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1.  Electrocardiographic Predictors of Incident Heart Failure in Men and Women Free From Manifest Cardiovascular Disease (from the Atherosclerosis Risk in Communities [ARIC] Study) 
The American journal of cardiology  2013;112(6):843-849.
The risk of incident hospitalized heart failure (HF) was evaluated for 23 electrocardiographic (ECG) variables in men and women free from cardiovascular disease. The hazard ratios with 95% confidence intervals were determined from Cox regression analysis for 13,428 participants 45 to 65 years old in the Atherosclerosis Risk in Communities (ARIC) study. New-onset HF during a 14-year follow-up period occurred in 695 men (11.9%) and 721 women (9.5%). Several ECG variables were significant predictors of incident HF when evaluated as single ECG variables. Predominant among them were spatial angles, reflecting deviations of the direction of the repolarization sequence from the normal reference direction. After controlling for collinearity among the ECG variables, the spatial angle between T peak and normal T reference vectors, Θ(Tp|Tref), was a significant independent predictor in men (HF risk increased 31%) and women (HF risk increased 46%). Other independent predictors in men included epicardial repolarization time (62% increased risk) and T wave peak to T wave end (TpTe) interval, reflecting global dispersion of repolarization (27% increased risk). The independent predictors in women, in addition to Θ(Tp|Tref), were Θ(R|STT) the spatial angle between the mean QRS and STT vectors (54% increased risk) and QRS nondipolar voltage (46% increased risk). In conclusion, wide Θ(Tp|Tref), wide Θ(R|STT), and increased QRS nondipolar voltage in women and wide Θ(Tp|Tref), increased epicardial repolarization time, prolonged TpTe interval and T wave complexity in men were independent predictors of incident HF, and the presence of these abnormal findings could warrant additional diagnostic evaluation for possible preventive action for HF.
doi:10.1016/j.amjcard.2013.05.011
PMCID: PMC3782380  PMID: 23768456
2.  US National Prevalence of Electrocardiographic Abnormalities in Black and White Middle Aged (45–64 Years) and Older (≥ 65 Years) Adults (From the Reasons For Geographic and Racial Differences In Stroke Study) 
The American Journal of Cardiology  2012;109(8):1223-1228.
A US national sample of 20,962 participants (57% women, 44% blacks) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study provided general population estimates for ECG abnormalities among black and white men and women. Participants were recruited during 2003–2007 by random selection from a commercially available nationwide list, with oversampling of blacks and persons from the stroke belt for a cooperation rate of 49%. Measurement of risk factors and 12-lead ECGs (centrally coded using Minnesota Code criteria) showed 28% had at least one major ECG abnormality. Prevalence of abnormalities was higher (35%+) for those 65 years and older with no differences between blacks and whites. However, among men less than 65 years, blacks had more major abnormalities than whites, most notably for atrial fibrillation, major Q waves and left ventricular hypertrophy (LVH). Men generally had more ECG abnormalities than women. The most common ECG abnormalities were T-wave abnormalities. Average heart rate corrected QT interval was longer in women than men, similar in whites and blacks and increased with age, whereas the average heart rate was higher in women than men and in blacks than whites and decreased with age. The prevalence of ECG abnormalities was related to hypertension, diabetes, blood pressure level and age. In conclusion, black men and women in the US have a significantly higher prevalence of ECG abnormalities than whites at ages 45–64 but these proportions, although larger, tend to equalize or reverse after age 65.
doi:10.1016/j.amjcard.2011.11.061
PMCID: PMC3319226  PMID: 22245412
ECG abnormalities; prevalence; black/white
3.  Different Patterns of Bundle Branch Blocks and the Risk of Incident Heart Failure in the Women’s Health Initiative (WHI) Study 
Circulation. Heart failure  2013;6(4):655-661.
Background
We evaluated the risk of incident heart failure (HF) associated with bundle branch blocks (BBB) in post-menopausal women.
