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1.  Association between Left Atrial Abnormality on ECG and Vascular Brain Injury on MRI in the Cardiovascular Health Study 
Background and Purpose
Emerging evidence suggests that atrial disease is associated with vascular brain injury in the absence of atrial fibrillation (AF).
Methods
The Cardiovascular Health Study prospectively enrolled community-dwelling adults ≥65 years of age. Among participants who underwent MRI, we examined associations of ECG left atrial abnormality with brain infarcts and leukoaraiosis. P-wave terminal force in lead V1 (PTFV1) was the primary measure of left atrial abnormality; P-wave area and duration were secondary predictors. We excluded participants with AF before or on their index ECG. Primary outcomes were incident infarcts and worsening leukoaraiosis from initial to follow-up scan approximately 5 years later. Secondary outcomes were prevalent infarcts and degree of leukoaraiosis on initial MRI. Relative risk and linear regression models adjusted for vascular risk factors.
Results
Among 3,129 participants with ≥1 scan, each SD increase in PTFV1 was associated with a 0.05-point (95% CI, 0.0003–0.10) higher baseline white matter grade on a 10-point scale. PTFV1 was associated with prevalent infarcts of any type (RR per SD, 1.09; 95% CI, 1.04–1.16), and more so with prevalent non-lacunar infarcts (RR per SD, 1.22; 95% CI, 1.08–1.38). Among 1,839 participants with 2 scans, PTFV1 was associated with worsening leukoaraiosis (RR per SD, 1.09; 95% CI, 1.01–1.18), but not incident infarcts (RR per SD, 1.06; 95% CI, 0.93–1.20). Sensitivity analyses adjusting for incident AF found similar results. P-wave area and duration were not associated with outcomes.
Conclusions
ECG left atrial abnormality is associated with vascular brain injury in the absence of documented AF.
doi:10.1161/STROKEAHA.114.007762
PMCID: PMC4342300  PMID: 25677594
Arrhythmia; atrium; ECG; embolism; cerebrovascular disease/stroke
2.  Association Between Hospitalization for Pneumonia and Subsequent Risk of Cardiovascular Disease 
JAMA  2015;313(3):264-274.
IMPORTANCE
The risk of cardiovascular disease (CVD) after infection is poorly understood.
OBJECTIVE
To determine whether hospitalization for pneumonia is associated with an increased short-term and long-term risk of CVD.
DESIGN, SETTINGS, AND PARTICIPANTS
We examined 2 community-based cohorts: the Cardiovascular Health Study (CHS, n = 5888; enrollment age, ≥65 years; enrollment period, 1989–1994) and the Atherosclerosis Risk in Communities study (ARIC, n = 15 792; enrollment age, 45-64 years; enrollment period, 1987–1989). Participants were followed up through December 31, 2010. We matched each participant hospitalized with pneumonia to 2 controls. Pneumonia cases and controls were followed for occurrence of CVD over 10 years after matching. We estimated hazard ratios (HRs) for CVD at different time intervals, adjusting for demographics, CVD risk factors, subclinical CVD, comorbidities, and functional status.
EXPOSURES
Hospitalization for pneumonia.
MAIN OUTCOMES AND MEASURES
Incident CVD (myocardial infarction, stroke, and fatal coronary heart disease).
RESULTS
Of 591 pneumonia cases in CHS, 206 had CVD events over 10 years after pneumonia hospitalization. Compared with controls, CVD risk among pneumonia cases was highest during the first year after hospitalization and remained significantly higher than among controls through 10 years. In ARIC, of 680 pneumonia cases, 112 had CVD events over 10 years after hospitalization. After the second year, CVD risk among pneumonia cases was not significantly higher than among controls.
PneumoniaCasesControlsHR (95% CI)CHSNo. of participants5911182CVD events 0-30 d5464.07 (2.86-5.27) 31-90 d1192.94 (2.18-3.70) 91 d-1 y22552.10 (1.59-2.60) 9-10 y4121.86 (1.18-2.55)ARICNo. of participants6801360CVD events 0-30 d432.38 (1.12-3.63) 31-90 d402.40 (1.23-3.47) 91 d-1 y1182.19 (1.20-3.19) 1-2 y871.88 (1.10-2.66)
CONCLUSIONS AND RELEVANCE
Hospitalization for pneumonia was associated with increased short-term and long-term risk of CVD, suggesting that pneumonia may be a risk factor for CVD.
doi:10.1001/jama.2014.18229
PMCID: PMC4687729  PMID: 25602997
3.  Resistive and Pulsatile Arterial Load as Predictors of Left Ventricular 
Hypertension  2014;65(1):85-92.
Arterial load is comprised of resistive and various pulsatile components, but their relative contributions to left ventricular (LV) remodeling in the general population are unknown. We studied 4,145 participants enrolled in the Multi-Ethnic Study of Atherosclerosis, who underwent cardiac magnetic resonance imaging and radial arterial tonometry. We computed systemic vascular resistance (SVR=mean arterial pressure/cardiac output), and indices of pulsatile load including total arterial compliance (TAC, approximated as stroke volume/central pulse pressure), forward wave amplitude (Pf), and reflected wave amplitude (Pb). TAC and SVR were adjusted for body surface area to allow for appropriate gender comparisons. We performed allometric adjustment of LV mass for body size and gender, and computed standardized regression coefficients (β) for each measure of arterial load. In multivariable regression models that adjusted for multiple confounders, SVR (β=0.08;P<0.001), TAC (β=0.44;P<0.001), Pb (β=0.73;P<0.001), and Pf (β=-0.23;P=0.001) were significant independent predictors of LV mass. Conversely, TAC (β=-0.43;P<0.001), SVR (β=0.22;P<0.001), and Pf (β=-0.18;P=0.004) were independently associated with the LV wall/LV cavity volume ratio. Women demonstrated greater pulsatile load than men, as evidenced by a lower indexed TAC (0.89 versus 1.04 mL/mmHg/m2, P<0.0001), while men demonstrated a higher indexed SVR (34.0 versus 32.8 Wood Units*m2, P<0.0001). In conclusion, various components of arterial load differentially associate with LV hypertrophy and concentric remodeling. Women demonstrated greater pulsatile load than men. For both LV mass and the LV wall/LV cavity volume ratio, the loading sequence (i.e. early load versus late load) is an important determinant of LV response to arterial load.
