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1.  Integrative pathway genomics of lung function and airflow obstruction 
Human Molecular Genetics  2015;24(23):6836-6848.
Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.
PMCID: PMC4643644  PMID: 26395457
2.  Case-control study of second-line therapies for type 2 diabetes in combination with metformin and the comparative risks of myocardial infarction and stroke 
Diabetes, obesity & metabolism  2015;17(12):1194-1197.
We conducted a population-based case-control study to assess the myocardial infarction (MI) and stroke risks associated with sulfonylureas and insulin when used in combination with metformin. Cases had type 2 diabetes and used metformin + insulin or metformin + sulfonylureas at the time of a first MI or first stroke from 1995–2010; controls used the same treatment combinations and were randomly sampled from the same population. MI and stroke diagnoses and potential confounders were validated by medical record reviews. Compared with metformin + sulfonylurea, metformin + insulin was associated with similar risks of MI or stroke (OR 0.98 [95% CI, 0.63–1.52]). Meta-analysis with another observational study improved the precision of the risk estimate (RR 0.92 [95% CI, 0.69–1.24]). Current evidence suggests that there may not be large differences in cardiovascular risk associated with the use of insulin or sulfonylureas when used in combination with metformin.
PMCID: PMC4626290  PMID: 26179389
sulfonylureas; metformin; insulin; myocardial infarction; stroke; cardiovascular outcomes; case-control study; comparative safety
3.  Coronary Artery Calcium Progression and Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Coronary artery calcium (CAC) measured at a single time point has been associated with an increased risk for atrial fibrillation (AF). It is unknown whether CAC progression over time carries a similar risk.
Methods and Results
This analysis included 5,612 study participants (mean age: 62 ± 10; 52% women; 39% whites; 27% blacks; 20% Hispanics; 12% Chinese-Americans) from the Multi-Ethnic Study of Atherosclerosis. Phantom-adjusted Agatston scores for baseline and follow-up measurements were used to compute change in CAC per year (≤0, 1 to 100, 101 to 300, and >300 units/year). AF was ascertained by review of hospital discharge records and from Medicare claims data through December 31, 2010. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between CAC progression and AF. Over a median follow-up of 5.6 years (25th, 75th percentiles=5.1, 6.8), a total of 203 (3.6%) incident AF cases were detected. Any CAC progression (>0/year) was associated with an increased risk for AF (HR=1.55, 95%CI=1.10, 2.19) and the risk increased with higher levels of CAC progression (≤0/year: HR=1.0 [reference]; 1 to 100/year: HR=1.47, 95%CI=1.03, 2.09; 101 to 300/year: HR=1.92, 95%CI=1.15, 3.20; >300/year: HR=3.23, 95%CI=1.48, 7.05). An interaction was observed by age with the association of CAC progression with AF being stronger for younger (<61 years: HR=3.53, 95%CI=1.29, 9.69) compared with older (≥61 years: HR=1.42, 95%CI=0.99, 2.04) participants (p-interaction=0.037).
CAC progression during an average of 5–6 years of follow-up is associated with an increased risk for AF.
PMCID: PMC4681308  PMID: 26659375
coronary calcium; atrial fibrillation; epidemiology
4.  Gene-gene Interaction Analyses for Atrial Fibrillation 
Scientific Reports  2016;6:35371.
Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27–1.65, P = 4.3 × 10–8). Eight additional gene-gene interactions were also marginally significant (P < 5 × 10–7). However, none of the top interactions were replicated. In summary, we did not find significant interactions that were associated with AF susceptibility. Future increases in sample size and denser genotyping might facilitate the identification of gene-gene interactions associated with AF.
PMCID: PMC5099695  PMID: 27824142
5.  Prospective study of circulating factor XI and incident venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE) 
American journal of hematology  2015;90(11):1047-1051.
Elevated plasma concentrations of coagulation factor XI may increase risk of venous thromboembolism (VTE), but prospective data are limited. We studied prospectively the associations of plasma factor XI and a key F11 genetic variant with incident VTE in whites and African Americans. We measured factor XI in 16,299 participants, initially free of VTE, in two prospective population cohorts. We also measured the F11 single nucleotide polymorphism rs4241824, which a genome-wide association study had linked to factor XI concentration. During follow-up, we identified 606 VTEs. The age, race, sex, and study-adjusted hazard ratio of VTE increased across factor XI quintiles (p<0.001 for trend), and the hazard ratio was 1.51 (95% CI 1.16, 1.97) for the highest versus lowest quintile overall, and was 1.42 (95% CI 1.03, 1.95) in whites and 1.72 (95% CI 1.08, 2.73) in African Americans. In whites, the F11 variant was associated with both factor XI concentration and VTE incidence (1.15-fold greater incidence of VTE per risk allele). In African Americans, these associations were absent. In conclusion, this cohort study documented that an elevated plasma factor XI concentration is a risk factor for VTE over extended follow-up, not only in whites but also in African Americans. In whites, the association of the F11 genetic variant with VTE suggests a causal relation, but we did not observe this genetic relation in African Americans.
