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1.  Association between inflammatory markers and liver fat: The Multi-Ethnic Study of Atherosclerosis 
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.
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.
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).
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.
PMCID: PMC4296580  PMID: 25598995
Inflammation; Non-alcoholic fatty liver disease; computed tomography scan; C reactive protein
2.  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.
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.
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.
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.
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.
PMCID: PMC3978772  PMID: 24176447
calcification; mitral valve; progression; risk factors; gender
3.  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.
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.
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.
PMCID: PMC3805818  PMID: 23932860
Systemic inflammation; right ventricle; heart failure; Multi-Ethnic Study of Atherosclerosis
4.  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.
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.
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.
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).
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.
PMCID: PMC3773571  PMID: 23744496
blood pressure; blood pressure variability; hypertension; mortality; myocardial infarction; stroke.
5.  Progression of Coronary Calcium and Incident Coronary Heart Disease Events: The Multi-Ethnic Study of Atherosclerosis 
Coronary artery calcium (CAC) predicts coronary heart disease (CHD) events and serial measurement of CAC has been proposed to evaluate atherosclerosis progression. We examined whether progression of CAC is a predictor of future CHD events.
Methods and Results
We studied 6,778 persons (52.8% female) aged 45–84 years from the Multi-Ethnic Study of Atherosclerosis. 5,682 persons had baseline and follow-up CAC scans approximately 2.5 ± 0.8 years apart; multiple imputation was used to account for the remainder (n=1,096) missing follow-up scans. Median follow-up duration from the baseline was 7.6 (max=9.0) years. CAC change was assessed by absolute change between baseline and follow-up CAC. Cox proportional hazards regression providing hazard ratios (HR) examined the relation of change in CAC with CHD events, adjusting for age, gender, ethnicity, baseline calcium score, and other risk factors. 343 total and 206 hard CHD events occurred. The annual change in CAC averaged 24.9 ± 65.3 units. Among persons without CAC at baseline (n=3,396), a 5 unit annual change in CAC was associated with an adjusted HR of 1.4 (1.0–1.9) for total and 1.5 (1.1–2.1) for hard CHD. Among those with CAC>0 at baseline HR’s (per 100 unit annual change) were 1.2 (1.1–1.4) and 1.3 (1.1–1.5), respectively. Among participants with baseline CAC, those with annual progression of ≥300 units had adjusted HR’s of 3.8 (1.5–9.6) for total and 6.3 (1.9–21.5) for hard CHD compared to those without progression.
Progression of CAC is associated with an increased risk for future hard and total CHD events.
PMCID: PMC4148074  PMID: 23500326
coronary calcification; atherosclerosis; imaging; coronary heart disease
6.  Study design considerations for evaluating the efficacy and safety of pancreatic enzyme replacement therapy in patients with cystic fibrosis 
Clinical investigation  2013;3(8):731-741.
In 2006, the US FDA issued a ‘Guidance for Industry’ regarding submission of New Drug Applications for pancreatic enzyme replacement therapy (PERT) products. Five oral delayed-release PERT products have been approved by the FDA, and several others are under development and/ or evaluation for New Drug Application submission. We present in this paper recommendations of the Cystic Fibrosis Foundation's Cystic Fibrosis (CF) Therapeutics Development Network and Data Safety Monitoring Board regarding study design considerations for evaluating PERT products in patients with CF. Careful attention to study design and accuracy of the outcome measures has confirmed our understanding of the efficacy and safety of PERT for the treatment of exocrine pancreatic insufficiency of CF.
PMCID: PMC4131768  PMID: 25132954
coefficient of fat absorption; cystic fibrosis; pancreatic enzyme replacement therapy; pancreatic insufficiency; study design
7.  N-terminal pro-B-type Natriuretic Peptide is a Major Predictor of the Development of Atrial Fibrillation: The Cardiovascular Health Study 
Circulation  2009;120(18):1768-1774.
Atrial fibrillation (AF), the most common cardiac rhythm abnormality, is associated with significant morbidity, mortality, and health care expenditures. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure, atrial fibrillation, and mortality.
Methods and Results
The relation between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and AF was studied in 5,445 Cardiovascular Health Study participants, using relative risk regression for predicting prevalent AF, and Cox proportional hazards for predicting incident AF. NT-proBNP levels were strongly associated with prevalent AF, with an unadjusted prevalence ratio of 128 for the highest quintile (95%CI 17.9, 913.3, p< 0.001); and adjusted prevalence ratio of 147 for the highest quintile (95% CI 20.4, 1064.3, p<0.001) compared to the lowest. After a median follow up of 10 years (maximum of 16 years), there were 1,126 cases of incident AF (a rate of 2.2 per 100 person years). NT-proBNP was highly predictive of incident AF with an unadjusted hazard ratio of 5.2 (95% CI 4.3, 6.4, p < 0.001) for the development of AF for the highest quintile compared to the lowest; for the same contrast, NT-proBNP remained the strongest predictor of incident AF after adjustment for an extensive number of covariates, including age, sex, medication use, blood pressure, echocardiographic parameters, diabetes, and heart failure; with an adjusted hazard ratio of 4.0 (CI 3.2, 5.0, p< 0.001).
In a community based population of older adults, NT-pro BNP was a remarkable predictor of incident AF, independent of any other previously described risk factor.