doi:10.1161/HYPERTENSIONAHA.114.04333
PMCID: PMC4268078  PMID: 25287396
left ventricular hypertrophy; left ventricular remodeling; arterial load; afterload; wave reflections; vascular resistance; arterial hemodynamics
4.  A Comparison of Coronary Artery Calcium Presence, Carotid Plaque Presence, and Carotid Intima-Media Thickness for Cardiovascular Disease Prediction in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Presence of coronary artery calcium (CAC), carotid plaque, and increased carotid intima media thickness (IMT) may indicate elevated cardiovascular disease (CVD) risk; however, no large studies have compared them directly. This study compares predictive utilities of CAC presence, carotid artery plaque presence, and high IMT for incident CVD events.
Methods and Results
Participants were from the Multi-Ethnic Study of Atherosclerosis. Predictive values of carotid plaque, IMT and CAC presence were compared using Cox proportional hazards models, c-statistics, and net reclassification indices. The 6,779 participants were mean (standard deviation) 62.2 (10.2) years old; 49.9% had CAC, 46.7% had carotid plaque. The mean left and right IMT were 0.754 (0.210) mm and 0.751 (0.187) mm, respectively. After 9.5 years (mean), 538 CVD events, 388 coronary heart disease (CHD) events, and 196 stroke/transient ischemic attacks (TIA) were observed. CAC presence was a stronger predictor of incident CVD and CHD than carotid ultrasound measures. Mean IMT ≥75th percentile (for age, sex and race) alone did not predict events. Compared to traditional risk factors, c-statistics for CVD (c=0.756) and CHD (c=0.752) increased most by adding of CAC presence (CVD 0.776, CHD, 0.784; p<0.001) followed by carotid plaque presence (CVD c=0.760, CHD 0.757; p<0.05). Compared to risk factors (c=0.782), carotid plaque presence (c=0.787, p=0.045) but not CAC (c=0.785, p=0.438) improved prediction of stroke/TIA.
Conclusions
In adults without CVD, CAC presence improves prediction of CVD and CHD more than carotid plaque presence or high IMT. CAC and carotid ultrasound parameters performed similarly for stroke/TIA event prediction.
doi:10.1161/CIRCIMAGING.114.002262
PMCID: PMC4299916  PMID: 25596139
atherosclerosis; cardiovascular disease; carotid artery; imaging; risk factor
5.  H2 Receptor Antagonists and Right Ventricular Morphology: The MESA Right Ventricle Study 
Rationale: H2 receptor antagonist (H2RA) use is common and may act directly on the heart through myocardial H2 receptors or indirectly through changes in pulmonary vascular resistance.
Objectives: To determine the relationship between histamine H2RA use and right ventricular (RV) morphology.
Methods: We studied 4,122 participants in the Multi-Ethnic Study of Atherosclerosis without clinical cardiovascular disease who had magnetic resonance imaging assessment of RV morphology and ascertainment of medication use. Multivariable linear regression estimated cross-sectional associations between H2RA use and RV morphology after adjusting for demographics, anthropometrics, smoking status, diabetes mellitus, and hypertension. Further adjustments for co-medication use, left ventricular parameters, lung structure and function, renal function, or inflammatory markers were considered in separate models. Analyses in a subcohort restricted to H2RA or proton pump inhibitor users accounted for confounding by the indication of gastroesophageal reflux disease.
Measurements and Main Results: H2RA use was associated with lower RV mass (–0.7 g; 95% confidence interval, –1.2 to –0.2 g; P = 0.004) and smaller RV end-diastolic volume (–4.2 ml; 95% confidence interval, –7.2 to –1.2 ml; P = 0.006). This relationship was unchanged with adjustment for co-medication use, lung structure and function, renal function, and inflammation. The relationship with RV mass was independent of left ventricular mass. Results were similar in the smaller cohort restricted to proton pump inhibitor and H2RA users.
Conclusions: H2RA use was associated with lower RV mass and smaller RV end-diastolic volume. Additional study of histamine and H2 receptors in cardiopulmonary diseases affecting the RV may have direct clinical relevance.
doi:10.1513/AnnalsATS.201407-344OC
PMCID: PMC4298988  PMID: 25295642
histamine; histamine H2 receptors; heart ventricles; pulmonary hypertension
6.  Reflection Magnitude as a Predictor of Mortality: The Multi-Ethnic Study of Atherosclerosis 
Hypertension  2014;64(5):958-964.
Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (RM, defined as the ratio of the amplitude of the backward wave [Pb] to that of the forward wave [Pf]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox-proportional hazards models, each 10% increase in RM was associated with a 31% increased risk for all-cause mortality (HR=1.31; 95%CI=1.11–1.55; P=0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95%CI=1.01–1.51, P=0.04), including the coronary calcium score, ankle-brachial index, common carotid intima-media thickness and ascending thoracic aortic Agatston score. Pb was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mmHg-increase in Pb=2.18, 95%CI=1.21–3.92, P=0.009). RM (HR=1.71, 95%CI 1.06–2.77, P=0.03) and Pb (HR=5.02, 95%CI=1.29–19.42, P=0.02) were mainly associated with cardiovascular mortality. In conclusion, RM is independently associated with all-cause mortality in a multi-ethnic population initially free of clinically-evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis.
doi:10.1161/HYPERTENSIONAHA.114.03855
PMCID: PMC4192021  PMID: 25259746
Reflection magnitude; mortality; wave reflections; atherosclerosis
7.  Predictors of Carotid Thickness and Plaque Progression Over a Decade: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background and Purpose
Carotid artery intima-media thickness (IMT) and plaque are non-invasive markers of subclinical arterial injury that predict incident cardiovascular disease. We evaluated predictors of longitudinal changes in IMT and new plaque over a decade in a longitudinal multiethnic cohort.