PMCID: PMC4618026  PMID: 26260105
deep vein thrombosis; factor XI; prospective study; pulmonary embolism
6.  Evidence of Heterogeneity by Race/Ethnicity in Genetic Determinants of QT Interval 
Epidemiology (Cambridge, Mass.)  2014;25(6):790-798.
QT-interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations.
Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n=16,398), African (n=5,437), American Indian (n=5,032), Hispanic (n=1,143), and Asian (n=932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test.
Of 21 SNPs, seven showed consistent direction of effect across all five populations, and an additional nine had estimated effects that were consistent across four populations. Despite consistent direction of effect, nine of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity.
These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.
PMCID: PMC4380285  PMID: 25166880
7.  Relation of Physical Activity and Incident Atrial Fibrillation (From the Multi-Ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2015;116(6):883-888.
Prior studies have raised the question of whether an association exists between physical activity and atrial fibrillation (AF). We used the Multi-Ethnic Study of Atherosclerosis (MESA) database to examine the association between physical activity and AF in a diverse population without clinically recognized cardiovascular disease (CVD). MESA participants (N=5793) with complete baseline physical activity and covariate data were included. Cox proportional hazards models were used to calculate hazard ratios (HR) for incident AF by levels of total intentional exercise and vigorous physical activity, independently and in combination. Multivariable models adjusted for demographics and CVD risk factors. During a mean follow-up of 7.7±1.9 years, 199 AF cases occurred. In the overall MESA population, neither vigorous physical activity nor total intentional exercise were independently associated with incident AF after adjusting for covariates. However, within the group that reported any vigorous physical activity, there was a statistically significant inverse association between total intentional exercise (modeled as a continuous variable) and incident AF. Among those who reported any vigorous physical activity, the top tertile of total intentional exercise was associated with a significantly lower risk of incident AF compared with the group with no total intentional exercise in the fully adjusted model (HR 0.46, 95%CI 0.22-0.98). In conclusion, neither total intentional exercise nor vigorous physical activity alone were associated with incident AF, but greater total intentional exercise was associated with a lower risk of incident AF among those that participated in any vigorous physical activity. As importantly, no subgroup of participants demonstrated an increased risk of incident AF with greater physical activity. The results re-emphasize the beneficial role of physical activity for cardiovascular health.
PMCID: PMC4554984  PMID: 26189040
activity; exercise; atrial fibrillation; MESA
8.  A Synthesis of Current Surveillance Planning Methods for the Sequential Monitoring of Drug and Vaccine Adverse Effects Using Electronic Health Care Data 
eGEMs  2016;4(1):1219.
The large-scale assembly of electronic health care data combined with the use of sequential monitoring has made proactive postmarket drug- and vaccine-safety surveillance possible. Although sequential designs have been used extensively in randomized trials, less attention has been given to methods for applying them in observational electronic health care database settings.
Existing Methods:
We review current sequential-surveillance planning methods from randomized trials, and the Vaccine Safety Datalink (VSD) and Mini-Sentinel Pilot projects—two national observational electronic health care database safety monitoring programs.
Future Surveillance Planning:
Based on this examination, we suggest three steps for future surveillance planning in health care databases: (1) prespecify the sequential design and analysis plan, using available feasibility data to reduce assumptions and minimize later changes to initial plans; (2) assess existing drug or vaccine uptake, to determine if there is adequate information to proceed with surveillance, before conducting more resource-intensive planning; and (3) statistically evaluate and clearly communicate the sequential design with all those designing and interpreting the safety-surveillance results prior to implementation. Plans should also be flexible enough to accommodate dynamic and often unpredictable changes to the database information made by the health plans for administrative purposes.
This paper is intended to encourage dialogue about establishing a more systematic, scalable, and transparent sequential design-planning process for medical-product safety-surveillance systems utilizing observational electronic health care databases. Creating such a framework could yield improvements over existing practices, such as designs with increased power to assess serious adverse events.
PMCID: PMC5051582  PMID: 27713904
adverse drug reaction reporting systems; drug-related side effects and adverse reactions; electronic health records; product surveillance, postmarketing; sequential analysis; vaccine/adverse effects
9.  Whole Exome Sequencing in Atrial Fibrillation 
PLoS Genetics  2016;12(9):e1006284.
Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13–1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.
Author Summary
Atrial fibrillation is a common and morbid cardiac arrhythmia. Atrial fibrillation is heritable, and numerous genome-wide susceptibility loci have been identified, predominantly in non-coding regions. Over 35 genes also have been implicated in atrial fibrillation pathogenesis mostly through prior smaller scale candidate gene association studies, which generally did not have robust replication to support the associations. Therefore, the role of coding variation in the biology of atrial fibrillation is unclear. We examined whole exome sequencing data from 1,734 individuals with and 9,423 without atrial fibrillation, and did not observe any significant associations between coding variation and the arrhythmia. Furthermore, we did not observe any enrichment for association in previously implicated atrial fibrillation genes. In aggregate, our findings suggest that large effect coding variation is unlikely to be a predominant mechanism of common forms of atrial fibrillation encountered in the community.
PMCID: PMC5010214  PMID: 27589061
10.  Genetic Mutations in African Patients with Atrial Fibrillation: Rationale and Design of the Study of Genetics of Atrial Fibrillation in an African Population (SIGNAL) 
American heart journal  2015;170(3):455-464.e5.
There is an urgent need to understand genetic associations with atrial fibrillation in ethnically diverse populations. There are no such data from sub-Saharan Africa, despite the fact that atrial fibrillation is one of the fastest-growing diseases. Moreover, patients with valvular heart disease are under-represented in studies of the genetics of atrial fibrillation.
We designed a case-control study of patients with and without a history of atrial fibrillation in Kenya. Cases with atrial fibrillation included those with and without valvular heart disease. Patients underwent clinical phenotyping and will have laboratory analysis and genetic testing of >240 candidate genes associated with cardiovascular diseases. A 12-month follow-up assessment will determine the groups’ morbidity and mortality. The primary analyses will describe genetic and phenotypic associations with atrial fibrillation.
We recruited 298 participants: 72 (24%) with non-valvular atrial fibrillation, 78 (26%) with valvular atrial fibrillation and 148 (50%) controls without atrial fibrillation. The mean age of cases and controls were 53 and 48 years, respectively. Most (69%) participants were female. Controls more often had hypertension (45%) than those with valvular atrial fibrillation (27%). Diabetes and current tobacco smoking were uncommon. A history of stroke was present in 25% of cases and in 5% of controls.
This is the first study determining genetic associations in valvular and non-valvular atrial fibrillation in sub-Saharan Africa with a control population. The results advance knowledge about atrial fibrillation and will enhance international efforts to decrease atrial fibrillation-related morbidity.
PMCID: PMC4575772  PMID: 26385028
atrial fibrillation; genetics; case-control study; sub-Saharan Africa
11.  The Association of the QT Interval with Atrial Fibrillation and Stroke: The Multi-Ethnic Study of Atherosclerosis 
Prolongation of the QT interval is associated with an increased risk of atrial fibrillation (AF) and stroke.
The purpose of this analysis was to determine if atrial fibrillation (AF) explains the association between prolonged QT and stroke.
A total of 6,305 participants (mean age 62 ± 10 years; 54% women; 38% whites; 27% blacks; 23% Hispanics; 12% Chinese-Americans) from the Multi-Ethnic Study of Atherosclerosis (MESA) were included in this analysis. A linear scale was used to compute heart rate adjusted QT interval (QTa). Prolonged QTa was defined as ≥460 ms in women and ≥450 ms in men. Incident AF cases were identified using hospital discharge records and Medicare claims data. Vascular neurologists adjudicated stroke events by medical record review. Cox Regression was used to examine the association between prolonged QTa and stroke with and without AF.
A total of 216 (3.4%) of study participants had prolonged QTa. Over a median follow-up of 8.5 years, 280 (4.4%) participants developed AF and 128 (2.0%) participants developed stroke. In a multivariable Cox regression analysis adjusted for socio-demographics, cardiovascular risk factors, and potential confounders, prolonged QTa was associated with an increased risk of AF (HR=1.7, 95%CI=1.1, 2.6) and stroke (HR=2.3, 95%CI=1.3, 4.1). When AF was included as a time-dependent covariate, the association between prolonged QTa and stroke was not substantively altered (HR=2.4, 95%CI=1.3, 4.3).
The increased risk of stroke in those with prolonged QT potentially is not explained by documented AF. Further research is needed to determine if subclinical AF cases explain the association between the QT interval and stroke.