Methods and Results
Cox’s regression was used to evaluate hazard ratios (HR) with 95% confidence intervals (CI) for HF among 65,975 participants of the Women’s Health Initiative (WHI) study during an average follow-up of 14 years. BBB observed in 1,676 women at baseline was categorized into left, right and indetermined-type BBB (LBBB, RBBB and IVCD, respectively). Compared to women with no BBB, LBBB and IVCD were strong predictors of incident HF in multivariable-adjusted risk models (HR 3.79, CI 2.95–4.87 for LBBB and HR 3.53, CI 2.14–5.81 for IVCD). RBBB was not a significant predictor of incident HF in multivariable-adjusted risk model but the combination of RBBB and left anterior fascicular bock (RBBB&LAFB) was a strong predictor (HR 2.96, CI 1.77–4.93). QRS duration was an independent predictor of incident HF only in LBBB, with more pronounced risk at QRS ≥140 ms than below 140 ms. RNDPV was an independent predictor in both RBBB and LBBB and in addition in LBBB, QRS/STT angle and ST J-point depression in aVL were independent predictors.
Conclusions
LBBB, IVCD and RBBB combined with LAFB are strong predictors of incident HF in multivariable-adjusted risk models but RBBB is not a significant predictor, QRS duration ≥140 ms may warrant consideration in LBBB as an indication for further diagnostic evaluation for possible therapeutic and preventive action.
doi:10.1161/CIRCHEARTFAILURE.113.000217
PMCID: PMC3969232  PMID: 23729198
heart failure; electrocardiography; bundle branch block; repolarization; QRS duration
4.  Severe obesity in children: prevalence, persistence and relation to hypertension 
Background
Newer approaches for classifying gradations of pediatric obesity by level of body mass index (BMI) percentage above the 95th percentile have recently been recommended in the management and tracking of obese children. Examining the prevalence and persistence of severe obesity using such methods along with the associations with other cardiovascular risk factors such as hypertension is important for characterizing the clinical significance of severe obesity classification methods.
Methods
This retrospective study was conducted in an integrated healthcare delivery system to characterize obesity and obesity severity in children and adolescents by level of body mass index (BMI) percentage above the 95th BMI percentile, to examine tracking of obesity status over 2–3 years, and to examine associations with blood pressure. Moderate obesity was defined by BMI 100-119% of the 95th percentile and severe obesity by BMI ≥120% × 95th percentile. Hypertension was defined by 3 consecutive blood pressures ≥95th percentile (for age, sex and height) on separate days and was examined in association with obesity severity.
Results
Among 117,618 children aged 6–17 years with measured blood pressure and BMI at a well-child visit during 2007–2010, the prevalence of obesity was 17.9% overall and was highest among Hispanics (28.9%) and blacks (20.5%) for boys, and blacks (23.3%) and Hispanics (21.5%) for girls. Severe obesity prevalence was 5.6% overall and was highest in 12–17 year old Hispanic boys (10.6%) and black girls (9.5%). Subsequent BMI obtained 2–3 years later also demonstrated strong tracking of severe obesity. Stratification of BMI by percentage above the 95th BMI percentile was associated with a graded increase in the risk of hypertension, with severe obesity contributing to a 2.7-fold greater odds of hypertension compared to moderate obesity.
Conclusion
Severe obesity was found in 5.6% of this community-based pediatric population, varied by gender and race/ethnicity (highest among Hispanics and blacks) and showed strong evidence for persistence over several years. Increasing gradation of obesity was associated with higher risk for hypertension, with a nearly three-fold increased risk when comparing severe to moderate obesity, underscoring the heightened health risk associated with severe obesity in children and adolescents.
doi:10.1186/1687-9856-2014-3
PMCID: PMC3976673  PMID: 24580759
Obesity; Children; Adolescents; Blood pressure
5.  Cohort Profile: The International Childhood Cardiovascular Cohort (i3C) Consortium 
This is a consortium of large children's cohorts that contain measurements of major cardiovascular disease (CVD) risk factors in childhood and had the ability to follow those cohorts into adulthood. The purpose of this consortium is to enable the pooling of data to increase power, most importantly for the follow-up of CVD events in adulthood. Within the consortium, we hope to be able to obtain data on the independent effects of childhood and early adult levels of CVD risk factors on subsequent CVD occurrence.