Methods
Carotid IMT and plaque were evaluated in Multi-Ethnic Study of Atherosclerosis participants at exams 1 and 5, a mean (standard deviation) of 9.4 (0.5) years later. Far wall carotid IMT was measured in both common (CCA) and internal carotid arteries. A plaque score was calculated from all carotid segments. Mixed effects longitudinal and multivariate regression models evaluated associations of baseline risk factors and time-updated medication use with IMT progression and plaque formation.
Results
The 3,441 MESA participants were 60.3 (9.4) years old (53% female; 26% African-American, 22% Hispanic, 13% Chinese); 1,620 (47%) had carotid plaque. Mean CCA IMT progression was 11.8 (12.8) μm/year. 1,923 (56%) of subjects developed new plaque. IMT progressed more slowly in Chinese (β=−2.89, p=0.001) and Hispanic participants (β=−1.81, p=0.02), and with higher baseline high-density lipoprotein cholesterol (per 5 mg/dL, β=−0.22, p=0.03), antihypertensive use (β=−2.06, p=0.0004), and time on antihypertensive medications (years) (β=−0.29, p<0.0001). Traditional risk factors were associated with new plaque formation, with strong associations for cigarette use (odds ratio 2.31, p<0.0001) and protection by African-American ethnicity (odds ratio 0.68, p<0.0001).
Conclusions
In a large, multi-ethnic cohort with a decade of follow-up, ethnicity is a strong, independent predictor of carotid IMT and plaque progression. Anti-hypertensive medication use was associated with less subclinical disease progression.
doi:10.1161/STROKEAHA.114.005669
PMCID: PMC4213289  PMID: 25213342
Carotid arteries; Risk Factors; Epidemiology; Atherosclerosis
8.  Associations of Circulating Lymphocyte Subpopulations with Type 2 Diabetes: Cross-Sectional Results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
PLoS ONE  2015;10(10):e0139962.
Objective
Distinct lymphocyte subpopulations have been implicated in the regulation of glucose homeostasis and obesity-associated inflammation in mouse models of insulin resistance. Information on the relationships of lymphocyte subpopulations with type 2 diabetes remain limited in human population-based cohort studies.
Methods
Circulating levels of innate (γδ T, natural killer (NK)) and adaptive immune (CD4+ naive, CD4+ memory, Th1, and Th2) lymphocyte subpopulations were measured by flow cytometry in the peripheral blood of 929 free-living participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Cross-sectional relationships of lymphocyte subpopulations with type 2 diabetes (n = 154) and fasting glucose and insulin concentrations were evaluated by generalized linear models.
Results
Each standard deviation (SD) higher CD4+ memory cells was associated with a 21% higher odds of type 2 diabetes (95% CI: 1–47%) and each SD higher naive cells was associated with a 22% lower odds (95% CI: 4–36%) (adjusted for age, gender, race/ethnicity, and BMI). Among participants not using diabetes medication, higher memory and lower naive CD4+ cells were associated with higher fasting glucose concentrations (p<0.05, adjusted for age, sex, and race/ethnicity). There were no associations of γδ T, NK, Th1, or Th2 cells with type 2 diabetes, glucose, or insulin.
Conclusions
A higher degree of chronic adaptive immune activation, reflected by higher memory and lower naive CD4+ cells, was positively associated with type 2 diabetes. These results are consistent with a role of chronic immune activation and exhaustion augmenting chronic inflammatory diseases, and support the importance of prospective studies evaluating adaptive immune activation and type 2 diabetes.
doi:10.1371/journal.pone.0139962
PMCID: PMC4601795  PMID: 26458065
9.  B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies 
Europace  2014;16(10):1426-1433.
Aims
B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.
Methods and results
We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56–1.76], P < 0.0001 and 1.18 (95% CI, 1.11–1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ2 = 17.0; CRP, χ2 = 10.5; BNP and CRP, χ2 = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022–0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322–0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.
Conclusion
B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.
doi:10.1093/europace/euu175
PMCID: PMC4197895  PMID: 25037055
Atrial fibrillation; Risk prediction; Epidemiology; Biomarker; B-type natriuretic peptide; C-reactive protein
10.  P-Wave Morphology and the Risk of Incident Ischemic Stroke in the Multi-Ethnic Study of Atherosclerosis 
Background and Purpose
Emerging data suggest that left atrial disease may cause ischemic stroke in the absence of atrial fibrillation or flutter (AF). If true, this condition may provide an etiology for many strokes currently classified as cryptogenic.
Methods
Among 6,741 participants in the Multi-Ethnic Study of Atherosclerosis who were free of clinically apparent cerebrovascular or cardiovascular disease (including AF) at baseline, we examined the association between markers of left atrial abnormality on a standard 12-lead electrocardiogram (ECG)—specifically, P-wave area, duration, and terminal force in lead V1 (PTFV1)—and the subsequent risk of ischemic stroke while accounting for incident AF.
Results
During a median follow-up of 8.5 years, 121 participants (1.8%) suffered a stroke and 541 participants (8.0%) were diagnosed with AF. In Cox proportional hazards models adjusting for potential baseline confounders, PTFV1 was more strongly associated with incident stroke (hazard ratio [HR] per 1-SD increase, 1.21; 95% confidence interval [CI], 1.02–1.44) than with incident AF (HR per 1-SD, 1.11; 95% CI, 1.03–1.21). The association between PTFV1 and stroke was robust in numerous sensitivity analyses accounting for AF, including analyses that excluded those with any incident AF or modeled any incident AF as having been present from baseline.