PMCID: PMC4945099  PMID: 25752461
atrial fibrillation; stroke; long QT
12.  Contraindications to Anticoagulation Therapy and Eligibility for Novel Anticoagulants in Older Patients With Atrial Fibrillation 
Cardiovascular therapeutics  2015;33(4):177-183.
Oral anticoagulation therapy prevents stroke and improves survival in patients with atrial fibrillation, but the therapy is underutilized. We sought to identify the prevalence of contraindications for oral anticoagulation and the proportion of patients potentially eligible for different agents.
We identified patients with nonacute atrial fibrillation in a nationally representative 5% sample of 2009 Medicare data. We divided the population into patients ineligible for any oral anticoagulant, patients eligible for warfarin only, and patients eligible for any anticoagulant. We compared patient characteristics and the use of anticoagulation among the subgroups.
Among 86,671 patients with atrial fibrillation, 1872 (2.2%) were ineligible for anticoagulation because of an absolute contraindication, most frequently a history of intracranial hemorrhage (60%). Patients ineligible for any anticoagulant were the same age as the overall group (mean age, 80.5 vs 80.4 years). However, they had higher rates of dementia (19% vs 8.6%) and heart failure (59% vs 43%) and higher mean CHADS2 scores (3.8 vs 2.8). Of the remaining 84,799 patients eligible for anticoagulation, 7146 (8.4%) had were eligible for warfarin only (most commonly because of mechanical heart valves [66%] and end-stage renal disease [12%]). Sixty-five percent of patients eligible for anticoagulation received warfarin, and the proportion was similar for patients with a relatively high risk of bleeding.
Older adults with atrial fibrillation rarely have absolute contraindications to oral anticoagulation therapy. Among patients without contraindications, most appeared to be eligible for any anticoagulant, and relatively high-risk features appeared not to influence warfarin use.
PMCID: PMC4497930  PMID: 25930214
13.  Ventricular Ectopy as a Predictor of Heart Failure and Death 
Studies of patients presenting for catheter ablation suggest that premature ventricular contractions (PVCs) are a modifiable risk factor for congestive heart failure (CHF). The relationship between PVC frequency, incident CHF, and mortality in the general population remains unknown.
The goal of this study was to determine whether PVC frequency ascertained using a 24-h Holter monitor is a predictor of LVEF decline, incident CHF, and death in a population-based cohort.
We studied the 1,139 Cardiovascular Health Study (CHS) participants randomly assigned to 24-h ambulatory electrocardiography (Holter) monitoring with a normal left ventricular ejection fraction (LVEF) and no history of CHF. PVC frequency was quantified using Holter studies, and LVEF was measured from baseline and 5-year echocardiograms. Participants were followed for incident CHF and death.
Those in the upper quartile versus the lowest quartile of PVC frequency had a multivariable adjusted 3-fold greater odds of a 5-year LVEF decline (OR: 3.10, 95% CI: 1.42 to 6.77, p = 0.005), and, over a median follow-up >13 years, a 48% increased risk of incident CHF (HR: 1.48, 95% CI: 1.08 to 2.04, p = 0.02), and a 31% increased risk of death (HR: 1.31, 95% CI: 1.06 to 1.63, p = 0.01). Similar statistically significant results were observed for PVCs analyzed as a continuous variable. The specificity for the 15-year risk of CHF exceeded 90% when PVCs comprised at least 0.7% of ventricular beats. The population-level risk for incident CHF attributed to PVCs was 8.1% (95% CI: 1.2 to14.9%).
In a population-based sample, a higher frequency of PVCs was associated with LVEF decline, increased incident CHF, and increased mortality. Given the capacity to prevent PVCs through medical or ablation therapy, PVCs may represent a modifiable risk factor for CHF and death.
PMCID: PMC4499114  PMID: 26160626
Arrhythmia; Mortality; Premature Ventricular Contractions
14.  Association of Sleep Apnea and Snoring With Incident Atrial Fibrillation in the Multi-Ethnic Study of Atherosclerosis 
American Journal of Epidemiology  2015;182(1):49-57.
The association between sleep apnea and atrial fibrillation (AF) has not been examined in a multiethnic adult population in prospective community-based studies. We prospectively (2000–2011) investigated the associations of physician-diagnosed sleep apnea (PDSA), which is considered more severe sleep apnea, and self-reported habitual snoring without PDSA (HS), a surrogate for mild sleep apnea, with incident AF in white, black, and Hispanic participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of clinical cardiovascular disease at baseline (2000–2002). Cox proportional hazards models were used to assess the associations, with adjustment for socioeconomic status, traditional vascular disease risk factors, race/ethnicity, body mass index, diabetes, chronic kidney disease, alcohol intake, and lipid-lowering therapy. Out of 4,395 respondents to a sleep questionnaire administered in MESA, 181 reported PDSA, 1,086 reported HS, and 3,128 reported neither HS nor PDSA (unaffected). Over an average 8.5-year follow-up period, 212 AF events were identified. As compared with unaffected participants, PDSA was associated with incident AF in the multivariable analysis, but HS was not (PDSA: hazard ratio = 1.76, 95% confidence interval: 1.03, 3.02; HS: hazard ratio = 1.02, 95% confidence interval: 0.72, 1.44). PDSA, a marker of more severe sleep apnea, was associated with higher risk of incident AF in this analysis of MESA data.
