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1.  Effect of Intensive Blood Pressure Lowering on Left Ventricular Hypertrophy in Patients with Diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure Trial 
Hypertension  2015;66(6):1123-1129.
Left ventricular hypertrophy (LVH), a marker of cardiac end-organ damage, is a common complication of hypertension. Regression of LVH is achievable by sustained lowering of systolic blood pressure (SBP). However, it is unknown whether a strategy aimed at lowering BP beyond that recommended would lower the risk of LVH. We examined the effect of intensive (SBP<120 mmHg), compared to standard (SBP<140 mmHg), BP lowering on the risk of LVH in 4,331 patients with diabetes from the from the ACCORD BP trial, a randomized controlled trial. The outcomes measures were electrocardiographic LVH defined by Cornell voltage (binary variable) and mean Cornell index (continuous variable). The baseline prevalence of LVH (5.3% vs. 5.4%, p= 0.91) and the mean Cornell index (1456 µV vs. 1470 µV, p=0.45) were similar in the intensive (n=2154) and standard (n=2177) BP lowering arms, respectively. However, after median follow up of 4.4 years, intensive, compared to standard, BP lowering was associated with a 39% lower risk of LVH (odds ratio(95% CI):0.61(0.43, 0.88); p=0.008) and a significantly lower adjusted mean Cornell index (1352 µV vs. 1447 µV; p<0.001). The lower risk of LVH associated with intensive BP lowering during follow up was due to more regression of baseline LVH and lower rate of developing new LVH, compared to standard BP lowering. No interactions by age, sex, or race were observed. These results provide evidence that targeting a systolic BP<120 mmHg, as compared with <140 mm Hg, in patients with hypertension and diabetes produces a greater reduction in LVH.
Clinical Trial Registration: number, NCT00000620
PMCID: PMC4644090  PMID: 26459421
Intensive Blood Pressure Lowering; Left Ventricular Hypertrophy; ACCORD
3.  Atrial Fibrillation and Risk of ST-Segment Elevation versus Non-ST Segment Elevation Myocardial Infarction: The Atherosclerosis Risk in Communities (ARIC) Study 
Circulation  2015;131(21):1843-1850.
It has recently been reported that atrial fibrillation [AF] is associated with an increased risk of myocardial infarction [MI]. However, the mechanism underlying this association is currently unknown. Further study of the relationship of AF with type of MI [ST elevation MI (STEMI) vs. non-ST elevation MI [NSTEMI] might shed light on the potential mechanisms.
Methods and Results
We examined the association between AF and incident MI in 14,462 participants [mean age 54 years, 56% women, 26% African Americans] from the Atherosclerosis Risk in Communities study who were free of coronary heart disease at baseline [1987–1989] with follow-up through December 31, 2010. AF cases were identified from study visits electrocardiogram and by review of hospital discharge records. Incident MI and its types were ascertained by an independent adjudication committee. Over a median follow up of 21.6 years, 1374 MI events occurred [829 NSTEMI, 249 STEMI, 296 unclassifiable]. In a multivariable adjusted model, AF [n=1545] as a time-varying variable was associated with a 63% increased risk of MI [HR (95% CI):1.63(1.32–2.02)]. However, AF was associated with NSTEMI [HR (95% CI): 1.80(1.39–2.31)] but not STEMI [HR (95% CI): 0.49(0.18–1.34)]; p-value for hazard ratios comparison=0.004. Combining the unclassifiable MI group with either STEMI or NSTEMI did not change this conclusion. The association between AF and MI, total and NSTEMI, was stronger in women than in men [interaction p-value<0.01 for both].
AF is associated with an increased risk of incident MI, especially in women. However, this association is limited to NSTEMI.
PMCID: PMC4447576  PMID: 25918127
Atrial Fibrillation; Myocardial Infarction; STEMI; NSTEMI
4.  Baseline cardiovascular risk in the INSIGHT Strategic Timing of AntiRetroviral Treatment trial 
HIV medicine  2015;16(0 0):46-54.
The Strategic Timing of AntiRetroviral Treatment (START) trial has recruited antiretroviral-naïve individuals with high CD4 cell counts from all world regions. We describe the distribution of cardiovascular (CVD) risk factors, overall and by geographic region, at study baseline.
The distribution of CVD risk factors was assessed and compared by geographic region among START participants who had baseline electrocardiogram (n=4019; 11% North America; 36% Europe/Australia/Israel; 26% South America; 4% Asia; 23% Africa; median age 36 years; 26% females).