Conclusions
We found an association between baseline P-wave morphology and incident stroke even after accounting for AF. This association may reflect an atrial cardiopathy that leads to stroke in the absence of AF.
doi:10.1161/STROKEAHA.114.006364
PMCID: PMC4146624  PMID: 25052322
Arrhythmia; atrium; electrocardiography; embolism; stroke
11.  An Analysis of Calibration and Discrimination Among Multiple Cardiovascular Risk Scores in a Modern Multiethnic Cohort 
Annals of internal medicine  2015;162(4):266-275.
Background
Accurate risk assessment of atherosclerotic cardiovascular disease (ASCVD) is essential to effectively balance the risks and benefits of therapy for primary prevention.
Objective
To compare the calibration and discrimination of the new American Heart Association (AHA) and American College of Cardiology (ACC) ASCVD risk score with alternative risk scores and to explore preventive therapy as a cause of the reported risk overestimation using the AHA-ACC-ASCVD score.
Design
Prospective epidemiologic study of ASCVD.
Setting
MESA (Multi-Ethnic Study of Atherosclerosis), a community-based, sex-balanced, multiethnic cohort.
Patients
4227 MESA participants aged 50 to 74 years and without diabetes at baseline.
Measurements
Observed and expected events for the AHA-ACC-ASCVD score were compared with 4 commonly used risk scores—and their respective end points—in MESA after a 10.2-year follow-up.
Results
The new AHA-ACC-ASCVD and 3 older Framingham-based risk scores overestimated cardiovascular events by 37% to 154% in men and 8% to 67% in women. Overestimation was noted throughout the continuum of risk. In contrast, the Reynolds Risk Score overestimated risk by 9% in men but underestimated risk by 21% in women. Aspirin, lipid-lowering or antihypertensive therapy, and interim revascularization did not explain the overestimation.
Limitation
Comparability of MESA with target populations for primary prevention and possibility of missed events in MESA.
Conclusion
Of the 5 risk scores, 4, including the new AHA-ACC-ASCVD score, showed overestimation of risk (25% to 115%) in a modern, multiethnic cohort without baseline clinical ASCVD. If validated, overestimation of ASCVD risk may have substantial implications for individual patients and the health care system.
Primary Funding Source
National Heart, Lung, and Blood Institute.
doi:10.7326/M14-1281
PMCID: PMC4414494  PMID: 25686167
12.  HIV and coronary artery calcium score: comparison of the Hawaii Aging with HIV Cardiovascular Study and Multi-Ethnic Study of Atherosclerosis (MESA) cohorts 
HIV clinical trials  2015;16(4):130-138.
Objectives
To determine the association of HIV, immunologic, and inflammatory factors on coronary artery calcium (CAC), a marker of subclinical atherosclerosis.
Methods
Cross-sectional study comparing baseline data of males from Hawaii Aging with HIV –Cardiovascular Study (HAHCS) with the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. The cohorts were pooled to determine effects of HIV on CAC and explore immunologic and inflammatory factors that may explain development of CAC in HIV. Multivariable regression models compared CAC prevalence in HAHCS with MESA adjusting for coronary heart disease (CHD) risk profiles.
Results
We studied 100 men from HAHCS and 2733 men from MESA. Positive CAC was seen in 58% HAHCS participants and 57% MESA participants. Mean CAC was 260.8 in HAHCS and 306.5 in MESA. Using relative risk (RR) regression, HAHCS participants had a greater risk (RR=1.20, P<0.05) of having positive CAC than MESA when adjusting for age, smoking status, diabetes, antihypertensive therapy, BMI, systolic blood pressure, total cholesterol, and HDL cholesterol. Among participants with positive CAC, HIV infection was not associated with larger amounts of CAC. Among HAHCS participants, current HIV viral load, CD4, length of HIV, interleukin 6 (IL-6), fibrinogen, C-reactive protein (CRP), and D-dimer were not associated with the presence or amount of CAC.
Discussion
HIV was independently associated with a positive CAC in men with increased likelihood occurring between 45 and 50 years of age. Current HIV viral load, CD4 count, length of HIV, and inflammatory markers were unrelated to either presence or amount of CAC.
doi:10.1179/1528433614Z.0000000016
PMCID: PMC4524807  PMID: 26038953
Antiviral therapy; Coronary artery calcium; MESA; Framingham Risk Score
13.  Risk Factors for Long-Term Coronary Artery Calcium Progression in the Multi-Ethnic Study of Atherosclerosis 
Background
Coronary artery calcium (CAC) detected by noncontrast cardiac computed tomography scanning is a measure of coronary atherosclerosis burden. Increasing CAC levels have been strongly associated with increased coronary events. Prior studies of cardiovascular disease risk factors and CAC progression have been limited by short follow-up or restricted to patients with advanced disease.
Methods and Results
We examined cardiovascular disease risk factors and CAC progression in a prospective multiethnic cohort study. CAC was measured 1 to 4 times (mean 2.5 scans) over 10 years in 6810 adults without preexisting cardiovascular disease. Mean CAC progression was 23.9 Agatston units/year. An innovative application of mixed-effects models investigated associations between cardiovascular disease risk factors and CAC progression. This approach adjusted for time-varying factors, was flexible with respect to follow-up time and number of observations per participant, and allowed simultaneous control of factors associated with both baseline CAC and CAC progression. Models included age, sex, study site, scanner type, and race/ethnicity. Associations were observed between CAC progression and age (14.2 Agatston units/year per 10 years [95% CI 13.0 to 15.5]), male sex (17.8 Agatston units/year [95% CI 15.3 to 20.3]), hypertension (13.8 Agatston units/year [95% CI 11.2 to 16.5]), diabetes (31.3 Agatston units/year [95% CI 27.4 to 35.3]), and other factors.