PMCID: PMC4479113  PMID: 25977516
atrial fibrillation; longitudinal studies; sleep apnea; snoring
15.  Ability of Reduced Lung Function to Predict Development of Atrial Fibrillation in Persons 45–84 Years of Age (From the Multi-Ethnic Study of Atherosclerosis-Lung Study) 
The American journal of cardiology  2015;115(12):1700-1704.
Atrial fibrillation (AF) occurs frequently in patients with chronic obstructive pulmonary disease (COPD). Epidemiological studies have found inconsistent associations between lung function and AF, and none have studied pulmonary emphysema, which overlaps only partially with COPD in the general population. In this study, we assessed the relationship between lung function measured by spirometry, the percent of emphysema-like lung on computed tomography and incident AF. The Multi-Ethnic Study of Atherosclerosis (MESA) study is a multicenter cohort study following 6814 subjects free of clinical cardiovascular disease including AF at baseline. Spirometry was performed in a subset of 3965 participants. Percent emphysema was defined on baseline CT scans as lung regions <950 hounsfield units. Incident AF was identified from hospital discharge diagnosis and Medicare claims data. Cox proportional hazards models were used to assess independent associations of lung volumes and percent emphysema with AF. 3811 participants with valid spirometry results were included in this study. The mean age was 64.5±9.8 years and 49.4% were men. AF developed in 149 individuals (3.8%) over a mean follow-up of 4.1 years after spirometry. Lower levels of forced expiratory volume at 1 second and forced vital capacity were associated with a higher risk of AF (HR 1.21 and 1.19 per 500ml respectively; p<0.001) after adjustment of demographic and cardiovascular risk factors. Percentage emphysema was not significantly related to AF. In conclusion, in a multi-ethnic community-based sample of individuals free of cardiovascular disease at baseline, functional airflow limitation was related to a higher risk of AF.
PMCID: PMC4450133  PMID: 25900353
Atrial Fibrillation; Lung function; Emphysema
16.  Geographic Variation in the Use of Catheter Ablation for Atrial Fibrillation Among Medicare Beneficiaries 
American heart journal  2015;169(6):775-782.e2.
Catheter ablation for atrial fibrillation is used increasingly in older patients, yet the risks and benefits are not completely understood. With such uncertainty, local medical opinion may influence catheter ablation use.
In a 100% sample of Medicare beneficiaries 65 years or older who underwent catheter ablation for atrial fibrillation between January 1, 2007, and December 31, 2009, we investigated variation in use by hospital referral region (HRR) for 20,176 catheter ablation procedures.
Across 274 HRRs, median age was 71.2 years (interquartile range, 70.5-71.8), a median of 98% of patients were white, and a median of 39% of patients were women. The median age-standardized prevalence of atrial fibrillation was 77.1 (69.4-84.2) per 1000 beneficiaries; the median rate of catheter ablation was 3.5 (2.4-4.9) per 1000 beneficiaries. We found no significant associations between the rate of catheter ablation and prevalence of atrial fibrillation (P = 0.99), end-of-life Medicare expenditures per capita (P = 0.09), or concentration of cardiologists (P = 0.45), but a slight association with Medicare expenditures per capita (linear regression estimate, 0.016; 95% CI, 0.001-0.031; P = 0.04). Examined HRR characteristics explained only 2% of the variation in HRR-level rates of catheter ablation (model R2 = 0.016).
The rate of catheter ablation for atrial fibrillation in older patients was low, varied substantially by region, and was not associated with the prevalence of atrial fibrillation, the availability of cardiologists, or end-of-life resource use, and was only slightly associated with overall Medicare expenditures per capita.
PMCID: PMC4451569  PMID: 26027614
17.  The Association of Sex Hormones with Carotid Artery Distensibility in Men and Postmenopausal Women: Multi- Ethnic Study of Atherosclerosis 
Hypertension  2015;65(5):1020-1025.
The decline in carotid distensibility with age is steeper in women than in men, however, the correlates of this sex difference are not known.