doi:10.1093/ije/dys004
PMCID: PMC3600617  PMID: 22434861
6.  Electrocardiographic Abnormalities in Elderly Chagas Disease Patients: 10‐Year Follow‐Up of the Bambuí Cohort Study of Aging 
Background
Electrocardiography has been considered an important tool in the management of Chagas disease (ChD) patients, although its value in elderly infected patients is unknown. This study was designed to investigate the prevalence and prognostic value of electrocardiographic abnormalities in Trypanosoma cruzi infected and noninfected older adults.
Methods and Results
We studied 1462 participants in Bambuí City, Brazil, with electrocardiogram (ECG) records classified by the Minnesota Code. Follow‐up time was 10 years; the endpoint was mortality. Adjustment for potential confounding variables included age, gender, conventional risk factors, and B‐type natriuretic peptide (BNP). The mean age was 69 years (60.9% women). The prevalence of ChD was 38.1% (n=557). ECG abnormalities were more frequent in ChD patients (87.6% versus 77.7%, P<0.001). Right bundle branch block (RBBB) with left anterior hemiblock (LAH) was strongly related to ChD (OR: 11.99 [5.60 to 25.69]). During the mean follow‐up time of 8.7 years, 556 participants died (253 with ChD), and only 89 were lost to follow‐up. ECG variables of independent prognostic value for death in ChD included absence of sinus rhythm, frequent ventricular and supraventricular premature beats, atrial fibrillation, RBBB, old and possible old myocardial infarction, and left ventricular hypertrophy. The presence of any major ECG abnormalities doubled the risk of death in ChD patients (HR: 2.18 [1.35 to 3.53]), but it also increased the risk in non‐ChD subjects (HR: 1.50 [1.07 to 2.10]); the risk of death increased with the number of major abnormalities in the same patient.
Conclusion
ECG abnormalities are more common among elderly Chagas disease patients and strongly predict adverse outcomes.
doi:10.1161/JAHA.113.000632
PMCID: PMC3959704  PMID: 24510116
Chagas disease; elderly; electrocardiography
7.  Use of Hundreds of Electrocardiograhpic Biomarkers for Prediction of Mortality in Post-Menopausal Women: The Women’s Health Initiative 
Background
Simultaneous contribution of hundreds of electrocardiographic biomarkers to prediction of long-term mortality in post-menopausal women with clinically normal resting electrocardiograms (ECGs) is unknown.
Methods and Results
We analyzed ECGs and all-cause mortality in 33,144 women enrolled in Women’s Health Initiative trials, who were without baseline cardiovascular disease or cancer, and had normal ECGs by Minnesota and Novacode criteria. Four hundred and seventy seven ECG biomarkers, encompassing global and individual ECG findings, were measured using computer algorithms. During a median follow-up of 8.1 years (range for survivors 0.5–11.2 years), 1,229 women died. For analyses cohort was randomly split into derivation (n=22,096, deaths=819) and validation (n=11,048, deaths=410) subsets. ECG biomarkers, demographic, and clinical characteristics were simultaneously analyzed using both traditional Cox regression and Random Survival Forest (RSF), a novel algorithmic machine-learning approach. Regression modeling failed to converge. RSF variable selection yielded 20 variables that were independently predictive of long-term mortality, 14 of which were ECG biomarkers related to autonomic tone, atrial conduction, and ventricular depolarization and repolarization.
Conclusions
We identified 14 ECG biomarkers from amongst hundreds that were associated with long-term prognosis using a novel random forest variable selection methodology. These were related to autonomic tone, atrial conduction, ventricular depolarization, and ventricular repolarization. Quantitative ECG biomarkers have prognostic importance, and may be markers of subclinical disease in apparently healthy post-menopausal women.
doi:10.1161/CIRCOUTCOMES.110.959023
PMCID: PMC3893688  PMID: 21862719
Electrocardiography; epidemiology; women; prognosis
8.  Association between Family Risk of Stroke and Myocardial Infarction with Prevalent Risk Factors and Coexisting Diseases 
Background
Familial transmission of stroke and myocardial infarction (MI) is partially mediated by transmission of cerebrovascular and cardiovascular risk factors. We examined relationships between family risk of stroke and MI with risk factors for these phenotypes.