Conclusions
CAC progression analyzed over 10 years of follow-up, with a novel analytical approach, demonstrated strong relationships with risk factors for incident cardiovascular events. Longitudinal CAC progression analyzed in this framework can be used to evaluate novel cardiovascular risk factors.
doi:10.1161/JAHA.114.001726
PMCID: PMC4599452  PMID: 26251281
atherosclerosis; calcium; risk factors
14.  Variation in the Percent of Emphysema-like Lung in a Healthy, Nonsmoking Multiethnic Sample. The MESA Lung Study 
Rationale: Computed tomography (CT)-based lung density is used to quantitate the percentage of emphysema-like lung (hereafter referred to as percent emphysema), but information on its distribution among healthy nonsmokers is limited.
Objectives: We evaluated percent emphysema and total lung volume on CT scans of healthy never-smokers in a multiethnic, population-based study.
Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study investigators acquired full-lung CT scans of 3,137 participants (ages 54–93 yr) between 2010–12. The CT scans were taken at full inspiration following the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) protocol. “Healthy never-smokers” were defined as participants without a history of tobacco smoking or respiratory symptoms and disease. “Percent emphysema” was defined as the percentage of lung voxels below −950 Hounsfield units. “Total lung volume” was defined by the volume of lung voxels.
Measurements and Main Results: Among 854 healthy never-smokers, the median percent emphysema visualized on full-lung scans was 1.1% (interquartile range, 0.5–2.5%). The percent emphysema values were 1.2 percentage points higher among men compared with women and 0.7, 1.2, and 1.2 percentage points lower among African Americans, Hispanics, and Asians compared with whites, respectively (P < 0.001). Percent emphysema was positively related to age and height and inversely related to body mass index. The findings were similar for total lung volume on CT scans and for percent emphysema defined at −910 Hounsfield units and measured on cardiac scans. Reference equations to account for these differences are presented for never, former and current smokers.
Conclusions: Similar to lung function, percent emphysema varies substantially by demographic factors and body size among healthy never-smokers. The presented reference equations will assist in defining abnormal values for percent emphysema and total lung volume on CT scans, although validation is pending.
doi:10.1513/AnnalsATS.201310-364OC
PMCID: PMC4213995  PMID: 24983825
emphysema; lung volumes; quantitative computed tomography; reference equations
15.  Association of emphysema-like lung on cardiac computed tomography and mortality in persons without airflow obstruction: the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study 
Annals of internal medicine  2014;161(12):863-873.
Background
Whereas low lung function is known to predict mortality in the general population, the prognostic significance of emphysema on computed tomography (CT) in persons without chronic obstructive pulmonary disease (COPD) remains uncertain.
Objective
To determine whether greater emphysema-like lung on CT is associated with all-cause mortality among persons without airflow obstruction or COPD in the general population.
Design
Prospective cohort study.
Setting
Population-based, multiethnic sample from 6 US communities.
Participants
2965 participants ages 45-84 years without airflow obstruction on spirometry.
Measurements
Emphysema-like lung was defined on cardiac CT as the number of lung voxels less than -950 Hounsfield Units, and was adjusted for the number of total imaged lung voxels.
Results
Among 2965 participants, 50.9% of whom never smoked, there were 186 deaths over a median of 6.2 years. Greater emphysema-like lung was independently associated with increased mortality (adjusted hazard ratio [HR]1.14 per one-half of the interquartile range, 95% CI 1.04-1.24, P=0.004), adjusting for potential confounders including cardiovascular risk factors and the forced expiratory volume in one second. Generalized additive models supported a linear association between emphysema-like lung and mortality without evidence for a threshold. The association was of greatest magnitude among smokers, although multiplicative interaction terms did not support effect modification by smoking status.
Limitations
Cardiac CT scans did not include lung apices. The number of deaths was limited among subgroup analyses.
Conclusions
Emphysema-like lung on CT was associated with all-cause mortality among persons without airflow obstruction or COPD in a general population sample, particularly among smokers. Recognition of the independent prognostic significance of emphysema on CT among patients without COPD on spirometry is warranted.
Primary Funding Source
NIH/NHLBI.
doi:10.7326/M13-2570
PMCID: PMC4347817  PMID: 25506855
16.  Associations of Pentraxin 3 with Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis 
Objective
Pentraxin 3 (PTX3) is likely a specific marker of vascular inflammation. However, associations of PTX3 with cardiovascular disease (CVD) risk have not been well studied in healthy adults or multi-ethnic populations. We examined associations of PTX3 with CVD risk factors, measures of subclinical CVD, coronary artery calcification (CAC) and CVD events in the Multi-Ethnic Study of Atherosclerosis (MESA).
Approach and Results
2838 participants free of prevalent CVD with measurements of PTX3 were included in the present study. Adjusting for age, sex and ethnicity, PTX3 was positively associated with age, obesity, insulin, systolic blood pressure, C-reactive protein (CRP) and carotid intima media thickness (all p<0.045). A one standard deviation increase in PTX3 (1.62 ng/ml) was associated with the presence of CAC in fully adjusted models including multiple CVD risk factors (relative risk; 95% confidence interval 1.05; 1-01-1.08). In fully adjusted models, a standard deviation higher level of PTX3 was associated with an increased risk of myocardial infarction (hazard ratio; 95% confidence interval 1.51; 1.16-1.97), combined CVD events (1.23; 1.05-1.45) and combined CHD events (1.33; 1.10-1.60) but not stroke, CVD-related mortality or all cause death.