PMCID: PMC4132053  PMID: 19841297
B-type natriuretic peptide; atrial fibrillation; BNP; NT-proBNP
8.  Associations between Aspirin and other non-steroidal anti-inflammatory drugs and aortic valve or coronary artery calcification: The Multi-Ethnic Study of Atherosclerosis and the Heinz Nixdorf Recall Study 
Atherosclerosis  2013;229(2):310-316.
The association between non-steroidal anti-inflammatory drugs (NSAIDs) and the incidence of valvular and arterial calcification is not well established despite known associations between these drugs and cardiovascular events.
To compare the association between the baseline use of aspirin with other NSAID class medications with the incidence and prevalence of aortic valve calcification (AVC) and coronary artery calcium (CAC).
The relationship of NSAID use to AVC and CAC detected by computed tomography was assessed in 6,814 participants within the Multi-Ethnic Study of Atherosclerosis (MESA) using regression modeling. Results were adjusted for age, sex, ethnicity, study site, anti-hypertensive medication use, education, income, health insurance status, diabetes, smoking, exercise, body mass index, blood pressure, serum lipids, inflammatory markers, fasting glucose, statin medication use, and a simple diet score. Medication use was assessed by medication inventory at baseline which includes the use of non-prescription NSAIDs. MESA collects information on both incident and prevalent calcification. The 4,814 participants of the Heinz Nixdorf Recall (HNR) Study, a German prospective cohort study with similar measures of calcification, were included in this analysis to enable replication.
Mean age of the MESA participants was 62 years (51% female). After adjustment for possible confounding factors, a possible association between aspirin use and incident AVC (Relative Risk(RR): 1.60; 95%Confidence Interval (CI): 1.19–2.15) did not replicate in the HNR cohort (RR: 1.06; 95%CI: 0.87–1.28). There was no significant association between aspirin use and incident CAC in the MESA cohort (RR 1.08; 95%CI: 0.91–1.29) or in the HNR cohort (RR 1.24; 95%CI: 0.87–1.77). Non-aspirin NSAID use was not associated with either AVC or CAC in either cohort. There were no associations between regular cardiac dose aspirin and incident calcification in either cohort.
Baseline NSAID use, as assessed by medication inventory, appears to have no protective effect regarding the onset of calcification in either coronary arteries or aortic valves.
PMCID: PMC3724227  PMID: 23880181
Non-steroidal anti-inflammatory drugs; aspirin; aortic valve calcification; coronary artery calcification; Multi-Ethnic Study of Atherosclerosis; Heinz Nixdorf Recall Study
9.  Thoracic Aortic Calcification and Coronary Heart Disease Events: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2010;215(1):196-202.
The presence and extent of coronary artery calcium (CAC) is an independent predictor of coronary heart disease (CHD) morbidity and mortality. Few studies have evaluated interactions or independent incremental risk for coronary and thoracic aortic calcification (TAC). The independent predictive value of TAC for CHD events is not well-established.
This study used risk factor and computed tomography scan data from 6,807 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Using the same images for each participant, TAC and CAC were each computed using the Agatston method. The study subjects were free of incident CHD at entry into the study.
The mean age of the study population (n=6807) was 62±10 years (47% males). At baseline, the prevalence of TAC and CAC was 28 % (1,904/6,809) and 50% (3393/6809), respectively. Over 4.5±0.9 years, a total of 232 participants (3.41%) had CHD events, of which 132 (1.94%) had a hard event (myocardial infarction, resuscitated cardiac arrest, or CHD death). There was a significant interaction between gender and TAC for CHD events (p<0.05). Specifically, in women, the risk of all CHD event was nearly 3-fold greater among those with any TAC (hazard ratio: 3.04, 95% CI; 1.60–5.76). After further adjustment for increasing CAC score, this risk was attenuated but remained robust (HR: 2.15, 95% CI: 1.10–4.17). Conversely, there was no significant association between TAC and incident CHD in men. In women, the likelihood ratio chi square statistics indicate that the addition of TAC contributed significantly to predicting incident CHD event above that provided by traditional risk factors alone (chi square= 12.44, p=0.0004) as well as risk factors + CAC scores (chi square= 5.33, p=0.02) . On the other hand, addition of TAC only contributed in the prediction of hard CHD events to traditional risk factors (chi-square=4.33, p=0.04) in women, without contributing to the model containing both risk factors and CAC scores (chi square=1.55, p=0.21).
Our study indicates that TAC is a significant predictor of future coronary events only in women, independent of CAC. On studies obtained for either cardiac or lung applications, determination of TAC may provide modest supplementary prognostic information in women with no extra cost or radiation.
PMCID: PMC4110678  PMID: 21227418
atherosclerosis; cardiac CT; coronary calcium; multi-detector CT; prognosis; thoracic atherosclerosis
10.  Ethnicity and Sex Modify the Association of Serum C-Reactive Protein with Microalbuminuria 
Ethnicity & disease  2008;18(3):324-329.
To study the association between serum C-reactive protein (CRP) and urinary albumin excretion in the Multi-Ethnic Study of Atherosclerosis and to assess whether the association is modified by ethnicity, sex, or systolic blood pressure.
This was a cross-sectional study of 6675 participants who were free from macro albuminuria and clinical cardiovascular disease (mean age 62.1 years, 53% female; 39% White, 27% African American, 22% Hispanic, and 12% Chinese). Urinary albumin excretion was measured by spot urine albumin-to-creatinine ratio (ACR). Effect modifications were tested after adjusting for age, diabetes, body mass index, smoking, use of angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, other antihypertensive drugs, estrogens, statins, and high-density lipoprotein cholesterol and triglyceride levels.