Methods
Cross-sectional association between the stratified log-rank family score (SLFS) for stroke and MI with prevalent risk factors was assessed in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort.
Results
Individuals in the 4th quartile of SLFS scores for stroke were more likely to have prevalent risk factors including hypertension (OR: 1.43; 95% CI: [1.30, 1.58]), left ventricular hypertrophy (OR 1.42; 95% CI: [1.16, 1.42]), diabetes (OR: 1.26; 95% CI: [1.12, 1.43]) and atrial fibrillation (OR 1.23; 95% CI: [1.03, 1.45]) compared to individuals in the 1st quartile. Likewise, individuals in the 4th quartile of SLFS scores for MI were more likely to have prevalent risk factors including hypertension (OR 1.57; 95% CI: [1.27, 1.94]) and diabetes (OR 1.29; 95% CI: [1.12, 1.43]) than the 1st quartile. In contrast to stroke, the family risk score for MI was associated with dyslipidemia (OR 1.38; 95% CI: [1.23, 1.55]) and overweight/obesity (OR 1.22; 95% CI: [1.10, 1.37]).
Conclusions
Family risk of stroke and MI are strongly associated with the majority of risk factors associated with each disease. Family history and genetic studies separating nonspecific contributions of intermediate phenotypes from specific contributions to the disease phenotype may lead to more thorough understanding of transmission for these complex disorders.
doi:10.1161/STROKEAHA.111.645044
PMCID: PMC3805250  PMID: 22328552
stroke; myocardial infarction; cohort studies; family risk; REGARDS
9.  Association of Prediabetes and Diabetes With Stroke Symptoms  
Diabetes Care  2012;35(9):1845-1852.
OBJECTIVE
Stroke symptoms among individuals reporting no physician diagnosis of stroke are associated with an increased risk of future stroke. Few studies have assessed whether individuals with diabetes or prediabetes, but no physician diagnosis of stroke, have an increased prevalence of stroke symptoms.
RESEARCH DESIGN AND METHODS
This study included 25,696 individuals aged ≥45 years from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who reported no history of stroke or transient ischemic attack at baseline (2003–2007). Glucose measurements, medication use, and self-reported physician diagnosis were used to categorize participants into diabetes, prediabetes, or normal glycemia groups. The presence of six stroke symptoms was assessed using a validated questionnaire.
RESULTS
The prevalence of any stroke symptom was higher among participants with diabetes (22.7%) compared with those with prediabetes (15.6%) or normal glycemia (14.9%). In multivariable models, diabetes was associated with any stroke symptom (prevalence odds ratio [POR] 1.28 [95% CI 1.18–1.39]) and two or more stroke symptoms (1.26 [1.12–1.43]) compared with normal glycemia. In analyses of individual stroke symptoms, diabetes was associated with numbness (1.15 [1.03–1.29]), vision loss (1.52 [1.31–1.76]), half-vision loss (1.54 [1.30–1.84]), and lost ability to understand people (1.34 [1.12–1.61]) after multivariable adjustment. No association was present between prediabetes and stroke symptoms.
CONCLUSIONS
In this population-based study, almost one in four individuals with diabetes reported stroke symptoms, which suggests that screening for stroke symptoms in diabetes may be warranted.
doi:10.2337/dc11-2140
PMCID: PMC3424995  PMID: 22699292
10.  The Sensitivity of the Methods of Detection of Atrial Fibrillation in Population Studies Affects Group-Specific Prevalence Estimates: Ethnic and Regional Distribution of Atrial Fibrillation in REGARDS Study 
Background
The paradox of reported low atrial fibrillation (AF) prevalence in blacks and in Southern U.S. states despite having high rates of stroke warrants investigation. We hypothesized that the ethnic and regional distribution of AF has been affected by the sensitivity of methods used to diagnose AF in prior reports.
