration or HCV treatment influence coronary plaque development.
PMCID: PMC4690151  PMID: 26216904
hepatitis C virus infection; atherosclerosis; plaque; cardiovascular disease; human immunodeficiency virus type 1
2.  Prognostic Significance of Biomarkers in Pulmonary Arterial Hypertension 
Rationale: Pulmonary arterial hypertension (PAH) is a rare progressive disease of the pulmonary vasculature that is characterized by endothelial dysfunction, inflammation, and right ventricular dysfunction.
Objectives: The main objective was to determine whether endothelial, inflammatory, and cardiac biomarkers would be associated with the World Health Organization functional assessment and survival in patients with PAH.
Methods: We performed a retrospective cohort study of patients with PAH enrolled in the Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension (ASA-STAT). Biomarkers (N-terminal fragment of pro-BNP [NT-pro-BNP], von Willebrand factor [vWF], soluble P selectin, C-reactive protein, total and high-density lipoprotein cholesterol, triglycerides, tumor necrosis factor, IL-6, β-thromboglobulin, and thromboxane B2) were measured at baseline. Patients from the study were followed until lung transplantation, death, or August 1, 2013. Ordinal logistic regression and Cox regression analyses were performed.
Measurements and Main Results: Sixty-five patients with PAH were enrolled. The mean age was 51 years, and 86% were women. Higher vWF activity, lower high-density lipoprotein cholesterol, and higher thromboxane B2 levels were associated with worse World Health Organization functional class after adjustment for age, sex, and etiology of PAH. Higher NT-pro-BNP levels, lower vWF activity, and lower total cholesterol were associated with an increased risk of death or lung transplant after adjustment for age, sex, etiology of PAH, and 6-minute-walk distance.
Conclusions: In patients with PAH, lower vWF activity and cholesterol levels and higher NT-pro-BNP levels at baseline were associated with an increased risk of death or transplantation.
Clinical trial registered with (NCT00384865).
PMCID: PMC4722842  PMID: 26501464
biomarkers; pulmonary arterial hypertension; World Health Organization functional class; survival
3.  Associations Between Antiretroviral Use and Subclinical Coronary Atherosclerosis 
AIDS (London, England)  2016;30(16):2477-2486.
HIV infection is associated with increased prevalence of subclinical coronary plaque. The extent to which such plaque reflects effects of HIV infection or effects of long-term antiretroviral (ART) use remains unclear and was the goal of this analysis.
Design and Methods
We compared the prevalence and extent of coronary plaque and stenosis between users of specific ART drugs or drug classes using coronary computed tomography (CT) among HIV-infected men in the Multicenter AIDS Cohort Study. To account for time-dependent confounders, including cardiovascular disease (CVD) risk factors and time-varying reasons for using specific treatments, we conducted fully adjusted logistic and linear models with inverse probability of treatment weighting.
There were 618 men who underwent non-contrast coronary CT; 450 also underwent coronary CT angiography. At the time of scanning 81% had undetectable plasma HIV RNA. In fully adjusted models, cumulative use of zidovudine, abacavir, darunavir and protease inhibitors as a drug class were inconsistently associated with specific forms of plaque presence or extent.
Among virally suppressed HIV-infected men with extensive ART exposure, no consistent associations between use of specific ART drugs and both subclinical coronary plaque presence and extent were apparent. Our findings support the hypothesis that, among virally suppressed persons, type of ART used is not in general a major determinant of subclinical coronary plaque risk.
PMCID: PMC5173385  PMID: 27490639
antiretroviral therapy; HIV; subclinical coronary plaque; atherosclerosis; coronary computed tomography (CT); coronary angiography
4.  Secondhand Smoke Exposure and Subclinical Cardiovascular Disease: The Multi‐Ethnic Study of Atherosclerosis 
Few studies have evaluated the association between secondhand smoke (SHS) and subclinical cardiovascular disease among ethnically diverse populations. This study assesses the impact of SHS on inflammation and atherosclerosis (carotid intima‐media thickness, coronary artery calcification, and peripheral arterial disease).
Methods and Results
We examined 5032 nonsmoking adults aged 45 to 84 years without prior cardiovascular disease participating in the Multi‐Ethnic Study of Atherosclerosis (MESA) from 2000 to 2002. SHS exposure was determined by self‐report, and urinary cotinine was measured in a representative subset (n=2893). The multi‐adjusted geometric mean ratios (95% CIs) for high‐sensitivity C‐reactive protein and interleukin‐6 comparing 407 participants with SHS ≥12 h/wk versus 3035 unexposed participants were 1.13 (1.02–1.26) and 1.04 (0.98–1.11), respectively. The multi‐adjusted geometric mean ratio for carotid intima‐media thickness was 1.02 (0.97–1.07). Fibrinogen and coronary artery calcification were not associated with SHS. The prevalence of peripheral arterial disease (ankle‐brachial index ≤0.9 or ≥1.4) was associated with detectable urinary cotinine (odds ratio, 2.10; 95% CI, 1.09–4.04) but not with self‐reported SHS. Urinary cotinine was not associated with inflammation or carotid intima‐media thickness.
Despite limited exposure assessment, this study supports the association of SHS exposure with inflammation and peripheral arterial disease.
PMCID: PMC5210438  PMID: 27993830
ankle‐brachial index; atherosclerosis; carotid intima‐media thickness; coronary artery calcium; inflammation; peripheral artery disease; secondhand smoke; smoking; Cardiovascular Disease; Epidemiology; Risk Factors; Lifestyle; Primary Prevention
5.  Association of N-Linked Glycoprotein Acetyls and Colorectal Cancer Incidence and Mortality 
PLoS ONE  2016;11(11):e0165615.