About 58.3% (n=2344) of the participants had at least one CVD risk factor and 18.9% (n=761) had two or more. The most common CVD risk factors were current smoking (32%), hypertension (19.3%) and obesity (16.5%). There were significant differences in the prevalence of CVD risk factors among geographic regions. The prevalence of at least one risk factor across regions was as follows: 70.0% North America, 65.1% Europe/Australia/Israel, 49.4% South America, 37.0% Asia, and 55.8% Africa (p-value<0.001). Significant regional differences were also observed when risk factors were used as part of the Framingham and D:A:D risk scores or used to define favourable risk profile.
CVD risk factors are common among START participants, and their distribution varies by geographic region. Better understanding of how and why CVD risk factors develop in people with HIV and their geographical distributions could shed light on appropriate strategies for CVD prevention and may inform the interpretation of the results of START as CVD is expected to be a major fraction of the primary endpoints observed.
PMCID: PMC4341949  PMID: 25711323
Cardiovascular risk; HIV; START trial
5.  Characterization of Metabolic Syndrome among Diverse Hispanics/Latinos Living in the United States: Latent Class Analysis from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) 
Empirical investigation of the adequacy of metabolic syndrome (MetS) diagnostic criteria, and whether meaningful subtypes of MetS exist, is needed among Hispanics/Latinos.
In 15825 US Hispanics/Latinos from HCHS/SOL, latent class analysis of MetS components (waist circumference, systolic and diastolic blood pressure, HDL cholesterol, triglycerides, glucose, and antihypertensive, lipid- and glucose-lowering medication use) was used to investigate (1) whether distinct subtypes of MetS could be identified, and how component levels differed between them, and (2) how identified subtypes related to covariates and cardiovascular disease (CVD) prevalence.
Two latent clusters emerged in both men (n=6317) and women (n=9508): one characterized by relatively healthy mean levels (Non-MetS cluster, 77.1% of men and 67.1% of women) and the other by clinically elevated mean levels (MetS cluster, 22.9% of men and 32.9% of women) across most MetS components. These clusters showed expected associations with covariates and CVD prevalence. Notable results suggest that (1) HDL cholesterol may poorly differentiate between US Hispanics/Latinos with and without MetS (mean = 45.4 vs. 44.6 mg/dL for men and 51.3 vs. 52.0 mg/dL for women in the MetS vs. Non-MetS clusters, respectively) and (2) the NCEP-ATP III 88 cm waist circumference cutoff for US females may not optimize diagnosis among Hispanic/Latino women (MetS cluster mean waist circumference = 102.5 cm).
Beyond classification into having MetS or not, additional subtypes of MetS do not clearly emerge in US Hispanics/Latinos. Current diagnostic cutoffs for some components may not optimize MetS identification among this population.
PMCID: PMC4417385  PMID: 25745986
6.  Progression of Electrocardiographic Abnormalities in Type 1 Diabetes During 16 Years of Follow‐up: The Epidemiology of Diabetes Interventions and Complications (EDIC) Study 
The electrocardiogram (ECG) is an objective tool for cardiovascular disease (CVD) risk assessment.
Methods and Results
We evaluated distribution of ECG abnormalities and risk factors for developing new abnormalities in 1314 patients with type 1 diabetes (T1D) from the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Annual ECGs were centrally read. ECG abnormalities were classified as major and minor according to the Minnesota ECG Classification. At EDIC year 1 (baseline), 356 (27.1%) of the participants had at least 1 ECG abnormality (major or minor) whereas 26 (2%) had at least one major abnormality. During 16 years of follow‐up, 1016 (77.3%) participants developed at least 1 new ECG abnormality (major or minor), whereas 172 (13.1%) developed at least 1 new major abnormality. Independent risk factors for developing new major ECG abnormalities were: age, current smoking, increased systolic blood pressure, and higher glycosylated hemoglobin (hazard ratio [HR] [95% CI]: 1.04 [1.02–1.06] per 1‐year increase, 1.75 [1.22–2.53], 1.03 [1.01–1.05] per 1 mm Hg increase, and 1.16 [1.04–1.29] per 10% increase, respectively). Independent risk factors for developing any new ECG abnormalities (major or minor) were age and systolic blood pressure (HR [95% CI]: 1.02 [1.01–1.03] per 1‐year increase and 1.01 [1.00–1.02] per 1 mm Hg increase, respectively).
New ECG abnormalities commonly occur in the course of T1D, consistent with the recognized increasing risk for CVD as patients age. Advanced age, increased systolic blood pressure, smoking, and higher HbA1c are independent risk factor for developing major ECG abnormalities, which underscores the importance of tight glucose control in T1D in addition to management of common CVD risk factors.
PMCID: PMC4943265  PMID: 26976878
electrocardiogram; The Epidemiology of Diabetes Interventions and Complications Study; type 1 diabetes; Electrocardiology (ECG); Epidemiology
7.  Determinants of Discrepancies in Detection and Comparison of the Prognostic Significance of Left Ventricular Hypertrophy by Electrocardiogram and Cardiac Magnetic Resonance Imaging 
The American journal of cardiology  2014;115(4):515-522.