Conclusions
In these apparently healthy adults, PTX3 was associated with CVD risk factors, subclinical CVD, CAC and incident coronary heart disease events independent of CRP and CVD risk factors. These results support the hypothesis that PTX3 reflects different aspects of inflammation than CRP and may provide additional insight into the development and progression of atherosclerosis.
doi:10.1111/jth.12557
PMCID: PMC4055511  PMID: 24628740
Atherosclerosis; Cardiovascular Diseases; Epidemiology; Inflammation; Pentraxin 3
17.  The Interaction of Age with Lipoproteins as Predictors of Aortic Valve Calcification in the Multi-Ethnic Study of Atherosclerosis 
Archives of internal medicine  2008;168(11):1200-1207.
Background
Previous epidemiologic studies have shown that low-density lipoprotein is an independent risk factor for prevalent aortic valve calcification (AVC); however, to our knowledge, the interactions between plasma lipoprotein concentrations and age on the relative risks (RRs) for AVC prevalence and severity have not been examined in a large, racially and ethnically diverse cohort.
Methods
Using stepwise RR regression, the relationships of baseline fasting lipid levels and lipoprotein levels to baseline prevalence and severity of AVC were determined in 5801 non–statin-using participants in the Multi-Ethnic Study of Atherosclerosis (MESA).
Results
In age-stratified, adjusted analyses, the low-density lipoprotein–associated RRs (95%confidence intervals) for prevalent AVC were higher for younger compared with older participants (age 45-54 years, 1.69 [1.19-2.39]; age 55-64 years, 1.48 [1.24-1.76]; age 65-74 years, 1.09 [0.95-1.25]; and age 75-84 years, 1.16 [0.99-1.36]; P interaction=.04]. There was a similar, significant interaction of age with total cholesterol–associated RR for prevalent AVC (P interaction=.04). In contrast, total- to high-density lipoprotein cholesterol ratio RRs were similar across all age strata (P interaction=.68). At multivariate analyses, no lipoprotein parameter was associated with AVC severity.
Conclusions
In this racially and ethnically diverse, preclinical cohort, low-density lipoprotein was a risk factor for AVC only in participants younger than 65 years, whereas the total cholesterol/high-density lipoprotein cholesterol ratio was associated with a modest increased risk of AVC across all ages. These findings may have important implications for the efficacy of and targets for dyslipidemia therapies in calcific aortic valve disease.
doi:10.1001/archinte.168.11.1200
PMCID: PMC4441013  PMID: 18541828
18.  Separate prediction of intracerebral hemorrhage and ischemic stroke 
Neurology  2014;82(20):1804-1812.
Objectives:
To develop and validate 10-year cumulative incidence functions of intracerebral hemorrhage (ICH) and ischemic stroke (IS).
Methods:
We used data on 27,493 participants from 3 population-based cohort studies: the Atherosclerosis Risk in Communities Study, median age 54 years, 45% male, median follow-up 20.7 years; the Rotterdam Study, median age 68 years, 38% male, median follow-up 14.3 years; and the Cardiovascular Health Study, median age 71 years, 41% male, median follow-up 12.8 years. Among these participants, 325 ICH events, 2,559 IS events, and 9,909 nonstroke deaths occurred. We developed 10-year cumulative incidence functions for ICH and IS using stratified Cox regression and competing risks analysis. Basic models including only established nonlaboratory risk factors were extended with diastolic blood pressure, total cholesterol/high-density lipoprotein cholesterol ratio, body mass index, waist-to-hip ratio, and glomerular filtration rate. The cumulative incidence functions' performances were cross-validated in each cohort separately by Harrell C-statistic and calibration plots.
Results:
High total cholesterol/high-density lipoprotein cholesterol ratio decreased the ICH rates but increased IS rates (p for difference across stroke types <0.001). For both the ICH and IS models, C statistics increased more by model extension in the Atherosclerosis Risk in Communities and Cardiovascular Health Study cohorts. Improvements in C statistics were reproduced by cross-validation. Models were well calibrated in all cohorts. Correlations between 10-year ICH and IS risks were moderate in each cohort.
Conclusions:
We developed and cross-validated cumulative incidence functions for separate prediction of 10-year ICH and IS risk. These functions can be useful to further specify an individual's stroke risk.
doi:10.1212/WNL.0000000000000427
PMCID: PMC4035707  PMID: 24759844
19.  CORONARY ARTERY CALCIUM IN RELATION TO INITIATION AND CONTINUATION OF CARDIOVASCULAR PREVENTIVE MEDICATIONS: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) 
Background
Whether measuring and reporting of coronary artery calcium scores (CACS) might lead to changes in cardiovascular risk management is not established. In this observational study we examined whether high baseline CACS were associated with the initiation as well continuation of new lipid lowering medication (LLM), blood pressure lowering medication (BPLM) and regular aspirin (ASA) use in a multi-ethnic population-based cohort.
Methods and Results
MESA is a prospective cohort study of 6814 participants free of clinical cardiovascular disease at entry who underwent CAC testing at baseline examination (exam 1). Information on LLM, BPLM and regular ASA usage was also obtained at baseline, and at exams 2 and 3 (average of 1.6 and 3.2 years after baseline respectively). In this study we examined: 1) initiation of these medications at exam 2 among participants not taking these medications at baseline; and 2) continuation of medication use to exam 3 among participants already on medication at baseline. Among MESA participants, initiation of LLM, BPLM and ASA was greater in those with higher CACS After taking into account age, gender, race, MESA site, LDL cholesterol, diabetes mellitus, BMI, smoking status, hypertension, systolic blood pressure, and SES (income, education and health insurance), the risk ratios for medication initiation comparing those with CACS>400 vs. CACS=0 were 1.53 (95% CI: 1.08, 2.15) for LLM, 1.55 (1.10-- 2.17) for BPLM, and 1.32 (1.03–1.69) for ASA initiation, respectively. The risk ratios for medication continuation among those with CAC>400 vs. CACS=0 were 1.10 (95% CI: 1.01–1.20) for LLM, 1.05 (1.02–1.08) for BPLM, and 1.14 (1.04- 1.25) for ASA initiation, respectively.