Acute phase proteins highlight the dynamic interaction between inflammation and oncogenesis. GlycA, a novel nuclear magnetic resonance (NMR) inflammatory marker that identifies primarily circulating N-acetyl glycan groups attached to acute phase proteins, may be a future CRC risk biomarker.
We examined the association between GlycA and incident CRC and mortality in two prospective cohorts (N = 34,320); Discovery cohort: 27,495 participants from Women's Health Study (WHS); Replication cohort: 6,784 participants from Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable Cox models were adjusted for clinical risk factors and compared GlycA to acute phase proteins (high-sensitivity C-reactive protein [hsCRP], fibrinogen, and soluble intercellular adhesion molecule-1 [sICAM-1]).
In WHS (median follow-up 19 years, 337 cases, 103 deaths), adjusted HRs (95% CIs) per SD increment of GlycA for CRC incidence and mortality were 1.19 (1.06–1.35; p = 0.004) and 1.24 (1.00–1.55; p = 0.05), respectively. We replicated findings in MESA (median follow-up 11 years, 70 cases, 23 deaths); HRs (95% CIs) per SD of GlycA for CRC incidence and mortality were 1.32 (1.06–1.65; p = 0.01) and 1.54 (1.06–2.23; p = 0.02), respectively, adjusting for age, sex, and race. Pooled analysis, adjusted HR (95% CI) per SD of GlycA for CRC incidence and mortality was 1.26 (1.15–1.39; p = 1 x 10−6). Other acute phase proteins (hsCRP, fibrinogen, and sICAM-1) had weaker or no association with CRC incidence, while only fibrinogen and GlycA were associated with CRC mortality.
The clinical utility of GlycA to personalize CRC therapies or prevention warrants further study.
Trial Registration WHS NCT00000479, MESA NCT00005487
PMCID: PMC5130185  PMID: 27902713
6.  Incidence and progression of coronary artery calcium (CAC) in HIV-infected and HIV-uninfected men 
AIDS (London, England)  2015;29(18):2427-2434.
To determine whether HIV-infected men have either higher incidence or more rapid progression of coronary artery calcium (CAC) compared to HIV-uninfected controls.
Prospective observational study.
Multicenter study in four USA academic research centers; University of Pittsburgh, Johns Hopkins University, University of California Los Angeles and Northwestern University.
825 men (541 HIV-infected and 284 HIV-uninfected) enrolled in the cardiovascular sub-study of the Multicenter AIDS Cohort Study who underwent serial cardiac CT imaging during a mean follow-up of 5 years (range, 2–8 years).
Main Outcome Measures
Incidence and progression of CAC assessed by cardiac computed tomography (CT).
During follow-up, 21% of HIV-infected men developed incident CAC as compared to 16% of HIV-uninfected men. This association persisted after adjustment for traditional and HIV-associated risk factors: HR 1.64 [1.13–3.14]. However, there was no association between HIV serostatus and CAC progression among men with CAC present at baseline. Current smoking and increased insulin resistance, both modifiable risk factors, were independently associated with increased incidence of CAC. No evidence supporting an elevated risk for either CAC progression or incidence was found for either dyslipidemia or long-term usage of antiretroviral therapy.
In this large study of HIV-infected and HIV-uninfected men who underwent serial cardiac CT scan imaging, HIV-infected men were at significantly higher risk for development of CAC: HR 1.64 [1.13–3.14]. In addition, two important and modifiable risk factors were identified for increased incidence of CAC. Taken together these findings underscore the potential importance for smoking cessation and interventions to improve insulin resistance among HIV-infected men.
PMCID: PMC4646724  PMID: 26558542
HIV; antiretroviral therapy; atherosclerosis; coronary artery calcium
7.  Prevalence of and factors associated with myocardial scar in a U.S. Cohort 
JAMA  2015;314(18):1945-1954.
Myocardial scarring leads to cardiac dysfunction and poor prognosis. The prevalence of and factors associated with unrecognized myocardial infarction and scar have not been previously defined using current methods in a multi-ethnic US population.
To determine prevalence of and factors associated with myocardial scar in middle and older aged individuals in the United States (U.S).
Design, Setting, and Participants
Multi-Ethnic Study of Atherosclerosis (MESA) is a population based cohort in the U.S. MESA participants were 45-84 years old and free of clinical cardiovascular disease (CVD) at baseline in 2000-2002. In the 10th year examination of MESA (2010-2012), 1840 participants underwent cardiac magnetic resonance imaging (CMR) with gadolinium to detect myocardial scar. CVD risk factors and coronary artery calcium scores were measured at baseline and year 10. Logistic regression models were used to estimate adjusted odds ratios for myocardial scar.
Cardiovascular risk factors, coronary artery calcium, left ventricle size and function, carotid intima media thickness
Main Outcome Measure
Myocardial scar detected by CMR.
Of 1840 participants (mean age 68±9 yrs, 52% male), 146 had myocardial scars (7.9%). Most myocardial scars (114/146, 78%) were undetected by electrocardiogram or by clinical adjudication. In adjusted models, age, male gender, body mass index, hypertension, and current smoking at baseline were associated with myocardial scar at year 10 [OR (95% CI): 1.6 (1.4, 1.9) per 8.9 years, p<0.001; 5.8 (3.6, 9.2) men vs. women, p<0.001; 1.3 (1.1, 1.6) per 4.8 kg/m2, p=0.005, 1.6 (1.1, 2.3) for hypertension present, p=0.009; 2.0 (1.2, 3.3) current vs. never smokers, p=0.006, respectively]. Age, gender and ethnicity adjusted CAC score at baseline was also associated with myocardial scar at year 10 [CAC categories of 1-99, 100-399 and ≥ 400 vs. CAC =0: OR (95% CI): 2.4 (1.5, 3.9), 3.0 (1.7, 5.1), 3.3 (1.7, 6.1), respectively, p≤0.001]. CAC score significantly added to the association of myocardial scar with age, gender, ethnicity and traditional CVD risk factors (c-statistic: 0.81 vs. 0.79, with vs. without CAC, respectively, p=0.012).