Despite the low sensitivity of the electrocardiogram (ECG) in detecting left ventricular hypertrophy (LVH), ECG-LVH is known to be a strong predictor of cardiovascular risk. Understanding reasons for the discrepancies in detection of LVH by ECG versus imaging could help improve the diagnostic ability of ECG. We examined factors associated with false-positive and false-negative ECG-LVH, using cardiac MRI as the gold standard. We also compared the prognostic significance of ECG-LVH and MRI-LVH as predictors of cardiovascular events. This analysis included 4748 participants (mean age 61.9 years, 53.5% females, 61.7% non-whites). Logistic regression with stepwise selection was used to identify factors associated with false-positive (n=208) and false-negative (n=387), compared to true-positive (n=208) and true-negative (n=4041) ECG-LVH, respectively. A false-negative ECG-LVH status was associated with increased odds of Hispanic race/ethnicity, current smoking, hypertension, increased systolic blood pressure, prolongation of QRS duration and higher body mass index, and with lower odds of increased ejection fraction (model generalized R2=0.20). A false-positive ECG-LVH status was associated with lower odds of Black race, Hispanic race/ethnicity, minor ST/T abnormalities, increased systolic blood pressure and presence of any major ECG abnormalities (model generalized R2=0.29). Both ECG-LVH and MRI-LVH were associated with increased risk of CVD events (HR (95% CI): 1.51(1.03,2.20) and 1.81(1.33,2.46), respectively). In conclusion, discrepancy in LVH detection by ECG and MRI can be relatively improved by considering certain participants characteristic. Discrepancy in diagnostic performance yet agreement on predictive ability suggests that LVH by ECG and imaging are likely to be two distinct, but somehow related phenotypes.
PMCID: PMC4312708  PMID: 25542394
Electrocardiogram; Cardiac MRI; Left ventricular hypertrophy; Left ventricular mass
8.  Coronary Artery Calcium and Risk of Atrial Fibrillation (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2014;114(11):1707-1712.
Calcified coronary arteries are associated with the development of cardiovascular disease and stroke. It is currently unknown whether coronary artery calcium (CAC) is associated with an increased risk of atrial fibrillation (AF). We addressed this question in 6,641 participants (mean age 62 ± 10; 53% women; 62% non-whites) from the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of baseline clinical cardiovascular disease and AF. CAC measurements were assessed by cardiac computed tomography (CT) at study baseline. AF was ascertained by review of hospital discharge records and from Medicare claims data until December 31, 2010. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95%CI) for the association between CAC and AF. During a median follow up of 8.5 years, 308 (4.6%) participants developed AF. In a model adjusted for socio-demographics, cardiovascular risk factors, and potential confounders, higher CAC scores were associated with an increased risk of AF (CAC=0: HR=1.0, referent; CAC=1–100: HR=1.4, 95%CI=1.01, 2.0; CAC=101–300: HR=1.6, 95%CI=1.1, 2.4; CAC>300: 2.1, 95%CI=1.4, 2.9). The addition of CAC to the Framingham Heart Study and the CHARGE AF risk scores yielded an integrated discrimination improvement (IDI) of 0.0033 (95%CI=0.0015, 0.0066) and 0.0028 (95%CI=0.0012, 0.0057) and with relative IDI of 0.10 (95%CI=0.061, 0.15) and 0.077 (95%CI=0.040, 0.11), respectively. In conclusion, CAC is independently associated with an increased risk of AF.
PMCID: PMC4253067  PMID: 25282316
coronary calcium; atrial fibrillation; epidemiology
9.  Prevalence and Determinants of Electrocardiographic Abnormalities in African Americans with Type 2 Diabetes 
Electrocardiographic (ECG) abnormalities are independently associated with poor outcomes in the general population. Their prevalence and determinants were assessed in the understudied African American population with type 2 diabetes.
Standard 12-lead ECGs were digitally recorded in 635 unrelated African American-Diabetes Heart Study (AA-DHS) participants, automatically processed at a central lab, read, and coded using standard Minnesota ECG Classification. Age- and sex-specific prevalence rates of ECG abnormalities were calculated and logistic regression models were fitted to examine cross-sectional associations between participant characteristics and ECG abnormalities.