We examined the association of bioavailable testosterone, estradiol, dehydroepiandrosterone and sex hormone binding globulin, in 2783 postmenopausal women and 2987 men aged 45–84 at the Multi-Ethnic Study of Atherosclerosis baseline examination. Carotid artery lumen diameters by ultrasound and brachial artery blood pressures were measured at systole and diastole. Regression models to determine the association of carotid distensibility coefficient and lumen diameter with sex-specific quartiles of sex hormones were adjusted for age, race, height, weight, diabetes, current smoking, antihypertensive medication use, total and high density lipoprotein cholesterol levels, and hormone replacement therapy in women. A higher DC indicates a more distensible vessel.
In women, higher dehydroepiandrosterone (p = 0.008) and lower sex hormone binding globulin (p = 0.039) were associated with lower distensibility; higher dehydroepiandrosterone and lower estradiol were associated with smaller carotid diameters. In men, higher Bio-T (p = 0.009) and lower estradiol (p = 0.007) were associated with greater distensibility and also with smaller diameters (p = 0.012 and 0.002, respectively).
An androgenic internal milieu is associated with lesser carotid distensibility and diameter remodeling in women, but the opposite is true for men. Higher levels of estradiol are associated with smaller carotid diameters in both sexes. Future longitudinal and experimental studies are needed to reveal the mechanism and clinical consequences of these associations.
PMCID: PMC4394007  PMID: 25753974
carotid compliance; sex hormones; ultrasound; sex-specific; aging
18.  Carotid Intima‐Media Thickness and Arterial Stiffness and the Risk of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study, Multi‐Ethnic Study of Atherosclerosis (MESA), and the Rotterdam Study 
We evaluated the association of carotid intima‐media thickness (cIMT), carotid plaque, carotid distensibility coefficient (DC), and aortic pulse wave velocity (PWV) with incident atrial fibrillation (AF) and their role in improving AF risk prediction beyond the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)‐AF risk score.
Methods and Results
We analyzed data from 3 population‐based cohort studies: Atherosclerosis Risk in Communities (ARIC) Study (n=13 907); Multi‐Ethnic Study of Atherosclerosis (MESA; n=6640), and the Rotterdam Study (RS; n=5220). We evaluated the association of arterial indices with incident AF and computed the C‐statistic, category‐based net reclassification improvement (NRI), and relative integrated discrimination improvement (IDI) of incorporating arterial indices into the CHARGE‐AF risk score (age, race, height weight, systolic and diastolic blood pressure, antihypertensive medication use, smoking, diabetes, previous myocardial infarction, and previous heart failure). Higher cIMT (meta‐analyzed hazard ratio [95% CI] per 1‐SD increment, 1.12 [1.08–1.16]) and presence of carotid plaque (1.30 [1.19–1.42]) were associated with higher AF incidence after adjustment for CHARGE‐AF risk‐score variables. Lower DC and higher PWV were associated with higher AF incidence only after adjustment for the CHARGE‐AF risk‐score variables excepting height, weight, and systolic and diastolic blood pressure. Addition of cIMT or carotid plaque marginally improved CHARGE‐AF score prediction as assessed by the relative IDI (estimates, 0.025–0.051), but not when assessed with the C‐statistic and NRI.
Higher cIMT, presence of carotid plaque, and greater arterial stiffness are associated with higher AF incidence, indicating that atherosclerosis and arterial stiffness play a role in AF etiopathogenesis. However, arterial indices only modestly improve AF risk prediction.
PMCID: PMC4889172  PMID: 27207996
arterial stiffness; atherosclerosis; atrial fibrillation; carotid intima‐media thickness; Atrial Fibrillation; Epidemiology
19.  Use of statins and antihypertensive medications in relation to risk of longstanding persistent atrial fibrillation 
The Annals of pharmacotherapy  2015;49(4):378-386.
After an initial episode of atrial fibrillation (AF), patients may develop longstanding persistent or permanent AF.
We evaluated whether use of statins, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers is associated with lower risk of longstanding persistent AF after an initial AF episode.
We conducted a population-based inception cohort study of participants enrolled in Group Health, aged 30–84 with newly-diagnosed AF in 2001–2004. We included only participants whose initial AF episode terminated within six months of onset. We ascertained the primary outcome of longstanding persistent AF from medical records, electrocardiograms, and administrative data. We determined time-varying medication use from Group Health pharmacy data.