The association between CRP and ACR was modified by ethnicity (P=.01) and sex (P<.001), but not by systolic blood pressure. After multivariate adjustment, the association remained in Chinese, African American, and Hispanic men and African American women (P<.02 for African American men, and P<.04 for the other subgroups).
The association between CRP and ACR was modified by ethnicity and sex; it was stronger in non-White men and African American women. These interactions have not been reported before, and future studies should consider them.
PMCID: PMC4089959  PMID: 18785447
Albuminuria; C-Reactive Protein; Ethnicity; Gender
11.  Genetic Ancestry and the Relationship of Cigarette Smoking to Lung Function and Percent Emphysema in Four Race/Ethnic Groups: a Cross-sectional Study 
Thorax  2013;68(7):634-642.
Cigarette smoking is the major cause of chronic obstructive pulmonary disease and emphysema. Recent studies suggest that susceptibility to cigarette smoke may vary by race/ethnicity; however, they were generally small and relied on self-reported race/ethnicity.
To test the hypothesis that relationships of smoking to lung function and percent emphysema differ by genetic ancestry and self-reported race/ethnicity among Whites, African-Americans, Hispanics and Chinese-Americans.
Cross-sectional population-based study of adults age 45-84 years in the United States
Principal components of genetic ancestry and continental ancestry estimated from one-million genome-wide single nucleotide polymorphisms. Pack-years calculated as years smoking cigarettes-per-day/20. Spirometry measured for 3,344 and percent emphysema on computed tomography for 8,224 participants.
The prevalence of ever-smoking was: Whites, 57.6%; African-Americans, 56.4%; Hispanics, 46.7%; and Chinese-Americans, 26.8%. Every 10 pack-years was associated with −0.73% (95% CI −0.90%, −0.56%) decrement in the forced expiratory volume in one second to forced vital capacity (FEV1/FVC) and a 0.23% (95% CI 0.08%, 0.38%) increase in percent emphysema. There was no evidence that relationships of pack-years to the FEV1/FVC, airflow obstruction and percent emphysema varied by genetic ancestry (all p>0.10), self-reported race/ethnicity (all p>0.10) or, among African-Americans, African ancestry. There were small differences in relationships of pack-years to the FEV1 among male Chinese-Americans and to the FEV1/FVC with African and Native American ancestry among male Hispanics only.
In this large cohort, there was little-to-no evidence that the associations of smoking to lung function and percent emphysema differed by genetic ancestry or self-reported race/ethnicity.
PMCID: PMC4020409  PMID: 23585509
cigarette smoke; genetic ancestry; lung function; chronic obstructive pulmonary disease; COPD; emphysema; FVC; Forced Vital Capacity; FEV1; Forced Expiratory Volume in 1 second
12.  Arterial Wave Reflections and Incident Cardiovascular Events and Heart Failure: The Multiethnic Study of Atherosclerosis 
Experimental and physiologic data mechanistically implicate wave reflections in the pathogenesis of left ventricular failure and cardiovascular disease, but their association with these outcomes in the general population is unclear.
To assess the relationship between central pressure profiles and incident cardiovascular events.
Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded non-invasively from 5,960 participants in the Multiethnic Study of Atherosclerosis (MESA). The central pressure waveform was separated into forward and reflected waves using a physiologic flow waveform. Reflection magnitude (RM=[reflected/forward wave amplitude] ×100), augmentation index (AIx=[second/first systolic peak] ×100) and pulse pressure amplification (PPA=[radial/aortic pulse pressure] ×100) were assessed as predictors of cardiovascular events (CVE) and congestive heart failure (CHF) during median 7.61 years of follow-up.
After adjustment for established risk factors, aortic AIx independently predicted hard CVE (HR per 10%-increase=1.08; 95%CI=1.01-1.14; P=0.016), whereas PPA independently predicted all CVE (HR per 10%-increase=0.82; 95%CI=0.70-0.96; P=0.012). RM was independently predictive of all CVE (hazard ratio [HR] per 10%-increase=1.34; 95%CI=1.08-1.67; P=0.009), hard CVE (HR per 10%-increase=1.46; 95%CI=1.12-1.90; P=0.006) and strongly predictive of new-onset CHF (HR per 10%-increase=2.69; 95%CI=1.79-4.04; P<0.0001), comparing favorably to other risk factors for CHF as judged by various measures of model performance, reclassification and discrimination. In a fully-adjusted model, compared to non-hypertensive subjects with low RM, the HR for hypertensive subjects with low RM, non-hypertensive subjects with high RM and hypertensive subjects with high RM were 1.81 (95%CI=0.85-3.86), 2.16 (95%CI=1.07-5.01) and 3.98 (95%CI=1.96-8.05), respectively.
Arterial wave reflections represent a novel strong risk factor for CHF in the general population.
PMCID: PMC4065497  PMID: 23103044
wave reflections; cardiovascular risk; heart failure. arterial hemodynamics; left ventricular afterload
13.  A comparison of outcomes with coronary artery calcium scanning in Unselected Populations - The Multi-Ethnic Study of Atherosclerosis (MESA) and Heinz Nixdorf Recall Study (HNR) 
The Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR)) differed in regards to informing physicians and patients of the results of their subclinical atherosclerosis.