Participants were 56% women with a mean age of 56 years; 60% had at least one minor or major ECG abnormality [23% ≥1 major (or major plus minor), and 37% ≥1 minor (with no major)]. Men had a higher prevalence of ≥1 minor or major ECG abnormality (66.1% men vs. 55.6% women, p=0.0089). In univariate analyses, age, past history of cardiovascular disease, diabetes duration, systolic blood pressure, sex and statin use were associated with the presence of any (major or minor) ECG abnormalities. In a multivariate model including variables, female sex (OR [95% CI] 0.79 [0.67,0.93]), statin use (0.79 [0.67,0.93]) and diabetes duration (1.03 [1.0,1.05]) remained statistically significant.
Nearly three out of five African Americans with diabetes had at least one ECG abnormality. Female sex and statin use were significantly associated with lower odds of any ECG abnormality and diabetes duration was significantly associated with higher odds of any ECG abnormality in the multivariable model.
PMCID: PMC4254487  PMID: 25455646
Electrocardiogram; Diabetes; African Americans; Heart; Hypertension; Cardiovascular Disease
10.  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
11.  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
12.  Individual Components of the Romhilt-Estes Left Ventricular Hypertrophy Score Differ in Their Prediction of Cardiovascular Events: the Atherosclerosis Risk in Communities (ARIC) Study 
American heart journal  2015;170(6):1220-1226.
It has been recently reported that the Romhilt-Estes (R-E) Score, originally proposed for detection of left ventricular hypertrophy (LVH) from the electrocardiogram (ECG), is a strong predictor of all-cause mortality. Whether the R-E score is also predictive of cardiovascular disease (CVD) and whether its individual components differ in their ability to predict different CVD outcomes is not well established.
This analysis includes 13,261 participants from the Atherosclerosis Risk in Communities (ARIC) study who were free of cardiovascular disease at baseline (1987–1989). Incident CVD, coronary heart disease (CHD), heart failure (HF) and stroke were ascertained by an adjudication committee through December 2010. R-E LVH score was measured from automatically processed baseline ECG data. Cox proportional hazard models were used to examine the association between baseline R-E overall score (overall) and each of its six individual components separately, with each of the CVD outcomes.
During a median follow-up of 21.8 years, 3,579, 2,205, 1,814, and 731 CVD, CHD, HF, and stroke events, respectively, occurred. In multivariable adjusted models, R-E score ≥ 4 points (compared to 0 points) was associated with increased risk of CVD, CHD, HF and stroke (HR (95%CI): 1.66(1.41–1.96), 1.66 (1.34–2.07), 1.97(1.60–2.43) and 1.49(1.07–2.07), respectively). The six component of the R-E score varied in their relationship with different CVD outcomes.
The R-E score is predictive of CVD outcomes. The six R-E score components differ in their associations with different CVD outcomes, indicating that they may be electrical biomarkers of different physiological events within the myocardium.
Graphical abstract
The Romhilt-Estes Score, at a level of > = 4 points, predicts new CV disease.
Each of the six ECG components demonstrates a unique response to multivariable adjustment in prediction of heart failure, coronary heart disease and stroke.
This suggests that each component is a unique electrical biomarker, indicating a different pathophysiological state and outcome.
PMCID: PMC4684592  PMID: 26678644
Romhilt-Estes Score; Left Ventricular Hypertrophy; ARIC study
13.  Perceived Stress and Atrial Fibrillation: The REasons for Geographic And Racial Differences in Stroke Study 
The association between perceived stress and atrial fibrillation (AF) remains unclear.
To examine the association between perceived stress and AF.
A total of 25,530 participants (mean age: 65 ± 9.4 years; 54% women; 41% blacks) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were included in this analysis. Logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI) for the association between the short version of the Cohen Perceived Stress Scale and AF.
In a multivariable analysis adjusted for demographics, cardiovascular risk factors, and potential confounders, the prevalence of AF was found to increase with higher levels of perceived stress (none: OR=1.0, referent; low stress: OR=1.12, 95%CI=0.98, 1.27; moderate stress: OR=1.27, 95%CI=1.11, 1.47; high stress: OR=1.60, 95%CI=1.39, 1.84).
Increasing levels of perceived stress are associated with prevalent AF in REGARDS.
PMCID: PMC4936185  PMID: 26044964
stress; atrial fibrillation; epidemiology
14.  Determinants of developing widened spatial QRS-T angle in HIV-infected individuals: Results from the Strategies for Management of Antiretroviral Therapy [SMART] Study 
Journal of electrocardiology  2013;47(2):264-271.
A widened electrocardiographic spatial QRS-T angle has been shown to be predictive of cardiovascular disease in HIV-infected individuals. However, determinants and risk factors of developing widened QRS-T angle over time in this population remain unknown.