Conclusions and Relevance
The prevalence of myocardial scars in a US community based multiethnic cohort was 7.9%, of which 78% were unrecognized by electrocardiography or clinical evaluation. Further studies are needed to understand the clinical consequences of these undetected scars and the utility of their identification.
PMCID: PMC4774246  PMID: 26547466
8.  HIV infection is associated with increased coronary non-calcified plaque among participants with coronary artery calcium score of zero: Multicenter AIDS Cohort Study (MACS) 
HIV medicine  2015;16(10):635-639.
HIV infected individuals bear increased cardiovascular risk even in the absence of traditional cardiovascular risk factors. In the general population, coronary artery calcium (CAC) scanning is of value for cardiovascular risk stratification, but whether a CAC score of zero implies a low non-calcified coronary plaque burden in HIV infected persons is unknown.
We assessed the prevalence of non-calcified coronary plaque and compared non-calcified coronary plaque burden between HIV infected and HIV uninfected participants who had CAC scores of zero in the Multicenter AIDS Cohort Study (MACS) using coronary CT angiography.
HIV infection was associated with the presence of non-calcified coronary plaque among these men with CAC scores of zero. In a model adjusted only for age, race, center, and pre or post 2001 cohort, the prevalence ratio for the presence of non-calcified plaque was 1.27 (95% confidence interval 1.04–1.56, p = 0.02). After additionally adjusting for CVD risk factors, HIV infection remained associated with the presence of non-calcified coronary plaque (PR 1.31; 95% CI 1.07–1.6, p = 0.01).
In conclusion, among men with CAC scores of zero, HIV infection is associated with an increased prevalence of non-calcified coronary plaque independent of traditional cardiovascular risk factors. This finding suggests that CAC scanning may underestimate plaque burden in HIV infected men.
PMCID: PMC4618024  PMID: 25968104
9.  Coronary calcification in SLE: comparison with the Multi-Ethnic Study of Atherosclerosis 
Rheumatology (Oxford, England)  2015;54(11):1976-1981.
Objective. Accelerated atherosclerosis is a major cause of morbidity and death in SLE. The purpose of this study was to determine whether the prevalence and extent of coronary artery calcium (CAC) is higher in female SLE patients compared with a non-SLE sample from the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods. CAC was measured in 80 female SLE patients and 241 female MESA controls from the Baltimore Field Centre, ages 45–64 years, without evidence of clinical cardiovascular disease. Binary regression was used to estimate the ratio of CAC prevalence in SLE vs MESA controls, controlling for demographic and cardiovascular risk factors. To compare the groups with respect to the quantity of CAC among those with non-zero Agatston scores, we used linear models in which the outcome was a log-transformed Agatston score.
Results. The prevalence of CAC was substantially higher in SLE. The differences were most pronounced and statistically significant in those aged 45–54 years (58% vs 20%, P < 0.0001), but were still observed among those aged 55–65 years (57% vs 36%, P = 0.069). After controlling for age, ethnicity, education, income, diabetes mellitus, hypertension, hyperlipidaemia, high-density lipoprotein levels, smoking, education and BMI, SLE patients still had a significantly higher prevalence of CAC than controls. Among those with CAC, the mean log Agatston score did not differ significantly between SLE and MESA participants.
Conclusion. Women with SLE have a higher prevalence of CAC than comparable women without SLE, even after adjusting for traditional cardiovascular risk factors, especially among those aged 45–54 years.
PMCID: PMC4715250  PMID: 26106213
systemic lupus erythematosus; atherosclerosis; coronary artery calcium; inflammation; MESA; computed tomography; statins; cardiovascular; Agatston score; cohort
10.  Ten-Year Coronary Heart Disease Risk Prediction Using Coronary Artery Calcium and Traditional Risk Factors: Derivation in the Multi-Ethnic Study of Atherosclerosis with Validation in the Heinz Nixdorf Recall Study and the Dallas Heart Study 
Several studies have demonstrated the tremendous potential of using coronary artery calcium (CAC) in addition to traditional risk factors for coronary heart disease (CHD) risk prediction. However, to date no risk score incorporating CAC has been developed.
Our goal was to derive and validate a novel risk score to estimate 10-year CHD risk using CAC and traditional risk factors.
Algorithm development was conducted in the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective community-based cohort study of 6814 participants aged 45–84, free of clinical heart disease at baseline and followed for 10 years. MESA is gender balanced and included 39% Non-Hispanic whites, 12% Chinese American, 28% African American, and 22% Hispanic Americans. External validation was conducted in the Heinz Nixdorf Recall Study (HNR) and the Dallas Heart Study (DHS).
Inclusion of CAC in the MESA risk score offered significant improvements in risk prediction (C-statistic 0.80 versus 0.75, p<0.0001). External validation in both HNR and DHS provided evidence of very good discrimination and calibration. Harrell’s C-statistic was 0.779 in HNR, and 0.816 in DHS. Additionally the difference in estimated 10-year risk between events and non-events was approximately 8–9%, indicating excellent discrimination. Mean calibration, or calibration-in-the-large, was excellent for both studies, with average predicted 10-year risk within half a percent of the observed event rate.
An accurate estimate of 10-year CHD risk can be obtained using traditional risk factors and CAC. The MESA risk score, which is available online on the MESA web site for easy use, can be used to aid clinicians in the communication of risk to patients and when determining risk-based treatment strategies.
PMCID: PMC4603537  PMID: 26449133
coronary disease; risk prediction; epidemiology; atherosclerosis
11.  Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease 
Diabetes  2015;64(10):3464-3474.