Among 1,317 participants with incident AF, 304 developed longstanding persistent AF. Our study suggests that current statin use vs. never use may be associated with lower risk for longstanding persistent AF. However, the association was not statistically significant when adjusted for age, sex, cardiovascular risk factors, and current use of antiarrhythmic medication (hazard ratio [HR] = 0.77; 95% confidence interval [CI]: 0.57, 1.03). In lagged analyses intended to reduce healthy user bias, current statin use one year prior vs. never use one year prior was not associated with risk for longstanding persistent AF (HR = 0.91; 95% CI: 0.67, 1.24). ACE inhibitor, ARB, and beta-blocker use were not associated with risk for longstanding persistent AF.
Current statin use may confer protection that wanes after discontinuing use. Alternatively, healthy user bias or chance may explain the association. The association of statin use with longstanding persistent AF warrants further investigation.
PMCID: PMC4562688  PMID: 25628466
antihypertensive agents; longstanding persistent atrial fibrillation; cohort studies; electrocardiography; hydroxymethylglutaryl-CoA reductase inhibitors; statins
20.  Multi-Ethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI 
Verhaaren, Benjamin F.J. | Debette, Stéphanie | Bis, Joshua C. | Smith, Jennifer A. | Ikram, M. Kamran | Adams, Hieab H. | Beecham, Ashley H. | Rajan, Kumar B. | Lopez, Lorna M. | Barral, Sandra | van Buchem, Mark A. | van der Grond, Jeroen | Smith, Albert V. | Hegenscheid, Katrin | Aggarwal, Neelum T. | de Andrade, Mariza | Atkinson, Elizabeth J. | Beekman, Marian | Beiser, Alexa S. | Blanton, Susan H. | Boerwinkle, Eric | Brickman, Adam M. | Bryan, R. Nick | Chauhan, Ganesh | Chen, Christopher P.L.H. | Chouraki, Vincent | de Craen, Anton J.M. | Crivello, Fabrice | Deary, Ian J. | Deelen, Joris | De Jager, Philip L. | Dufouil, Carole | Elkind, Mitchell S.V. | Evans, Denis A. | Freudenberger, Paul | Gottesman, Rebecca F. | Guðnason, Vilmundur | Habes, Mohamad | Heckbert, Susan R. | Heiss, Gerardo | Hilal, Saima | Hofer, Edith | Hofman, Albert | Ibrahim-Verbaas, Carla A. | Knopman, David S. | Lewis, Cora E. | Liao, Jiemin | Liewald, David C.M. | Luciano, Michelle | van der Lugt, Aad | Martinez, Oliver O. | Mayeux, Richard | Mazoyer, Bernard | Nalls, Mike | Nauck, Matthias | Niessen, Wiro J. | Oostra, Ben A. | Psaty, Bruce M. | Rice, Kenneth M. | Rotter, Jerome I. | von Sarnowski, Bettina | Schmidt, Helena | Schreiner, Pamela J. | Schuur, Maaike | Sidney, Stephen S. | Sigurdsson, Sigurdur | Slagboom, P. Eline | Stott, David J.M. | van Swieten, John C. | Teumer, Alexander | Töglhofer, Anna Maria | Traylor, Matthew | Trompet, Stella | Turner, Stephen T. | Tzourio, Christophe | Uh, Hae-Won | Uitterlinden, André G. | Vernooij, Meike W. | Wang, Jing J. | Wong, Tien Y. | Wardlaw, Joanna M. | Windham, B. Gwen | Wittfeld, Katharina | Wolf, Christiane | Wright, Clinton B. | Yang, Qiong | Zhao, Wei | Zijdenbos, Alex | Jukema, J. Wouter | Sacco, Ralph L. | Kardia, Sharon L.R. | Amouyel, Philippe | Mosley, Thomas H. | Longstreth, W. T. | DeCarli, Charles C. | van Duijn, Cornelia M. | Schmidt, Reinhold | Launer, Lenore J. | Grabe, Hans J. | Seshadri, Sudha S. | Ikram, M. Arfan | Fornage, Myriam
The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multi-ethnic genome-wide association studies.
Methods and Results
We included 21,079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (N=17,936), African (N=1,943), Hispanic (N=795), and Asian (N=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each SNP and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (p=2.7×10−19) and identified novel loci on chr10q24 (p=1.6×10−9) and chr2p21 (p=4.4×10−8). In the multi-ethnic meta-analysis, we identified two additional loci, on chr1q22 (p=2.0×10−8) and chr2p16 (p=1.5×10−8). The novel loci contained genes that have been implicated in Alzheimer’s disease (chr2p21, chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24, chr2p16).
We identified four novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of white matter hyperintensities in addition to previously-proposed ischemic mechanisms.