This study investigates whether the association of coronary artery calcium (CAC) with incident non-fatal and fatal cardiovascular (CVD) events is different among these two large, population-based observational studies.
All Caucasian subjects aged 45–75 years, free of baseline cardiovascular disease were included (n=2232 in MESA, n=3119 HNR participants). We studied the association between CAC and event rates at 5 years, including hard cardiac events (MI, cardiac death, resuscitated cardiac arrest), and separately added revascularizations, and strokes (fatal and non-fatal) to determine adjusted hazard ratios (HR).
Both cohorts demonstrated very low CHD (including revascularization) rates with zero calcium (1.13 and 1.16% over 5 years in MESA and HNR respectively) and increasing significantly in both groups with CAC 100–399 (6.71 and 4.52% in MESA and HNR) and CAC >400 (12.5 and 13.54% in MESA and HNR respectively) and demonstrating strong independent predictive values for scores of 100–399 and >400, despite multivariable adjustment for risk factors. Risk factor adjusted five year revascularization rates were nearly identical for HNR and MESA, and generally low for both studies (1.4% [45/3119] for HNR and 1.9% [43/2232] for MESA) over 5 years.
Across two culturally diverse populations, CAC >400 is a strong predictor of events. High CAC did not determininistically result in revascularization and knowledge of CAC did not increase revascularizations.
PMCID: PMC3732186  PMID: 23849491
coronary artery calcification; subclinical atherosclerosis; Multi-Ethnic Study of Atherosclerosis (MESA); Heinz Nixdorf Recall Study (HNR)
14.  Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders 
den Hoed, Marcel | Eijgelsheim, Mark | Esko, Tõnu | Brundel, Bianca J J M | Peal, David S | Evans, David M | Nolte, Ilja M | Segrè, Ayellet V | Holm, Hilma | Handsaker, Robert E | Westra, Harm-Jan | Johnson, Toby | Isaacs, Aaron | Yang, Jian | Lundby, Alicia | Zhao, Jing Hua | Kim, Young Jin | Go, Min Jin | Almgren, Peter | Bochud, Murielle | Boucher, Gabrielle | Cornelis, Marilyn C | Gudbjartsson, Daniel | Hadley, David | Van Der Harst, Pim | Hayward, Caroline | Heijer, Martin Den | Igl, Wilmar | Jackson, Anne U | Kutalik, Zoltán | Luan, Jian’an | Kemp, John P | Kristiansson, Kati | Ladenvall, Claes | Lorentzon, Mattias | Montasser, May E | Njajou, Omer T | O’Reilly, Paul F | Padmanabhan, Sandosh | Pourcain, Beate St. | Rankinen, Tuomo | Salo, Perttu | Tanaka, Toshiko | Timpson, Nicholas J | Vitart, Veronique | Waite, Lindsay | Wheeler, William | Zhang, Weihua | Draisma, Harmen H M | Feitosa, Mary F | Kerr, Kathleen F | Lind, Penelope A | Mihailov, Evelin | Onland-Moret, N Charlotte | Song, Ci | Weedon, Michael N | Xie, Weijia | Yengo, Loic | Absher, Devin | Albert, Christine M | Alonso, Alvaro | Arking, Dan E | de Bakker, Paul I W | Balkau, Beverley | Barlassina, Cristina | Benaglio, Paola | Bis, Joshua C | Bouatia-Naji, Nabila | Brage, Søren | Chanock, Stephen J | Chines, Peter S | Chung, Mina | Darbar, Dawood | Dina, Christian | Dörr, Marcus | Elliott, Paul | Felix, Stephan B | Fischer, Krista | Fuchsberger, Christian | de Geus, Eco J C | Goyette, Philippe | Gudnason, Vilmundur | Harris, Tamara B | Hartikainen, Anna-liisa | Havulinna, Aki S | Heckbert, Susan R | Hicks, Andrew A | Hofman, Albert | Holewijn, Suzanne | Hoogstra-Berends, Femke | Hottenga, Jouke-Jan | Jensen, Majken K | Johansson, Åsa | Junttila, Juhani | Kääb, Stefan | Kanon, Bart | Ketkar, Shamika | Khaw, Kay-Tee | Knowles, Joshua W | Kooner, Angrad S | Kors, Jan A | Kumari, Meena | Milani, Lili | Laiho, Päivi | Lakatta, Edward G | Langenberg, Claudia | Leusink, Maarten | Liu, Yongmei | Luben, Robert N | Lunetta, Kathryn L | Lynch, Stacey N | Markus, Marcello R P | Marques-Vidal, Pedro | Leach, Irene Mateo | McArdle, Wendy L | McCarroll, Steven A | Medland, Sarah E | Miller, Kathryn A | Montgomery, Grant W | Morrison, Alanna C | Müller-Nurasyid, Martina | Navarro, Pau | Nelis, Mari | O’Connell, Jeffrey R | O’Donnell, Christopher J | Ong, Ken K | Newman, Anne B | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P | Psaty, Bruce M | Rao, Dabeeru C | Ring, Susan M | Rossin, Elizabeth J | Rudan, Diana | Sanna, Serena | Scott, Robert A | Sehmi, Jaban S | Sharp, Stephen | Shin, Jordan T | Singleton, Andrew B | Smith, Albert V | Soranzo, Nicole | Spector, Tim D | Stewart, Chip | Stringham, Heather M | Tarasov, Kirill V | Uitterlinden, André G | Vandenput, Liesbeth | Hwang, Shih-Jen | Whitfield, John B | Wijmenga, Cisca | Wild, Sarah