Obesity is linked to type 2 diabetes (T2D) and cardiovascular diseases; however, the underlying molecular mechanisms remain unclear. We aimed to identify obesity-associated molecular features that may contribute to obesity-related diseases. Using circulating monocytes from 1,264 Multi-Ethnic Study of Atherosclerosis (MESA) participants, we quantified the transcriptome and epigenome. We discovered that alterations in a network of coexpressed cholesterol metabolism genes are a signature feature of obesity and inflammatory stress. This network included 11 BMI-associated genes related to sterol uptake (↑LDLR, ↓MYLIP), synthesis (↑SCD, FADS1, HMGCS1, FDFT1, SQLE, CYP51A1, SC4MOL), and efflux (↓ABCA1, ABCG1), producing a molecular profile expected to increase intracellular cholesterol. Importantly, these alterations were associated with T2D and coronary artery calcium (CAC), independent from cardiometabolic factors, including serum lipid profiles. This network mediated the associations between obesity and T2D/CAC. Several genes in the network harbored C-phosphorus-G dinucleotides (e.g., ABCG1/cg06500161), which overlapped Encyclopedia of DNA Elements (ENCODE)-annotated regulatory regions and had methylation profiles that mediated the associations between BMI/inflammation and expression of their cognate genes. Taken together with several lines of previous experimental evidence, these data suggest that alterations of the cholesterol metabolism gene network represent a molecular link between obesity/inflammation and T2D/CAC.
PMCID: PMC4587646  PMID: 26153245
12.  DNA Methylation of the Aryl Hydrocarbon Receptor Repressor Associations with Cigarette Smoking and Subclinical Atherosclerosis 
Tobacco smoke contains numerous agonists of the aryl-hydrocarbon receptor (AhR) pathway, and activation of the AhR pathway was shown to promote atherosclerosis in mice. Intriguingly, cigarette smoking is most strongly and robustly associated with DNA modifications to an AhR pathway gene, the aryl-hydrocarbon receptor repressor (AHRR). We hypothesized that altered AHRR methylation in monocytes, a cell type sensitive to cigarette smoking and involved in atherogenesis, may be a part of the biological link between cigarette smoking and atherosclerosis.
Methods and Results
DNA methylation profiles of AHRR in monocytes (542 CpG sites ± 150kb of AHRR, using Illumina 450K array) were integrated with smoking habits and ultrasound-measured carotid plaque scores from 1,256 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Methylation of cg05575921 significantly associated (p = 6.1×10−134) with smoking status (current vs. never). Novel associations between cg05575921 methylation and carotid plaque scores (p = 3.1×10−10) were identified, which remained significant in current and former smokers even after adjusting for self-reported smoking habits, urinary cotinine, and well-known CVD risk factors. This association replicated in an independent cohort using hepatic DNA (n = 141). Functionally, cg05575921 was located in a predicted gene expression regulatory element (enhancer), and had methylation correlated with AHRR mRNA profiles (p = 1.4×10−17) obtained from RNA sequencing conducted on a subset (n = 373) of the samples.
These findings suggest AHRR methylation may be functionally related to AHRR expression in monocytes, and represents a potential biomarker of subclinical atherosclerosis in smokers.
PMCID: PMC4618776  PMID: 26307030
smoking; atherosclerosis; gene expression/regulation; epidemiology; epigenetics; DNA methylation
13.  Relation of Physical Activity and Incident Atrial Fibrillation (From the Multi-Ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2015;116(6):883-888.
Prior studies have raised the question of whether an association exists between physical activity and atrial fibrillation (AF). We used the Multi-Ethnic Study of Atherosclerosis (MESA) database to examine the association between physical activity and AF in a diverse population without clinically recognized cardiovascular disease (CVD). MESA participants (N=5793) with complete baseline physical activity and covariate data were included. Cox proportional hazards models were used to calculate hazard ratios (HR) for incident AF by levels of total intentional exercise and vigorous physical activity, independently and in combination. Multivariable models adjusted for demographics and CVD risk factors. During a mean follow-up of 7.7±1.9 years, 199 AF cases occurred. In the overall MESA population, neither vigorous physical activity nor total intentional exercise were independently associated with incident AF after adjusting for covariates. However, within the group that reported any vigorous physical activity, there was a statistically significant inverse association between total intentional exercise (modeled as a continuous variable) and incident AF. Among those who reported any vigorous physical activity, the top tertile of total intentional exercise was associated with a significantly lower risk of incident AF compared with the group with no total intentional exercise in the fully adjusted model (HR 0.46, 95%CI 0.22-0.98). In conclusion, neither total intentional exercise nor vigorous physical activity alone were associated with incident AF, but greater total intentional exercise was associated with a lower risk of incident AF among those that participated in any vigorous physical activity. As importantly, no subgroup of participants demonstrated an increased risk of incident AF with greater physical activity. The results re-emphasize the beneficial role of physical activity for cardiovascular health.
PMCID: PMC4554984  PMID: 26189040
activity; exercise; atrial fibrillation; MESA
14.  High-Sensitivity Cardiac Troponin T and Risk of Hypertension 
Circulation  2015;132(9):825-833.
Hypertension is often preceded by cardiac structural abnormalities. Thus, we assessed whether high-sensitivity cardiac troponin-T (hs-cTNT), a marker of chronic subclinical myocardial damage, can identify persons at risk for hypertension or left ventricular hypertrophy (LVH).