Methods and Results
Spatial QRS-T angle was automatically measured from standard electrocardiogram of 1444 HIV-infected individuals without baseline widened spatial QRS-T angle from the Strategies for Management of Antiretroviral Therapy [SMART], a clinical trial comparing two antiretroviral treatment strategies [Drug Conservation (DC) vs. Viral Suppression (VS)]. Conditional logistic regression analysis was used to examine the association between baseline characteristics and incident widened spatial QRS-T angle (a new angle ≥ 93 degrees in males and ≥ 74 degrees in females). During 2544 person-years of follow-up, 199 participants developed widened angle at a rate of 7.8 per 100 person-years. In unadjusted models, female sex, black race (vs. white), DC treatment strategy, current and past smokers (vs. never), history of alcohol abuse, greater body mass index, history of diabetes and higher levels of hs-C-reactive protein were associated with incident widened spatial QRS-T angle. When these variables entered together in the same model with adjustment for demographics and treatment strategy, DC treatment strategy [OR (95% CI): 1.50 (1.09, 2.07)], female gender [1.69 (1.17, 2.45)], current and past smoking (vs. never) [2.49 (1.63, 3.81) and 1.93 (1.21, 3.09), respectively], and diabetes [2.28 (1.33, 3.91)] predicted incident widened spatial QRS-T angle.
Drug conservation treatment strategy, female gender, smoking, and diabetes are independently predictive of incident widened spatial QRS-T angle in HIV-infected individuals.
PMCID: PMC3951578  PMID: 24406207
Spatial QRS-T angle; Electrocardiogram; cardiovascular disease; HIV/AIDS
15.  The Interrelationship between Electrocardiographic Left Ventricular Hypertrophy and QT Prolongation as Predictors of Increased Risk of Mortality in the General Population 
Prolonged-QT commonly coexists in the electrocardiogram (ECG) with left ventricular hypertrophy (ECG-LVH). However, it is unclear to what extent QT prolongation coexisting with ECG-LVH can explain the prognostic significance of ECG-LVH, and whether prolonged-QT coexisting with ECG-LVH should be considered as an innocent consequence of ECG-LVH.
Methods and Results
The study population consisted of 7506 participants (mean age 59.4±13.3 years, 49% whites, 47% males) from the US Third National Health and Nutrition Examination Survey (NHANES-III). ECG-LVH was defined by Cornell voltage criteria. Prolonged heart rate-adjusted QT (prolonged-QTa) was defined as QTa ≥ 460 ms in women or 450 ms in men. Cox proportional hazards analysis was used to calculate the hazard ratios (HR) with 95% confidence intervals (CI) for the risk of all-cause mortality for various combinations of ECG-LVH and prolonged-QTa. ECG-LVH was present in 4.2% (n=312) of the participants, of whom 16.4% had prolonged-QTa. In a multivariable adjusted model and compared to the group without ECG-LVH or prolonged-QTa, mortality risk was highest in the group with concomitant ECG-LVH and prolonged-QTa (HR (95% CI): 1.63(1.12, 2.36)), followed by isolated ECG-LVH (1.48 (1.24, 1.77)), and then isolated prolonged-QTa (1.27 (1.12, 1.46)). In models with similar adjustment where ECG-LVH and prolonged-QTa were entered as two separate variables and subsequently additionally adjusted for each other, the mortality risk was essentially unchanged for both variables.
Although prolonged-QT commonly coexists with LVH, both are independent markers of poor prognosis. Concomitant presence of prolonged-QT and ECG-LVH carries a higher risk than either predictor alone.
PMCID: PMC4314284  PMID: 24762807
Prolonged-QTa; Left Ventricular Hypertrophy; Mortality; NHANES
16.  Reference ranges of PR duration and P-wave indices in individuals free of cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Journal of electrocardiology  2013;46(6):10.1016/j.jelectrocard.2013.05.006.
In this brief report, we provide normal reference ranges for PR duration [unadjusted and heart rate adjusted] and P-wave indices [duration, amplitude and terminal force in V1] in individuals free of cardiovascular disease and its risk factors. We used automatically processed digital ECG data from 1252 US participants [mean age 59 (± 10) years, 738 women, 588 whites, 207 African-Americans, 217 Hispanics, 240 Chinese] from the Multi-Ethnic Study of Atherosclerosis [MESA]. In multivariable adjusted linear regression models with PR and each P-wave variable as a separate outcome, significant age, sex and race differences in these markers were observed. Subsequently, we report reference ranges for abnormal [2nd and 98th percentiles], borderline abnormal [5th and 95th percentiles] and mean [SD] values of PR and P-wave indices stratified by age [middle age (45–64 years) and seniors (65–84 years)], sex [men and women] and race [whites, African Americans, Hispanics and Chinese].
PMCID: PMC3795794  PMID: 23806475
P-wave indices; PR interval; MESA
17.  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
18.  Electrocardiographic Left Atrial Abnormality and Stroke Subtype in ARIC 
Annals of neurology  2015;78(5):670-678.