H | Willemsen, Gonneke | Wilson, James F | Witteman, Jacqueline C M | Wong, Andrew | Wong, Quenna | Jamshidi, Yalda | Zitting, Paavo | Boer, Jolanda M A | Boomsma, Dorret I | Borecki, Ingrid B | Van Duijn, Cornelia M | Ekelund, Ulf | Forouhi, Nita G | Froguel, Philippe | Hingorani, Aroon | Ingelsson, Erik | Kivimaki, Mika | Kronmal, Richard A | Kuh, Diana | Lind, Lars | Martin, Nicholas G | Oostra, Ben A | Pedersen, Nancy L | Quertermous, Thomas | Rotter, Jerome I | van der Schouw, Yvonne T | Verschuren, W M Monique | Walker, Mark | Albanes, Demetrius | Arnar, David O | Assimes, Themistocles L | Bandinelli, Stefania | Boehnke, Michael | de Boer, Rudolf A | Bouchard, Claude | Caulfield, W L Mark | Chambers, John C | Curhan, Gary | Cusi, Daniele | Eriksson, Johan | Ferrucci, Luigi | van Gilst, Wiek H | Glorioso, Nicola | de Graaf, Jacqueline | Groop, Leif | Gyllensten, Ulf | Hsueh, Wen-Chi | Hu, Frank B | Huikuri, Heikki V | Hunter, David J | Iribarren, Carlos | Isomaa, Bo | Jarvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kiemeney, Lambertus A | van der Klauw, Melanie M | Kooner, Jaspal S | Kraft, Peter | Iacoviello, Licia | Lehtimäki, Terho | Lokki, Marja-Liisa L | Mitchell, Braxton D | Navis, Gerjan | Nieminen, Markku S | Ohlsson, Claes | Poulter, Neil R | Qi, Lu | Raitakari, Olli T | Rimm, Eric B | Rioux, John D | Rizzi, Federica | Rudan, Igor | Salomaa, Veikko | Sever, Peter S | Shields, Denis C | Shuldiner, Alan R | Sinisalo, Juha | Stanton, Alice V | Stolk, Ronald P | Strachan, David P | Tardif, Jean-Claude | Thorsteinsdottir, Unnur | Tuomilehto, Jaako | van Veldhuisen, Dirk J | Virtamo, Jarmo | Viikari, Jorma | Vollenweider, Peter | Waeber, Gérard | Widen, Elisabeth | Cho, Yoon Shin | Olsen, Jesper V | Visscher, Peter M | Willer, Cristen | Franke, Lude | Erdmann, Jeanette | Thompson, John R | Pfeufer, Arne | Sotoodehnia, Nona | Newton-Cheh, Christopher | Ellinor, Patrick T | Stricker, Bruno H Ch | Metspalu, Andres | Perola, Markus | Beckmann, Jacques S | Smith, George Davey | Stefansson, Kari | Wareham, Nicholas J | Munroe, Patricia B | Sibon, Ody C M | Milan, David J | Snieder, Harold | Samani, Nilesh J | Loos, Ruth J F
Nature genetics  2013;45(6):621-631.
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
PMCID: PMC3696959  PMID: 23583979
15.  Comparison of Factors Associated with Carotid Intima-Media Thickness in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR) 
The measurement of carotid intima-media thickness (CIMT) is a valid method to quantify levels of atherosclerosis. The present study was conducted to compare the strengths of associations between CIMT and cardiovascular risk factors in two different populations.
The Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR) are two population-based prospective cohort studies of subclinical cardiovascular disease. All Caucasian subjects aged 45 to 75 years from these cohorts who were free of baseline cardiovascular disease (n = 2,820 in HNR, n = 2,270 in MESA) were combined. CIMT images were obtained using B-mode sonography at the right and left common carotid artery and measured 1 cm starting from the bulb.
In both studies, age, male sex, and systolic blood pressure showed the strongest association (P < .0001 for each) for a higher CIMT. The mean of mean far wall CIMT was slightly higher in MESA participants (0.71 vs 0.67 mm). Almost all significant variables were consistent between the two cohorts in both magnitude of association with CIMT and statistical significance, including age, sex, smoking, diabetes, cholesterol levels, and blood pressure. For example, the association with systolic blood pressure was (ΔSD = 0.011; 95% confidence interval, 0.0009 to 0.014) per mm Hg in MESA and (ΔSD = 0.010; 95% confidence interval, 0.005 to 0.021) per mm Hg in HNR. This consistency persisted throughout the traditional (Framingham) risk factors.
A comparison of the associations between traditional cardiovascular risk factors and CIMT across two culturally diverse populations showed remarkable consistency.
PMCID: PMC3694173  PMID: 23611058
Carotid intima-media thickness; Subclinical atherosclerosis; Multi-Ethnic Study of Atherosclerosis; MESA; Heinz Nixdorf Recall Study; HNR
16.  Racial Variations in the Prevalence of Refractive Errors in the United States: The Multi-Ethnic Study of Atherosclerosis 
American journal of ophthalmology  2013;155(6):1129-1138.e1.
To describe racial variations in the prevalence of refractive errors among adult white, Chinese, Hispanic, and black subjects in the United States.