Methods and Results
We studied 6,516 ARIC Study participants, free of prevalent hypertension and cardiovascular disease at baseline (1990–1992). We examined the association of baseline hs-cTNT categories with incident diagnosed hypertension (defined by self-report of a diagnosis or medication use during a maximum of 19.9 years of follow-up) and with incident visit-based hypertension (defined by self-report, medication use, or measured BP >140/90 mmHg over 6 years). Relative to hs-cTNT <5ng/L, adjusted hazard ratios for incident diagnosed hypertension were 1.16 (95% CI 1.08, 1.25) for persons with hs-cTNT 5–8ng/L, 1.29 (1.14, 1.47) for hs-cTNT 9–13ng/L, and 1.31 (1.07, 1.61) for hs-cTNT ≥14ng/L (p-trend <0.001). Associations were stronger for incident visit-based hypertension. These associations were driven by higher relative hazard in normotensive persons (compared to those with prehypertension, p-interaction=0.001). Baseline hs-cTNT was also strongly associated with incident LVH by electrocardiography over 6 years (e.g. adjusted HR 5.19 [1.49–18.08] for hs-cTNT ≥14ng/L vs <5ng/L). Findings were not appreciably changed after accounting for competing deaths or adjustment for baseline BP levels or NT-proBNP.
In an ambulatory population with no history of cardiovascular disease, hs-cTNT was associated with incident hypertension and risk of LVH. Further research is needed to determine whether hs-cTNT can identify persons who may benefit from ambulatory BP monitoring or hypertension prevention lifestyle strategies.
PMCID: PMC4558242  PMID: 26152706
Hypertension; Hypertrophy; Tests; Epidemiology; Prevention
15.  Pulmonary Microvascular Blood Flow in Mild Chronic Obstructive Pulmonary Disease and Emphysema. The MESA COPD Study 
Rationale: Smoking-related microvascular loss causes end-organ damage in the kidneys, heart, and brain. Basic research suggests a similar process in the lungs, but no large studies have assessed pulmonary microvascular blood flow (PMBF) in early chronic lung disease.
Objectives: To investigate whether PMBF is reduced in mild as well as more severe chronic obstructive pulmonary disease (COPD) and emphysema.
Methods: PMBF was measured using gadolinium-enhanced magnetic resonance imaging (MRI) among smokers with COPD and control subjects age 50 to 79 years without clinical cardiovascular disease. COPD severity was defined by standard criteria. Emphysema on computed tomography (CT) was defined by the percentage of lung regions below −950 Hounsfield units (−950 HU) and by radiologists using a standard protocol. We adjusted for potential confounders, including smoking, oxygenation, and left ventricular cardiac output.
Measurements and Main Results: Among 144 participants, PMBF was reduced by 30% in mild COPD, by 29% in moderate COPD, and by 52% in severe COPD (all P < 0.01 vs. control subjects). PMBF was reduced with greater percentage emphysema−950HU and radiologist-defined emphysema, particularly panlobular and centrilobular emphysema (all P ≤ 0.01). Registration of MRI and CT images revealed that PMBF was reduced in mild COPD in both nonemphysematous and emphysematous lung regions. Associations for PMBF were independent of measures of small airways disease on CT and gas trapping largely because emphysema and small airways disease occurred in different smokers.
Conclusions: PMBF was reduced in mild COPD, including in regions of lung without frank emphysema, and may represent a distinct pathological process from small airways disease. PMBF may provide an imaging biomarker for therapeutic strategies targeting the pulmonary microvasculature.
PMCID: PMC4595687  PMID: 26067761
pulmonary microvascular blood flow (PMBF); gadolinium-enhanced MRI; chronic obstructive pulmonary disease (COPD); lung emphysema; small airway disease
16.  HIV Infection Is Associated With Progression of Subclinical Carotid Atherosclerosis 
Human immunodeficiency virus (HIV) infection was associated with greater increases in focal carotid artery plaque over 7 years among both women and men, particularly among those with lower CD4+ counts. Increased plaque was observed even among HIV-infected individuals with persistent virologic suppression.
Background. Individuals infected with human immunodeficiency virus (HIV) live longer as a result of effective treatment, but long-term consequences of infection, treatment, and immunological dysfunction are poorly understood.
Methods. We prospectively examined 1011 women (74% HIV-infected) in the Women's Interagency HIV Study and 811 men (65% HIV-infected) in the Multicenter AIDS Cohort Study who underwent repeated B-mode carotid artery ultrasound imaging in 2004–2013. Outcomes included changes in right common carotid artery intima-media thickness (CCA-IMT) and new focal carotid artery plaque formation (IMT >1.5 mm) over median 7 years. We assessed the association between HIV serostatus and progression of subclinical atherosclerosis, adjusting for demographic, behavioral, and cardiometabolic risk factors.
Results. Unadjusted mean CCA-IMT increased (725 to 752 µm in women, 757 to 790 µm in men), but CCA-IMT progression did not differ by HIV serostatus, either in combined or sex-specific analyses. Focal plaque prevalence increased from 8% to 15% in women and 25% to 34% in men over 7 years. HIV-infected individuals had 1.6-fold greater risk of new plaque formation compared with HIV-uninfected individuals (relative risk [RR] 1.61, 95% CI, 1.12–2.32), adjusting for cardiometabolic factors; the association was similar by sex. Increased plaque occurred even among persistently virologically suppressed HIV-infected individuals compared with uninfected individuals (RR 1.56, 95% CI, 1.07–2.27). HIV-infected individuals with baseline CD4+ ≥500 cells/µL had plaque risk not statistically different from uninfected individuals.
Conclusions. HIV infection is associated with greater increases in focal plaque among women and men, potentially mediated by factors associated with immunodeficiency or HIV replication at levels below current limits of detection.
PMCID: PMC4607734  PMID: 25904369
HIV infection; cardiovascular disease; atherosclerosis; intima-media thickness; viral load
17.  HIV and Coronary Arterial Remodeling from the Multicenter AIDS Cohort Study (MACS) Miller, HIV and coronary artery remodeling 
Atherosclerosis  2015;241(2):716-722.
Positive remodeling (PR), a coronary artery characteristic associated with risk for myocardial infarction (MI), may be more prevalent in HIV-infected (HIV+) people. We evaluated the prevalence of PR using coronary CT angiography (CCTA) in HIV+ and HIV-uninfected (HIV−) men.