To assess the relationship between abnormally increased P-wave terminal force in lead V1 (PTFV1), an electrocardiographic (ECG) marker of left atrial abnormality, and incident ischemic stroke subtypes. We hypothesized that associations would be stronger with non-lacunar stroke, since we expected left atrial abnormality to reflect the risk of thromboembolism rather than in-situ cerebral small-vessel occlusion.
Our cohort comprised 14,542 participants 45-64 years of age prospectively enrolled in the Atherosclerosis Risk in Communities (ARIC) study and free of clinically apparent atrial fibrillation (AF) at baseline. Left atrial abnormality was defined as PTFV1 >4,000 μV*ms. Outcomes were adjudicated ischemic stroke, non-lacunar (including cardioembolic) ischemic stroke, and lacunar stroke.
During a median follow-up period of 22 years (interquartile range, 19-23 years), 904 participants (6.2%) experienced a definite or probable ischemic stroke. A higher incidence of stroke occurred in those with baseline left atrial abnormality (incidence rate per 1,000 person-years, 6.3; 95% CI, 5.4-7.4) than in those without (incidence rate per 1,000 person-years, 2.9; 95% CI, 2.7-3.1; P < 0.001). In Cox regression models adjusted for potential confounders and incident AF, left atrial abnormality was associated with incident ischemic stroke (HR, 1.33; 95% CI, 1.11-1.59). This association was limited to non-lacunar stroke (HR, 1.49; 95% CI, 1.07-2.07) as opposed to lacunar stroke (HR, 0.89; 95% CI, 0.57-1.40).
We found an association between ECG-defined left atrial abnormality and subsequent non-lacunar ischemic stroke. Our findings suggest that an underlying atrial cardiopathy may cause left atrial thromboembolism in the absence of recognized AF.
PMCID: PMC4624007  PMID: 26179566
19.  Electrocardiographic Left Atrial Abnormality and Risk of Stroke: The Northern Manhattan Study 
Background and Purpose
Electrocardiographic (ECG) left atrial abnormality has been associated with stroke independently of atrial fibrillation (AF), suggesting that atrial thromboembolism may occur in the absence of AF. If true, we would expect an association with cryptogenic or cardioembolic stroke rather than non-cardioembolic stroke.
We conducted a case-cohort analysis in the Northern Manhattan Study, a prospective cohort study of stroke risk factors. P-wave terminal force in lead V1 (PTFV1) was manually measured from baseline ECGs of participants in sinus rhythm who subsequently had ischemic stroke (N = 241) and a randomly selected subcohort without stroke (N = 798). Weighted Cox proportional hazards models were used to examine the association between PTFV1 and stroke etiological subtypes while adjusting for baseline demographic characteristics, history of AF, heart failure, diabetes, hypertension, tobacco use, and lipid levels.
Mean PTFV1 was 4,452 (±3,368) μV*ms among stroke cases and 3,934 (±2,541) μV*ms in the subcohort. PTFV1 was associated with ischemic stroke (adjusted hazard ratio [HR] per standard deviation [SD], 1.20; 95% confidence interval [CI], 1.03-1.39) and the composite of cryptogenic or cardioembolic stroke (adjusted HR per SD, 1.31; 95% CI, 1.08-1.58). There was no definite association with non-cardioembolic stroke subtypes (adjusted HR per SD, 1.14; 95% CI, 0.92-1.40). Results were similar after excluding participants with a history of AF at baseline or new AF during follow-up.
ECG-defined left atrial abnormality was associated with incident cryptogenic or cardioembolic stroke independently of the presence of AF, suggesting atrial thromboembolism may occur without recognized AF.
PMCID: PMC4624510  PMID: 26396031
Atrial fibrillation; atrium; cardiomyopathy; embolism; embolic stroke
20.  Inflammation and Hemostasis in Atrial Fibrillation and Coronary Heart Disease: The REasons for Geographic And Racial Differences in Stroke Study 
Atherosclerosis  2015;243(1):192-197.
Recent studies suggest atrial fibrillation (AF) is an independent risk factor for coronary heart disease (CHD).
To determine if alterations in hemostasis or inflammation explain the association between AF and CHD.
C-reactive protein (CRP), D-dimer, factor VIII, and fibrinogen were measured in incident CHD cases (n=647) and a stratified cohort random sample (CRS, n=1,104) between 2003 and 2007 from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Using a case-cohort approach, Cox models examined whether inflammation or hemostasis biomarkers explained the association between AF and CHD.