PMCID: PMC4427240  PMID: 25663218
Genome Wide Association Study; cerebral small vessel disease; single nucleotide polymorphisms cerebrovascular disorders; white matter disease; hypertension; high blood pressure
21.  Genome-Wide Association Study of L-Arginine and Dimethylarginines Reveals Novel Metabolic Pathway for Symmetric Dimethylarginine 
Dimethylarginines (DMA) interfere with nitric oxide (NO) formation by inhibiting NO synthase (asymmetric dimethylarginine, ADMA) and L-arginine uptake into the cell (ADMA and symmetric dimethylarginine, SDMA). In prospective clinical studies ADMA has been characterized as a cardiovascular risk marker whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterise the environmental and genetic contributions to inter-individual variability of these biomarkers.
Methods and Results
This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (FHS (n=2992), GHS (n=4354) and MONICA/KORA F3 (n=581)) and identified replicated loci (DDAH1, MED23, Arg1 and AGXT2) associated with the inter-individual variability in ADMA, L-arginine and SDMA. Experimental in-silico and in-vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants and various cardiometabolic risk factors. AGXT2 variants were not associated with post-stroke survival in the Leeds study, nor were they associated with incident stroke in the CHARGE consortium.
These GWAS support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and L-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.
PMCID: PMC4797637  PMID: 25245031
biomarker; endothelial function; nitric oxide; Genome Wide Association Study
22.  Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium 
PLoS ONE  2016;11(3):e0144997.
Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.
We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10−6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.
In Stage I 15 loci passed the threshold of 5×10−6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10−3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10−9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10−3).
QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
PMCID: PMC4780701  PMID: 26950853
23.  Sustained Pre-hypertensive Blood Pressure and Incident Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis 
The association between sustained pre-hypertension and AF has not been thoroughly examined.
This study included 5,311 participants (mean age 62 ± 10 years; 47% male; 42.9% non-whites) from the Multi-Ethnic Study of Atherosclerosis. Sustained exposure was based on 2 or more visits within the same blood pressure category (optimal: <120/80 mm Hg; pre-hypertension: 120–139/80–89 mm Hg; hypertension: ≥140/90 mm Hg or antihypertensive medication use) during visits 1, 2, and 3. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between blood pressure category and AF.
Over a median follow-up of 5.3 years, 182 (3.4%) participants developed AF. Pre-hypertension and hypertension were associated with an increased risk of AF compared with participants who had optimal blood pressure (optimal: HR=1.0, referent; pre-hypertension: HR=1.8, 95%CI=1.004, 3.2; hypertension: HR=2.6, 95%CI=1.6, 4.4).
Sustained pre-hypertension is associated with an increased risk of AF.
PMCID: PMC4369319  PMID: 25795549
blood pressure; atrial fibrillation; epidemiology; risk factors
24.  Mitral annular calcification and incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis 
Europace  2014;17(3):358-363.
The associations of mitral annular calcification (MAC) with atrial fibrillation (AF) risk factors and related outcomes suggest a possible association between MAC and AF. The aim of this study was to examine the association between MAC and AF in a racially and ethnically diverse population.
Methods and results
This analysis included 6641 participants (mean age 62 ± 10 years; 53% women; 27% Blacks; 22% Hispanics; 12% Chinese-Americans) from the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of clinical cardiovascular disease and AF at baseline. The presence of MAC was defined by cardiac computed tomography (CT) as an Agatston score >0. Atrial fibrillation was ascertained by hospital discharge records and from Medicare claims data until 31 December 2010. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between MAC and AF. At baseline, 619 (9.3%) participants had MAC. Over a median follow-up of 8.5 years, 308 (4.6%) participants developed AF. In a multivariable adjusted model, MAC was associated with an increased risk of AF (HR = 1.9, 95% CI = 1.5, 2.5). This association was consistent across subgroups of age, sex, race/ethnicity (Whites vs. non-Whites), hypertension, diabetes, and left atrial enlargement. The addition of MAC to the Framingham Heart Study and CHARGE AF risk scores for AF improved the C-statistics from 0.769 to 0.776 (P = 0.038) and 0.788 to 0.792 (P = 0.089), respectively.
The presence of MAC was predictive of incident AF in MESA. Potentially, these findings suggest a usefulness of cardiac CT to identify individuals at risk for AF.
PMCID: PMC4415068  PMID: 25341740
Mitral annulus calcification; Epidemiology; Atrial fibrillation
25.  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).
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.
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.
ECG left atrial abnormality is associated with vascular brain injury in the absence of documented AF.
PMCID: PMC4342300  PMID: 25677594
Arrhythmia; atrium; ECG; embolism; cerebrovascular disease/stroke

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