Conclusion
CACS>400 was associated with a higher likelihood of initiation and continuation of LLM, BPLM and ASA. The association was weaker for continuation than for initiation of these preventive therapies.
doi:10.1161/CIRCOUTCOMES.109.893396
PMCID: PMC4402976  PMID: 20371760
Coronary artery calcification; Computed tomography; Medications; Adherence; Prevention
20.  Height and Risk of Sudden Cardiac Death: The Atherosclerosis Risk in Communities and Cardiovascular Health Studies 
Annals of epidemiology  2013;24(3):174-179.e2.
Purpose
Sudden cardiac death (SCD) is an important cause of mortality in the adult population. Height has been associated with cardiac hypertrophy and an increased risk of arrhythmias, but also with decreased risk of coronary heart disease, suggesting a complex association with SCD.
Methods
We examined the association of adult height with the risk of physician-adjudicated SCD in two large population-based cohorts: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) study.
Results
Over an average follow-up time of 11.7 years in CHS, there were 199 (3.6%) cases of SCD among 5,556 participants. In ARIC, over 12.6 years, there were 227 (1.5%) cases of SCD among 15,633 participants. In both cohorts, there was a trend towards decreased SCD with taller height. In fixed effects meta-analysis, the pooled hazard ratio per 10 cm of height was 0.84 (95%CI 0.73, 0.98, p=0.03). The association of increased height with lower risk of SCD was slightly attenuated after inclusion of risk factors associated with height, such as hypertension and left ventricular hypertrophy. The association appeared stronger among men than women in both cohorts.
Conclusion
In two population-based prospective cohorts of different ages, greater height was associated with lower risk of SCD.
doi:10.1016/j.annepidem.2013.11.008
PMCID: PMC3945001  PMID: 24360853
Body height; risk factors; death; sudden; cardiac
21.  Late Systolic Central Hypertension as a Predictor of Incident Heart Failure: The Multi‐Ethnic Study of Atherosclerosis 
Background
Experimental studies demonstrate that high aortic pressure in late systole relative to early systole causes greater myocardial remodeling and dysfunction, for any given absolute peak systolic pressure.
Methods and Results
We tested the hypothesis that late systolic hypertension, defined as the ratio of late (last one third of systole) to early (first two thirds of systole) pressure–time integrals (PTI) of the aortic pressure waveform, independently predicts incident heart failure (HF) in the general population. Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded noninvasively from 6124 adults. The late/early systolic PTI ratio (L/ESPTI) was assessed as a predictor of incident HF during median 8.5 years of follow‐up. The L/ESPTI was predictive of incident HF (hazard ratio per 1% increase=1.22; 95% CI=1.15 to 1.29; P<0.0001) even after adjustment for established risk factors for HF (HR=1.23; 95% CI=1.14 to 1.32: P<0.0001). In a multivariate model that included brachial systolic and diastolic blood pressure and other standard risk factors of HF, L/ESPTI was the modifiable factor associated with the greatest improvements in model performance. A high L/ESPTI (>58.38%) was more predictive of HF than the presence of hypertension. After adjustment for each other and various predictors of HF, the HR associated with hypertension was 1.39 (95% CI=0.86 to 2.23; P=0.18), whereas the HR associated with a high L/E was 2.31 (95% CI=1.52 to 3.49; P<0.0001).
Conclusions
Independently of the absolute level of peak pressure, late systolic hypertension is strongly associated with incident HF in the general population.
doi:10.1161/JAHA.114.001335
PMCID: PMC4392425  PMID: 25736440
arterial hemodynamics; heart failure; late systolic load; left ventricular afterload
22.  Association between inflammatory markers and liver fat: The Multi-Ethnic Study of Atherosclerosis 
BACKGROUND
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease. Data is emerging that an independent association between markers of subclinical atherosclerosis and NAFLD exists and it may be considered as an independent predictor of cardiovascular (CV) outcomes. We aim to better characterize the relationship between NAFLD and inflammatory markers in a multi-ethnic cohort by assessing fatty liver on computed tomography (CT) scans.
METHODS
The Multi-Ethnic Study of Atherosclerosis (MESA) is a longitudinal, population-based study from four ethnic groups free of CV disease at baseline. The inflammatory markers studied include: C-reactive protein (CRP) and interleukin 6 (IL-6). On CT scans liver-to-spleen ratio (LSR: Hounsfield Units (HU) of the liver divided by HU of spleen) of <1 and liver attenuation of <40 HU were used as criteria for fatty liver. Unadjusted and adjusted multivariate linear and logistic regression analysis was performed.
RESULTS
4038 participants amongst 6814 MESA population with visible spleen on the CT scan, available CRP and IL-6 levels and no reported liver cirrhosis were included. The average age was 61 +/− 10 years, 37% Caucasians and 45% were males. Mean CRP and IL-6 were 2.36 mg/dl and 1.37 pg/ml respectively. 696 participants (17%) had LSR of <1 and 253 (6%) had liver attenuation of <40 HU. When using LSR <1 as a continuous variable, the correlation (adjusted odds ratio (OR)) with CRP >2.0 was 0.037 (95% CI: 0.02-0.054) and with IL-6 was 0.014 (95% CI: 0.004-0.023). On the other hand when presence and absence of LSR <1 was considered, higher ORs for association with CRP >2: 1.41 (95% CI: 1.16 to 1.73) and IL6:1.18 (95% CI: 1.05 to 1.31) were found. Similarly, the adjusted association of per unit decrease in liver attenuation with CRP>2 was 1.92 (95% CI: 1.20 to 2.63) while for IL-6 was 1.08 (95% CI: 0.69 to 1.47). When considering presence and absence of liver attenuation <40 HU the OR for CRP >2 was 2.27 (95% CI: 1.62 to 3.16) and for IL-6 was 1.33 (95% CI: 1.13 to 1.58).