Men enrolled in the Multicenter AIDS Cohort Study underwent CCTA if they were 40–70 years, had normal kidney function and no history of coronary revascularization. Multivariable logistic regression models were used to estimate the odds ratio (OR) of PR by HIV serostatus, adjusting for demographics and coronary artery disease (CAD) risk factors. Analysis of PR among atherosclerotic segments further adjusted for plaque type and stenosis. The prevalence of PR was 8.4% versus 12.1% (p=0.10) for HIV− and HIV+ men, respectively. After demographic adjustment, HIV+ men had twice the odds of PR [OR 2.01(95% CI 1.20–3.38)], which persisted after CAD risk factor adjustment [1.76(1.00–3.10)]. Higher systolic blood pressure, total cholesterol, diabetes medication use, older age, segment number with plaque present, mixed and non-calcified plaque, and stenosis>50%, were associated with increased odds of PR, while higher HDL cholesterol, higher nadir CD4 count, and black race were associated with lower PR odds. Among atherosclerotic segments, the association between HIV infection and PR persisted, but was not statistically significantly.
HIV+ men have more positively remodeled arterial segments, which may be due to more coronary segments with atherosclerosis or HIV-related immunosuppression. Further studies are needed to evaluate whether PR contributes to higher rates of MI in HIV+ individuals.
PMCID: PMC4509808  PMID: 26132282
Coronary disease; imaging; epidemiology; AIDS
18.  25-hydroxyvitamin D levels, vitamin D binding protein gene polymorphisms and incident coronary heart disease among whites and blacks: the ARIC Study 
Atherosclerosis  2015;241(1):12-17.
In observational studies, low 25-hydroxyvitamin D (25(OH)D) has been associated with increased risk of coronary heart disease (CHD), and this association may vary by race. Racial differences in the frequency of vitamin D binding protein (DBP) single nucleotide polymorphisms (SNPs) might account for similar bioavailable vitamin D in blacks despite lower mean 25(OH)D. We hypothesized that the associations of low 25(OH)D with CHD risk would be stronger among whites and among persons with genotypes associated with higher DBP levels.
We measured 25(OH)D by mass spectroscopy in 11,945 participants in the ARIC Study (baseline 1990–1992, mean age 57 years, 59% women, 24% black). Two DBP SNPs (rs7041; rs4588) were genotyped. We used adjusted Cox proportional hazards models to examine the association of 25(OH)D with adjudicated CHD events through December 2011.
Over a median of 20 years, there were 1230 incident CHD events. Whites in the lowest quintile of 25(OH)D (<17 ng/ml) compared to the upper 4 quintiles had an increased risk of incident CHD (HR 1.28, 95% CI 1.05–1.56), but blacks did not (1.03, 0.82–1.28), after adjustment for demographics and behavioral/socioeconomic factors (p-interaction with race=0.22). Results among whites were no longer significant after further adjustment for potential mediators of this association (i.e. diabetes, hypertension). There was no statistically significant interaction of 25(OH)D with the DBP SNPs rs4588 (p=0.92) or rs7041 (p=0.87) in relation to CHD risk.
Low 25(OH)D was associated with incident CHD in whites, but no interactions of 25(OH)D with key DBP genotypes was found.
PMCID: PMC4466162  PMID: 25941991
19.  Anatomic Fat Depots and Coronary Plaque Among Human Immunodeficiency Virus-Infected and Uninfected Men in the Multicenter AIDS Cohort Study 
Open Forum Infectious Diseases  2016;3(2):ofw098.
Methods. In a cross-sectional substudy of the Multicenter AIDS Cohort Study, noncontrast cardiac computed tomography (CT) scanning for coronary artery calcium (CAC) scoring was performed on all men, and, for men with normal renal function, coronary CT angiography (CTA) was performed. Associations between fat depots (visceral adipose tissue [VAT], abdominal subcutaneous adipose tissue [aSAT], and thigh subcutaneous adipose tissue [tSAT]) with coronary plaque presence and extent were assessed with logistic and linear regression adjusted for age, race, cardiovascular disease (CVD) risk factors, body mass index (BMI), and human immunodeficiency virus (HIV) parameters.
Results. Among HIV-infected men (n = 597) but not HIV-uninfected men (n = 343), having greater VAT was positively associated with noncalcified plaque presence (odds ratio [OR] = 1.04, P < .05), with a significant interaction (P < .05) by HIV serostatus. Human immunodeficiency virus-infected men had lower median aSAT and tSAT and greater median VAT among men with BMI <25 and 25–29.9 kg/m2. Among HIV-infected men, VAT was positively associated with presence of coronary plaque on CTA after adjustment for CVD risk factors (OR = 1.04, P < .05), but not after additional adjustment for BMI. There was an inverse association between aSAT and extent of total plaque among HIV-infected men, but not among HIV-uninfected men. Lower tSAT was associated with greater CAC and total plaque score extent regardless of HIV serostatus.
Conclusions. The presence of greater amounts of VAT and lower SAT may contribute to increased risk for coronary artery disease among HIV-infected persons.