Cross-sectional data from a prospective cohort study—the Multi-Ethnic Study of Atherosclerosis (MESA).
A total of 6000 adults aged 45 to 84 years living in the United States participated in the study. Refractive error was assessed, without cycloplegia, in both eyes of all participants using an autorefractor. After excluding eyes with cataract, cataract surgery, or previous refractive surgery, the eye with the larger absolute spherical equivalent (SE) value for each participant was used to classify refractive error. Any myopia was defined as SE of −1.0 diopters (D) or less; high myopia was defined as SE of −5.0 D or less; any hyperopia was defined as SE of +1.0 D or more; clinically significant hyperopia was defined as SE of +3.0 D or more. Astigmatism was defined as a cylinder value of +1.0 D or more.
After excluding 508 participants with cataracts in both eyes, 838 participants with cataract surgery, 90 participants with laser refractive surgery, and 134 participants who refused to remove their contact lenses for the refraction measurement, 4430 adults with refractive error assessment in at least 1 eye contributed to the analysis. The prevalence of myopia among MESA participants was 25.1%, with lowest rates in Hispanic participants (14.2%), followed by black (21.5%) and white participants (31.0%), and highest rates in Chinese participants (37.2%). The overall rates of high myopia and astigmatism were 4.6% and 45.0%, respectively, with Chinese subjects also having the highest rates of high myopia (11.8%) and astigmatism (53.4%). The overall prevalence of any hyperopia was 38.2% and clinically significant hyperopia was 6.1%, with Hispanic participants having the highest rates of hyperopia (50.2%) and clinically significant hyperopia (8.8%). In multivariate analyses adjusting for age, sex, race, and study site, higher education level, being employed, and being taller were associated with a higher prevalence of myopia. In contrast, lower educational level and being shorter were associated with a higher prevalence of hyperopia.
Myopia and astigmatism were most prevalent in the Chinese population, with Chinese subjects having 3 times the prevalence of myopia as Hispanic subjects. Hyperopia was most common in Hispanic subjects. These findings provide further insights into variations in refractive errors among different racial groups and have important implications for the eye care services in the United States.
PMCID: PMC3759975  PMID: 23453694
17.  Pentraxin-3 and the right ventricle: the Multi-Ethnic Study of Atherosclerosis–Right Ventricle Study 
Pulmonary Circulation  2014;4(2):250-259.
Pentraxin-3 (PTX3) is a protein mediator of innate immunity that is elevated in the setting of left heart disease and pulmonary arterial hypertension. The relationship between PTX3 and right ventricular (RV) structure and function is not known. We included men and women with magnetic resonance imaging assessment of RV structure and function and measurement of PTX3 from the Multi-Ethnic Study of Atherosclerosis, a study of individuals free of clinical cardiovascular disease. Multivariable linear regression estimated associations between PTX3 protein levels and RV measures after adjusting for demographic characteristics, anthropometrics, smoking status, diabetes mellitus, hypertension, and corresponding left ventricular (LV) parameters. Instrumental variable analysis exploiting Mendelian randomization was attempted using two-stage least squares regression. The study sample included 1,779 participants with available PTX3 levels, RV measures, and all covariables. Mean PTX3 level was 2.1 ng/mL. Higher PTX3 was independently associated with greater RV mass and larger RV end-diastolic volume with and without adjustment for the corresponding LV parameters or C-reactive protein (all P < .05). There was no association between PTX3 and RV ejection fraction or stroke volume. Single-nucleotide polymorphisms were not associated with PTX3 protein levels or RV measures after accounting for race. Instrumental variable analysis could not be reliably performed. Higher PTX3 protein levels were associated with greater RV mass and larger RV end-diastolic volume. These associations were independent of common cardiovascular risk factors and LV morphologic changes. Inflammation is associated with differences in the pulmonary circulation-RV axis in adults without clinical cardiovascular disease.
PMCID: PMC4070771  PMID: 25006444
pulmonary hypertension; heart failure; inflammation; right ventricle; Mendelian randomization
18.  Methods for Estimation of Disparities in Medication Use in an Observational Cohort Study: Results from the Multi-Ethnic Study of Atherosclerosis 
Evaluating disparities in health care is an important aspect of understanding differences in disease risk. The purpose of this study is to describe methodology for estimating such disparities, with application to a large multi-ethnic cohort study.
The Multi-Ethnic Study of Atherosclerosis (MESA) includes 6814 participants aged 45–84 years free of cardiovascular disease. Prevalence ratio (PR) regression was used to model baseline lipid lowering medication (LLM) or anti-hypertensive medication use at baseline as a function of gender, race, risk factors and estimated pre-treatment biomarker values.
Hispanics and African-Americans had lower prevalence of medication use than non-Hispanic whites, even at the same risk factor profile. This became non-significant after adjustment for socio-economic status. Although gender did not influence the prevalence of LLM use (PR=1.09, 95% CI 0.95 to 1.25), there were differences in the association of diabetes and HDL with LLM use by gender. Men were significantly less likely to be on anti-hypertensive medications than women (PR=0.86, 95% CI 0.80 to 0.92, p<0.001) and this was not explained by risk factors or socioeconomic status. Lack of health insurance strongly influenced medication use, controlling for risk factors and other markers of socio-economic status.
Disparities exist in the treatment of cholesterol and hypertension. Hispanics and African Americans had less use of LLM, men had less use of anti-hypertensives. Risk factors have differential associations with medication use depending on gender. Methods described in this paper can provide improved disparity estimation in observational cohort studies.