In participants free of CHD at baseline, 12.2% of CHD cases and 7.1% of the CRS had AF. Over a median follow-up of 4.4 years, all biomarkers were associated with an increased risk of CHD in those with and those without AF after adjusting for CHD risk factors. The association of D-dimer with CHD was greater in those with AF (HR 2.52, 95% CI=1.49, 4.26) than those without AF (HR 1.34, 95% CI=1.12, 1.61) (p-interaction=0.02). Similar interactions were not observed for the other biomarkers.
Our results suggest that alterations in D-dimer, a marker of hemostasis, explain the association between AF and CHD. Potentially, D-dimer is a useful biomarker to assess CHD risk in persons with AF.
PMCID: PMC4634936  PMID: 26398291
atrial fibrillation; coronary disease; biological markers
21.  Environmental Tobacco Smoke and Atrial Fibrillation: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
To examine the association between environmental tobacco smoke (ETS) exposure and atrial fibrillation.
We examined the cross-sectional association between ETS exposure and atrial fibrillation in 12,021 participants (mean age: 65 ± 9.9 years; 60% women; 40% blacks) from the REasons for Geographic And Racial Differences in Stroke study who self-identified as never smokers between 2003 and 2007.
A total of 2,503 (21%) participants reported ETS exposure. In a multivariate logistic regression model adjusted for socio-demographics and potential confounders, ETS exposure was significantly associated with atrial fibrillation (OR=1.27, 95%CI=1.08, 1.50).
Our findings suggest that the harmful effects of ETS exposure extend to sustained arrhythmias such as atrial fibrillation.
PMCID: PMC4636018  PMID: 26539762
environmental tobacco smoke; arrhythmia; epidemiology
22.  Sodium Excretion and the Risk of Cardiovascular Disease in Patients With Chronic Kidney Disease 
JAMA  2016;315(20):2200-2210.
Patients with chronic kidney disease (CKD) are at an increased risk of cardiovascular disease (CVD) compared with the general population. Prior studies have produced contradictory results on the association of dietary sodium intake with risk of CVD, and this relationship has not been investigated in patients with CKD.
To evaluate the association between urinary sodium excretion and clinical CVD events among patients with CKD.
A prospective cohort study of patients with CKD from 7 locations in the United States enrolled in the Chronic Renal Insufficiency Cohort Study and followed up from May 2003 to March 2013.
The cumulative mean of urinary sodium excretion from three 24-hour urinary measurements and calibrated to sex-specific mean 24-hour urinary creatinine excretion.
A composite of CVD events defined as congestive heart failure, stroke, ormyocardial infarction. Events were reported every 6 months and confirmed by medical record adjudication.
Among 3757 participants (mean age, 58 years; 45% women), 804 composite CVD events (575 heart failure, 305 myocardial infarction, and 148 stroke) occurred during a median 6.8 years of follow-up. From lowest (<2894 mg/24 hours) to highest (≥4548 mg/24 hours) quartile of calibrated sodium excretion, 174, 159, 198, and 273 composite CVD events occurred, and the cumulative incidence was 18.4%, 16.5%, 20.6%, and 29.8% at median follow-up. In addition, the cumulative incidence of CVD events in the highest quartile of calibrated sodium excretion compared with the lowest was 23.2% vs 13.3% for heart failure, 10.9% vs 7.8% for myocardial infarction, and 6.4% vs 2.7% for stroke at median follow-up. Hazard ratios of the highest quartile compared with the lowest quartile were 1.36 (95% CI, 1.09–1.70; P = .007) for composite CVD events, 1.34 (95% CI, 1.03–1.74; P = .03) for heart failure, and 1.81 (95% CI, 1.08–3.02; P = .02) for stroke after multivariable adjustment. Restricted cubic spline analyses of the association between sodium excretion and composite CVD provided no evidence of a nonlinear association (P = .11) and indicated a significant linear association (P < .001).
Among patients with CKD, higher urinary sodium excretion was associated with increased risk of CVD.
PMCID: PMC5087595  PMID: 27218629
23.  Atrial Fibrillation and the Risk of Myocardial Infarction 
JAMA internal medicine  2014;174(1):107-114.
Myocardial infarction (MI) is an established risk factor for atrial fibrillation (AF). However, the extent to which AF is a risk factor for MI has not been investigated.
To examine the risk of incident MI associated with AF.
A prospective cohort of 23 928 participants residing in the continental United States and without coronary heart disease at baseline were enrolled from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort between 2003 and 2007, with follow-up through December 2009.
Expert-adjudicated total MI events (fatal and nonfatal).