PMCID: PMC4943560  PMID: 27419170
adiposity; coronary plaque
20.  Low-Density Lipoprotein Cholesterol Levels and Statin Treatment by HIV Status Among Multicenter AIDS Cohort Study Men 
Treating cardiovascular disease (CVD) risk factors, including dyslipidemia, is important in HIV care. Low-density lipoprotein cholesterol (LDL-c) target achievement is a readily available benchmark for dyslipidemia control, although use of this target is not uniformly endorsed by professional societies. We examined whether HIV serostatus is associated with not achieving LDL-c target. Among Multicenter AIDS Cohort Study (MACS) participants completing visit 56 (10/1/2011–3/31/2012), we categorized each man as on or off statin therapy and used NCEP ATP III guidelines to determine if each man was at LDL-c target or not at target. We compared proportions of men not at target and determined predictors using multivariate logistic regression. Sixty of 543 (11.1%) HIV-infected men and 87 of 585 (14.9%) HIV-uninfected men not receiving statin therapy were not at target (p=0.07), while 31 of 230 (13.5%) HIV-infected and 29 of 204 (14.2%) HIV-uninfected men receiving statin therapy were not at target (p=0.82). Factors associated with not being at target (among men not receiving statin therapy) included current smoking (OR=2.31, 95% CI 1.31, 4.06) and a diagnosis of hypertension (OR=4.69, 95% CI 2.68, 8.21). Factors associated with not being at target (among men receiving statin therapy) included current smoking (OR=2.72, 95% CI 1.30, 5.67) and diabetes (OR=5.31, 95% CI 2.47, 11.42). HIV-infected and HIV-uninfected men receiving statin therapy demonstrated similar nonachievement of LDL-c targets. Comorbidities (e.g., diabetes) lowered targets and may explain why goals were less likely to be met.
PMCID: PMC4458749  PMID: 25664922
21.  Inflammatory Markers Associated With Subclinical Coronary Artery Disease: The Multicenter AIDS Cohort Study 
Despite evidence for higher risk of coronary artery disease among HIV+ individuals, the underlying mechanisms are not well understood. We investigated associations of inflammatory markers with subclinical coronary artery disease in 923 participants of the Multicenter AIDS Cohort Study (575 HIV+ and 348 HIV− men) who underwent noncontrast computed tomography scans for coronary artery calcification, the majority (n=692) also undergoing coronary computed tomography angiography.
Methods and Results
Outcomes included presence and extent of coronary artery calcification, plus computed tomography angiography analysis of presence, composition, and extent of coronary plaques and severity of coronary stenosis. HIV+ men had significantly higher levels of interleukin‐6 (IL‐6), intercellular adhesion molecule‐1, C‐reactive protein, and soluble‐tumor necrosis factor‐α receptor (sTNFαR) I and II (all P<0.01) and a higher prevalence of noncalcified plaque (63% versus 54%, P=0.02) on computed tomography angiography. Among HIV+ men, for every SD increase in log‐interleukin‐6 and log intercellular adhesion molecule‐1, there was a 30% and 60% increase, respectively, in the prevalence of coronary stenosis ≥50% (all P<0.05). Similarly, sTNFαR I and II in HIV+ participants were associated with an increase in prevalence of coronary stenosis ≥70% (P<0.05). Higher levels of interleukin‐6, sTNFαR I, and sTNFαR II were also associated with greater coronary artery calcification score in HIV+ men (P<0.01).
Higher inflammatory marker levels are associated with greater prevalence of coronary stenosis in HIV+ men. Our findings underscore the need for further study to elucidate the relationships of inflammatory pathways with coronary artery disease in HIV+ individuals.
PMCID: PMC4937277  PMID: 27353609
atherosclerosis; cardiac biomarkers; cardiac computed tomography; coronary artery calcium; coronary artery disease; coronary computed tomography scan; epidemiology; HIV; HIV infection; inflammation; Epidemiology; Inflammation; Computerized Tomography (CT); Biomarkers; Imaging
22.  Metal mixtures in urban and rural populations in the US: The Multi-Ethnic Study of Atherosclerosis and the Strong Heart Study☆ 
Environmental research  2016;147:356-364.
Natural and anthropogenic sources of metal exposure differ for urban and rural residents. We searched to identify patterns of metal mixtures which could suggest common environmental sources and/or metabolic pathways of different urinary metals, and compared metal-mixtures in two population-based studies from urban/sub-urban and rural/town areas in the US: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Strong Heart Study (SHS).
We studied a random sample of 308 White, Black, Chinese-American, and Hispanic participants in MESA (2000–2002) and 277 American Indian participants in SHS (1998–2003). We used principal component analysis (PCA), cluster analysis (CA), and linear discriminant analysis (LDA) to evaluate nine urinary metals (antimony [Sb], arsenic [As], cadmium [Cd], lead [Pb], molybdenum [Mo], selenium [Se], tungsten [W], uranium [U] and zinc [Zn]). For arsenic, we used the sum of inorganic and methylated species (∑As).
All nine urinary metals were higher in SHS compared to MESA participants. PCA and CA revealed the same patterns in SHS, suggesting 4 distinct principal components (PC) or clusters (∑As-U-W, Pb-Sb, Cd-Zn, Mo-Se). In MESA, CA showed 2 large clusters (∑As-Mo-Sb-U-W, Cd-Pb-Se-Zn), while PCA showed 4 PCs (Sb-U-W, Pb-Se-Zn, Cd-Mo, ∑As). LDA indicated that ∑As, U, W, and Zn were the most discriminant variables distinguishing MESA and SHS participants.
In SHS, the ∑As-U-W cluster and PC might reflect groundwater contamination in rural areas, and the Cd-Zn cluster and PC could reflect common sources from meat products or metabolic interactions. Among the metals assayed, ∑As, U, W and Zn differed the most between MESA and SHS, possibly reflecting disproportionate exposure from drinking water and perhaps food in rural Native communities compared to urban communities around the US.
PMCID: PMC4827253  PMID: 26945432
Metals; Urine; Biomarker; Statistical methods; Exposure sources
23.  Elevated Levels of Monocyte Activation Markers Are Associated With Subclinical Atherosclerosis in Men With and Those Without HIV Infection 
The Journal of Infectious Diseases  2014;211(8):1219-1228.
Background. Heightened immune activation among human immunodeficiency virus (HIV)–infected persons may contribute to atherosclerosis. We assessed associations of serologic markers of monocyte activation, soluble CD163 (sCD163) and soluble CD14 (sCD14), and monocyte chemoattractant protein 1 (CCL2) with subclinical atherosclerosis among men with and those without HIV infection in the Multicenter AIDS Cohort Study.