PMCID: PMC3652567  PMID: 23382107
disparities; medication; statistical methods; statins; anti-hypertensives
19.  Comparative Efficacy and Safety of Four Randomized Regimens to Treat Early Pseudomonas aeruginosa Infection in Children with Cystic Fibrosis 
While therapy for early Pa acquisition has been shown to be efficacious, the best regimen to achieve airway clearance has not been delineated.
To investigate the efficacy and safety of four anti-pseudomonal treatments in children with cystic fibrosis (CF) with recently acquired Pa.
Design, Setting, and Patients
In a multicenter trial in the US, 304 children with CF ages 1–12 years within 6 months of Pa detection were randomized to one of four antibiotic regimens for an 18-month period (six 12-week quarters) between December 2004 and June 2009. Participants randomized to cycled therapy received tobramycin inhalation solution (300 mg BID) for 28 days, with oral ciprofloxacin (15–20 mg/kg BID) or oral placebo for 14 days every quarter, while participants randomized to culture-based therapy received the same treatments only during quarters with positive Pa cultures.
Main outcome measures
The primary endpoints were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of Pa-positive cultures.
The intention-to-treat analysis included 304 participants. There was no interaction between treatments. There were no statistically significant differences in exacerbation rates between cycled and culture-based groups (hazard ratio [HR], 0.95, 95%CI, 0.54–1.66) or ciprofloxacin and placebo (HR 1.45, 95%CI, 0.82–2.54). The ORs of Pa positive culture comparing cycled vs. culture-based group were 0.78 (95%CI, 0.49–1.23) and OR 1.10; 95%CI, 0.71–1.71) comparing ciprofloxacin vs. placebo. Adverse events were similar across groups.
No difference in rate of exacerbation or prevalence of Pa positivity was detected between cycled and culture-based therapies. Adding ciprofloxacin produced no benefits.
PMCID: PMC3991697  PMID: 21893650
Antimicrobials; Tobramycin Inhalation Solution; Ciprofloxacin; Pseudomonas aeruginosa; Mucoviscidosis; Clinical trial; Cystic Fibrosis
20.  Amino terminal pro–B-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy 
Background and Purpose
Because of its association with atrial fibrillation and heart failure, we hypothesized that amino terminal pro–B-type natriuretic peptide (NT-proBNP) would identify a subgroup of patients from the Warfarin–Aspirin Recurrent Stroke Study (WARSS), diagnosed with inferred non-cardioembolic ischemic strokes, where anticoagulation would be more effective than antiplatelet agents in reducing risk of subsequent events.
NT-proBNP was measured in stored serum collected at baseline from participants enrolled in WARSS, a previously reported randomized trial. Relative effectiveness of warfarin and aspirin in preventing recurrent ischemic stroke or death over two years was compared based on NT-proBNP concentrations.
About 95% of 1028 patients with assays had NT-proBNP below 750 pg/mL, and among them, no evidence for treatment effect modification was evident. For 49 patients with NT-proBNP >750 pg/mL, the two-year rate of events per 100 person-years was 45.9 for the aspirin group and 16.6 for the warfarin group, while for 979 patients with NT-proBNP ≤750 pg/mL, rates were similar for both treatments. For those with NT-proBNP >750 pg/mL, the hazard ratio was 0.30 (95% confidence interval 0.12 to 0.84, p-value=0.021) significantly favoring warfarin over aspirin. A formal test for interaction of NT-proBNP with treatment was significant (p-value=0.01).
For secondary stroke prevention, elevated NT-proBNP concentrations may identify a subgroup of ischemic stroke patients without known atrial fibrillation, about 5% based on the current study, who may benefit more from anticoagulants than antiplatelet agents.
Clinical Trial Registration
This trial was not registered because enrollment began prior to 2005.
PMCID: PMC3583375  PMID: 23339958
aspirin; warfarin; NT-proBNP; secondary stroke prevention
21.  Effects of respiratory and non-respiratory factors on disability among older adults with airway obstruction: The Cardiovascular Health Study 
COPD  2013;10(5):588-596.
High rates of disability associated with chronic airway obstruction may be caused by impaired pulmonary function, pulmonary symptoms, other chronic diseases, or systemic inflammation.
We analyzed data from the Cardiovascular Health Study, a longitudinal cohort of 5888 older adults. Categories of lung function (normal; restricted; borderline, mild-moderate, and severe obstruction) were delineated by baseline spirometry (without bronchodilator). Disability-free years were calculated as total years alive and without self-report of difficulty performing ≥1 Instrumental Activities of Daily Living over 6 years of follow-up. Using linear regression, we compared disability-free years by lung disease category, adjusting for demographic factors, body mass index, smoking, cognition, and other chronic comorbidities. Among participants with airflow obstruction, we examined the association of respiratory factors (FEV1 and dyspnea) and non-respiratory factors (ischemic heart disease, congestive heart failure, diabetes, muscle weakness, osteoporosis, depression and cognitive impairment) on disability-free years.
The average disability free years were 4.0 out of a possible 6 years. Severe obstruction was associated with 1 fewer disability-free year compared to normal spirometry in the adjusted model. For the 1,048 participants with airway obstruction, both respiratory factors (FEV1 and dyspnea) and non-respiratory factors (heart disease, coronary artery disease, diabetes, depression, osteoporosis, cognitive function, and weakness) were associated with decreased disability-free years.