Over 6.9 years of follow-up (median 4.5 years), 648 incident MI events occurred. In a sociodemographic-adjusted model, AF was associated with about 2-fold increased risk of MI (hazard ratio [HR], 1.96 [95% CI, 1.52–2.52]). This association remained significant (HR, 1.70 [95% CI, 1.26–2.30]) after further adjustment for total cholesterol, high-density lipoprotein cholesterol, smoking status, systolic blood pressure, blood pressure–lowering drugs, body mass index, diabetes, warfarin use, aspirin use, statin use, history of stroke and vascular disease, estimated glomerular filtration rate, albumin to creatinine ratio, and C-reactive protein level. In subgroup analysis, the risk of MI associated with AF was significantly higher in women (HR, 2.16 [95% CI, 1.41–3.31]) than in men (HR, 1.39 [95% CI, 0.91–2.10]) and in blacks (HR, 2.53 [95% CI, 1.67–3.86]) than in whites (HR, 1.26 [95% CI, 0.83–1.93]); for interactions, P = .03 and P = .02, respectively. On the other hand, there were no significant differences in the risk of MI associated with AF in older (≥75 years) vs younger (<75 years) participants (HR, 2.00 [95% CI, 1.16–3.35] and HR, 1.60 [95% CI, 1.11–2.30], respectively); for interaction, P = .44.
AF is independently associated with an increased risk of incident MI, especially in women and blacks. These findings add to the growing concerns of the seriousness of AF as a public health burden: in addition to being a well-known risk factor for stroke, AF is also associated with increased risk of MI.
PMCID: PMC4115282  PMID: 24190540
24.  Minor Isolated Q Waves and Cardiovascular Events in the MESA Study 
The American journal of medicine  2013;126(5):450.e9-450.e16.
The significance of minor isolated Q waves in the resting electrocardiograms (ECGs) of apparently healthy individuals is unknown.
To examine the association between minor isolated Q waves and incident cardiovascular disease events in the Multi-Ethnic Study of Atherosclerosis (MESA).
This analysis included 6551 MESA participants (38% white, 28% black, 22% Hispanic, 12% Chinese) who were free of cardiovascular disease at enrollment. Cox proportional hazards models were used to examine the association between minor isolated Q waves defined by the Minnesota ECG Classification with adjudicated incident cardiovascular events.
During up to 7.8 years of follow-up, 423 events occurred, with a rate of 10.7 events per 1000 person-years. A significant interaction between minor isolated Q waves and race/ethnicity was observed (P = .030). In models stratified by race/ethnicity and adjusted for demographics, socioeconomic status, common cardiovascular risk factors, and other ECG abnormalities, presence of isolated minor Q waves was significantly associated with incident cardiovascular events in Hispanics (hazard ratio [HR] 2.62; 95% confidence interval [CI], 1.42-4.82), but not in whites (HR 0.65; 95% CI, 0.32-1.33) or blacks (HR 1.46; 95% CI, 0.74-2.89). Despite the statistically significant association in the Chinese population, the small number of events precluded solid conclusions in this race/ethnicity.
The prognostic significance of minor isolated Q waves varies across races/ethnicities; they carry a high risk for future cardiovascular events in apparently healthy Hispanics, but not in whites or blacks.
PMCID: PMC3741651  PMID: 23582938
Electrocardiography; MESA; Minor isolated Q waves; Race/ethnicity
25.  Effect of Falls on Frequency of Atrial Fibrillation and Mortality Risk (From the REasons for Geographic And Racial Differences in Stroke [REGARDS] Study) 
The American journal of cardiology  2015;116(8):1213-1218.
It is unclear if persons who have atrial fibrillation (AF) have a higher fall risk compared with those in the general population and if falls increase mortality beyond that observed in AF. A total of 24,117 (mean age=65±9.3; 55% female; 38% black) participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were included. AF was identified from baseline electrocardiogram data and by self-reported history. Falls were considered present if participants reported 2 or more falls within the year prior to the baseline examination. Logistic regression was used to examine the relationship between prevalent AF and falls. Cox regression was used to examine the risk of death among those with AF and falls, separately and in combination, compared with those without either condition. A total of 2,007 (8.3%) participants had baseline AF and 1,655 (6.7%) reported falls. A higher prevalence of falls was reported in those with AF (n=209; 10%) than those without AF (n=1,446; 6.5%) (p<0.0001). After adjustment for fall risk factors, AF was significantly associated with falls (OR=1.22, 95%CI=1.04, 1.44). Compared with no history of AF or falls, the concomitant presence of AF and falls (HR=2.12, 95%CI=1.64, 2.74) was associated with a higher risk of death than AF (HR=1.44, 95%CI=1.28, 1.62) or falls (HR=1.61, 95%CI=1.42, 1.82). In conclusion, persons with AF are more likely to report a history of falls in REGARDS. Additionally, AF participants who report falls have an increased risk of death than those with either condition in isolation.
PMCID: PMC4589487  PMID: 26279105
atrial fibrillation; falls; mortality

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