CONCLUSION
CRP and IL-6 levels were found to be significantly associated with liver fat assessed on CT scan after adjusting for other risk factors for atherosclerosis.
doi:10.4172/2155-9880.1000344
PMCID: PMC4296580  PMID: 25598995
Inflammation; Non-alcoholic fatty liver disease; computed tomography scan; C reactive protein
23.  Risk Factors Associated with the Incidence and Progression of Mitral Annulus Calcification: The Multi-Ethnic Study of Atherosclerosis 
American heart journal  2013;166(5):904-912.
Background
Significant cardiovascular morbidity has been associated with mitral annulus calcification (MAC), but limited data exist regarding its progression. The purpose of this study was to examine the natural history of and risk factors for MAC progression.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) is a longitudinal cohort study of participants aged 45–84 years without clinical cardiovascular disease who underwent serial cardiac computed tomography studies with quantification of MAC. Regression models were used to identify risk factors associated with MAC incidence and progression.
Results
Prevalent MAC was observed in 534 of 5,895 (9%) participants. Over a median 2.3 years, 280 (5%) developed incident MAC. After adjustment, age was the strongest predictor of incident MAC (adjusted OR, 2.25 per 10 yrs; 95% CI, 1.97 to 2.58; P<0.0001). Female gender, white ethnicity, body mass index, diabetes, hypertension, hyperlipidemia, serum cholesterol, smoking, and interleukin-6 were also significant predictors of incident MAC. In participants with prevalent MAC, the median rate of change was 10.1 [IQR, −6.7, 60.7] Agatston units (AU)/year. Baseline MAC severity was the predominant predictor of rate of MAC progression (β-coefficient per 10 AU, 0.88; 95% CI, 0.85 to 0.91; P<0.0001), although ethnicity and smoking status possessed modest influence.
Conclusions
Several cardiovascular risk factors predicted incident MAC, as did female gender. Severity of baseline MAC was the primary predictor of MAC progression, suggesting that, while atherosclerotic processes may initiate MAC, they are only modestly associated with its progression over these time frames.
doi:10.1016/j.ahj.2013.08.015
PMCID: PMC3978772  PMID: 24176447
calcification; mitral valve; progression; risk factors; gender
24.  Relationship of CRP, IL-6, and Fibrinogen with Right Ventricular Structure and Function: The MESA-Right Ventricle Study 
International journal of cardiology  2013;168(4):3818-3824.
Background/objectives
Inflammation contributes to the pathogenesis of disease associated with the left ventricle (LV); yet, our understanding of the effect of inflammation on the right ventricle (RV) is quite limited.
Methods and results
The relationships of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with RV morphology and function (from cardiac MRI) were examined in participants free of clinical cardiovascular disease (n=4,009) from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of CRP, IL-6 and fibrinogen with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF). Unadjusted and adjusted analyses revealed strong inverse associations between both CRP and IL-6 with RV mass, RVEDV, RVESV and RVSV (all p<0.01); there were no associations with RVEF. These relationships remained significant after adjustment for the respective LV parameters and lung function. However, GAM models suggested that extreme values of CRP and IL-6 might have positive associations with RV parameters. Fibrinogen showed significant associations in unadjusted models, but no associations after adjustment or in sensitivity analyses.
Conclusion
Levels of CRP and IL-6 are independently associated with RV morphology even after adjustment for the respective LV measure in this multi-ethnic population free of cardiovascular disease. Systemic inflammation may contribute to RV structural changes independent of effects on the LV.
doi:10.1016/j.ijcard.2013.06.028
PMCID: PMC3805818  PMID: 23932860
Systemic inflammation; right ventricle; heart failure; Multi-Ethnic Study of Atherosclerosis
25.  Blood Pressure Variability and the Risk of All-Cause Mortality, Incident Myocardial Infarction, and Incident Stroke in the Cardiovascular Health Study 
American Journal of Hypertension  2013;26(10):1210-1217.
BACKGROUND
Recent reports have linked variability in visit-to-visit systolic blood pressure (SBP) to risk of mortality and stroke, independent of the effect of mean SBP level. This study aimed to evaluate whether variability in SBP is associated with all-cause mortality, incident myocardial infarction (MI), and incident stroke, independent of mean SBP or trends in SBP levels over time.
METHODS
The Cardiovascular Health Study is a longitudinal cohort study of vascular risk factors and disease in the elderly. Participants who attended their first 5 annual clinic visits and experienced no event before the 5th visit were eligible (n = 3,852). Primary analyses were restricted to participants not using antihypertensive medications throughout the first 5 clinic visits (n = 1,642). Intraindividual SBP variables were defined using each participant’s 5-visit blood pressure measures. Cox proportional hazards models estimated adjusted hazard ratios (HRs) per SD increase in intraindividual SBP variability, adjusted for intraindividual SBP mean and change over time.
RESULTS
Over a mean follow-up of 9.9 years, there were 844 deaths, 203 MIs, and 195 strokes. Intraindividual SBP variability was significantly associated with increased risk of mortality (HR = 1.13; 95% confidence interval (CI) = 1.05–1.21) and of incident MI (HR = 1.20; 95%CI = 1.06–1.36), independent of the effect from adjustment factors. Intraindividual SBP variability was not associated with risk of stroke (HR = 1.03; 95% CI = 0.89–1.21).
CONCLUSIONS
Long-term visit-to-visit SBP variability was independently associated with a higher risk of subsequent mortality and MI but not stroke. More research is needed to determine the relationship of BP variability with cardiovascular risk and the clinical implications.
doi:10.1093/ajh/hpt092
PMCID: PMC3773571  PMID: 23744496
blood pressure; blood pressure variability; hypertension; mortality; myocardial infarction; stroke.

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