Severe obstruction is associated with greater disability compared to patients with normal spirometery. Both respiratory and non-respiratory factors contribute to disability in older adults with abnormal spirometry.
PMCID: PMC3903127  PMID: 23819728
Chronic airflow obstruction; instrumental activities of daily living; disability; disablement process
22.  Von Willebrand Factor and the Right Ventricle (The MESA-Right Ventricle Study) 
The American journal of cardiology  2012;110(12):1846-1851.
Elevation in plasma activity of von Willebrand Factor (vWF) reflects endothelial dysfunction and predicts death in pulmonary arterial hypertension (PAH). Higher vWF activity is also associated with lower right ventricular (RV) ejection fraction in PAH. Little is known about the relationship between vWF and RV structure and function in adults without cardiovascular disease. In the current investigation, we included 1,976 participants with MRI assessment of RV structure and function and measurement of vWF activity from the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression was used to estimate the associations between vWF activity and measures of RV structure and function after adjusting for demographics, anthropometrics, smoking, diabetes mellitus, hypertension and the corresponding left ventricular (LV) parameter. The average vWF activity was 140.7 ± 57.2%. Elevated vWF activity was independently associated with lower RV mass, RV end-diastolic volume and RV stroke volume in models with and without adjustment for the corresponding LV parameter (all p < 0.05). There was no association observed between vWF activity and RV ejection fraction. In conclusion, higher vWF activity is associated with lower RV mass, RV end-diastolic volume and RV stroke volume. These associations are independent of common cardiovascular risk factors and LV morphologic changes.
PMCID: PMC3696516  PMID: 22995970
Cardiovascular Imaging; Biomarkers; Pulmonary Hypertension; Right Ventricle
23.  N-terminal pro-B-type Natriuretic Peptide is Associated with Sudden Cardiac Death Risk: the Cardiovascular Health Study 
Sudden cardiac death (SCD), the cause of 250,000-450,000 deaths per year, is a major public health problem. The majority of those affected do not have a prior cardiovascular diagnosis. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure and mortality, as well as sudden death in women.
To examine the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and SCD in the Cardiovascular Health Study population.
The risk of SCD associated with baseline NT-proBNP was examined in 5447 participants. Covariate-adjusted Cox model regressions were used to estimate the hazard ratios of developing SCD as a function of baseline NT-proBNP
Over a median follow-up of 12.5 years (maximum of 16), there were 289 cases of SCD. Higher NT-proBNP levels were strongly associated with SCD, with an unadjusted hazard ratio of 4.2 (95% CI: 2.9, 6.1, p<0.001) in the highest quintile compared to the lowest. NT-proBNP remained associated with SCD even after adjustment for numerous clinical characteristics and risk-factors (age, sex, race, and other associated conditions), with an adjusted hazard ratio for the 5th versus the 1st quintile of 2.5 (95% CI: 1.6, 3.8, p<0.001).
NT-proBNP provides information regarding the risk of sudden cardiac death in a community based population of older adults, beyond other traditional risk factors. This biomarker may ultimately prove useful in targeting the population at risk with aggressive medical management of comorbid conditions.
PMCID: PMC3826546  PMID: 21044699
Sudden cardiac death; B-type natriuretic peptide; BNP; NT-proBNP
24.  Prospective Study of Particulate Air Pollution Exposures, Subclinical Atherosclerosis, and Clinical Cardiovascular Disease 
American Journal of Epidemiology  2012;176(9):825-837.
The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45–84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.
PMCID: PMC3571256  PMID: 23043127
air pollution; atherosclerosis; cardiovascular diseases; environmental exposure; epidemiologic methods; particulate matter
25.  The impact of height on the risk of atrial fibrillation: the Cardiovascular Health Study 
European Heart Journal  2012;33(21):2709-2717.
Atrial fibrillation (AF) is the most common sustained arrhythmia. Increased body size has been associated with AF, but the relationship is not well understood. In this study, we examined the effect of increased height on the risk of AF and explore potential mediators and implications for clinical practice.
Methods and results
We examined data from 5860 individuals taking part in the Cardiovascular Health Study, a cohort study of older US adults followed for a median of 13.6 (women) and 10.3 years (men). Multivariate linear models and age-stratified Cox proportional hazards and risk models were used, with focus on the effect of height on both prevalent and incident AF. Among 684 (22.6%) and 568 (27.1%) incident cases in women and men, respectively, greater height was significantly associated with AF risk [hazard ratio (HR)women per 10 cm 1.32, confidence interval (CI) 1.16–1.50, P < 0.0001; HRmen per 10 cm 1.26, CI 1.11–1.44, P < 0.0001]. The association was such that the incremental risk from sex was completely attenuated by the inclusion of height (for men, HR 1.48, CI 1.32–1.65, without height, and HR 0.94, CI 0.85–1.20, with height included). Inclusion of height in the Framingham model for incident AF improved discrimination. In sequential models, however, we found minimal attenuation of the risk estimates for AF with adjustment for left ventricular (LV) mass and left atrial (LA) dimension. The associations of LA and LV size measurements with AF risk were weakened when indexed to height.
Independent from sex, increased height is significantly associated with the risk of AF.
PMCID: PMC3681530  PMID: 22977225
Atrial fibrillation; Cardiovascular risk factors; Echocardiography; Risk prediction

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