Methods. We performed noncontrast computed tomography on 906 men (566 HIV-infected men and 340 HIV-uninfected men), 709 of whom also underwent coronary computed tomographic angiography. Associations between each biomarker and the prevalence of coronary plaque, the prevalence of stenosis of ≥50%, and the extent of plaque were assessed by logistic and linear regression, adjusting for age, race, HIV serostatus, and cardiovascular risk factors.
Results. Levels of all biomarkers were higher among HIV-infected men, of whom 81% had undetectable HIV RNA, and were associated with lower CD4+ T-cell counts. In the entire population and among HIV-infected men, higher biomarker levels were associated with a greater prevalence of coronary artery stenosis of ≥50%. Higher sCD163 levels were also associated with greater prevalences of coronary artery calcium, mixed plaque, and calcified plaque; higher CCL2 levels were associated with a greater extent of noncalcified plaque.
Conclusions. sCD163, sCD14, and CCL2 levels were elevated in treated HIV-infected men and associated with atherosclerosis. Monocyte activation may increase the risk for cardiovascular disease in individuals with HIV infection.
PMCID: PMC4402336  PMID: 25362192
human immunodeficiency virus; inflammation; monocyte activation; atherosclerosis; plaque
24.  Race is a key variable in assigning lipoprotein(a) cutoff values for coronary heart disease risk assessment: the Multi-Ethnic Study of Atherosclerosis 
We aimed to examine associations of Lp(a) concentrations with coronary heart disease (CHD) and determine whether current Lp(a) clinical laboratory cut points identify risk of disease incidence in four races/ethnicities of the Multi-Ethnic Study of Atherosclerosis (MESA).
Approach and Results
A subcohort of 1,323 Black, 1,677 Caucasian, 548 Chinese-American, and 1,044 Hispanic MESA participants were followed over a mean 8.5 year period in which 235 incident CHD events were recorded. Lp(a) mass concentrations were measured using a turbidimetric immunoassay. Cox regression analysis determined associations of Lp(a) with CHD risk with adjustments for lipid and non-lipid variables. Lp(a) concentrations were continuously associated with risk of CHD incidence in Black [hazard ratio (HR)=1.49; 95% CI: 1.09 – 2.04] and Caucasian participants (HR=1.22; 95% CI: 1.02 – 1.45). Examining Lp(a) risk by the 50 mg/dL cut point revealed higher risks of incident CHD in all races except Chinese Americans: Blacks (HR=1.69; 95% CI: 1.03 – 2.76); Caucasians (HR=1.82; 95% CI: 1.15 – 2.88); Hispanics (HR=2.37; 95% CI: 1.17 – 4.78). The lower Lp(a) cut point of 30 mg/dL identified higher risk of CHD in Black participants alone (HR: 1.87; 95% CI: 1.08 – 3.21).
Our findings suggest that the 30 mg/dL cutoff for Lp(a) is not appropriate in Caucasian and Hispanic individuals, and the higher 50 mg/dL cutoff should be considered. In contrast, the 30 mg/dL cutoff remains suitable in Black individuals. Further research is necessary to develop the most clinically useful Lp(a) cutoff values in individual races/ethnicities.
PMCID: PMC4377643  PMID: 25810300
Lipoprotein (a); coronary heart disease; race; lipid; risk factor
25.  The Relationship of Cigarette Smoking with Inflammation and Subclinical Vascular Disease: The Multi-Ethnic Study of Atherosclerosis 
We sought to assess the impact of smoking status, cumulative pack-years, and time since cessation (the latter in former-smokers only) on three important domains of cardiovascular disease (CVD): inflammation, vascular dynamics and function, and subclinical atherosclerosis.
Approach and Results
The MESA cohort enrolled 6,814 adults without prior CVD. Smoking variables were determined by self-report and confirmed with urinary cotinine. We examined cross-sectional associations between smoking parameters and; 1) inflammatory biomarkers (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], and fibrinogen); 2) vascular dynamics and function (brachial flow-mediated dilation [FMD] and carotid distensibility by ultrasound, as well as aortic distensibility by MRI); and 3) subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness [CIMT], and ankle-brachial index [ABI]). We identified 3,218 never-smokers, 2,607 former-smokers, and 971 current-smokers. Mean age was 62 years and 47% were male. There was no consistent association between smoking and vascular distensibility or FMD outcomes. In contrast, compared to never-smokers, the adjusted association between current-smoking and measures of either inflammation or subclinical atherosclerosis was consistently stronger than for former-smoking (e.g. odds-ratio (OR) for hs-CRP > 2mg/L of 1.7 [95%CI, 1.5-2.1] Vs. 1.2 [1.1-1.4], OR for CAC > 0 of 1.8 [1.5-2.1] Vs. 1.4 [1.2-1.6], respectively). Similar associations were seen for IL-6, fibrinogen, CIMT, and ABI. A monotonic relationship was also found between increasing pack-years exposure and elevated inflammatory markers. Further, current smokers with hsCRP > 2mg/L were more likely to have increased CIMT, abnormal ABI, and CAC > 75th percentile for age, sex and race (relative to smokers with hsCRP < 2mg/L, interaction p < 0.05 for all three outcomes). In contrast, time since quitting in former-smokers was independently associated with lower inflammation and atherosclerosis (e.g. OR for hsCRP > 2mg/L of 0.91 [0.88-0.95] and OR for CAC > 0 of 0.94 [0.90-0.97] for every 5-year cessation interval).
These findings expand our understanding of the harmful effects of smoking and help explain the cardiovascular benefits of smoking cessation.
PMCID: PMC4484586  PMID: 25745060
Smoking; Inflammation; Atherosclerosis; Coronary Artery Calcium

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