Methods
18,833 black and white participants from the U.S. national study REasons For Geographic And Racial Differences In Stroke (REGARDS) study were included in this analysis. Levels of sensitivity to detect AF, from the least to the most sensitive, were created with graded combinations of self-report (SR) and ECG methods as follows: (a) Both SR and ECG, (b) ECG alone, (c) SR alone and (d) SR or ECG. Geographic regions were dichotomized as Stroke-Belt (the Southern U.S. states) and non Stroke-Belt. Logistic regression analysis estimated the odd ratios of AF associated with Stroke-Belt and black ethnicity across each diagnostic combination.
Results
Stroke-Belt was significantly associated with AF detected by “Both SR and ECG” (Multivariable adjusted OR (95% CI): 0.66 (0.47, 0.92)), an association that was no longer significant when AF was diagnosed with a more sensitive method, “SR or ECG”, (OR (95% CI): (0.95 (0.85, 1.06)). Similarly, the association between black ethnicity and AF was sequentially attenuated as measured across the 4 increasingly sensitive AF detection methods (OR: 0.20, 0.40, 0.70, 0.71 respectively).
Conclusions
The association between AF and Stroke-Belt or black ethnicity has an inverse relationship with the sensitivity to detect AF; as the sensitivity increases, the association attenuates (or even reverses), a finding that may partially explain the reported lower prevalence of AF in populations with higher stroke rates.
PMCID: PMC2750004  PMID: 19561382
Atrial fibrillation; Race/ethnicity; REGARDS study
11.  Regional Differences in Diabetes as a Possible Contributor to the Geographic Disparity in Stroke Mortality 
Background and Purpose
Diabetes and hypertension impart approximately the same increased relative risk for stroke, although hypertension has a larger population-attributable risk because of its higher population prevalence. With a growing epidemic of obesity and associated increasing prevalence of diabetes that disproportionately impacts the southeastern Stroke Belt states, any potential contribution of diabetes to the geographic disparity in stroke mortality will only increase.
Methods
Racial and geographic differences in diabetes prevalence and diabetes awareness, treatment, and control were assessed in the REasons for Geographic And Racial Differences in Stroke study, a national population-based cohort of black and white participants older than 45 years of age. At the time of this report, 21 959 had been enrolled.
Results
The odds of diabetes were significantly increased in both white and black residents of the stroke buckle (OR, 1.26; [1.10, 1.44]; OR, 1.45 [1.26, 1.66], respectively) and Stroke Belt (OR, 1.22; [1.09, 1.36]; OR, 1.13 [1.02, 1.26]) compared to the rest of the United States. In the buckle, regional differences were not fully mediated and remained significant when controlling for socioeconomic status and risk factors. Addition of hypertension to the models did not reduce the magnitude of the associations. There were no significant differences by region with regard to awareness, treatment, or control for either race.
Conclusions
These analyses support a possible role of regional variation in the prevalence of diabetes as, in part, an explanation for the regional variation in stroke mortality but fail to support the potential for a contribution of regional differences in diabetes management.
doi:10.1161/STROKEAHA.107.507053
PMCID: PMC3725822  PMID: 18388336
diabetes; geography; racial differences
12.  Moderate Waist Circumference and Hypertension Prevalence: The REGARDS Study 
American journal of hypertension  2011;24(4):482-488.
Background
High waist circumference (WC) (women: >88 cm; men: >102 cm) increases cardiovascular risk. Less is known about moderate WC (women: 80–88 cm; men: 94–102 cm). Therefore, we examined the association between moderate WC and hypertension prevalence, independent of body mass index (BMI).
Methods
Among 24,247 eligible adults 45–84 years old, when recruited from January 2003 to October 2007 in the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort, we examined hypertension prevalence (systolic blood pressure (BP) ≥140 mm Hg, or diastolic BP ≥90 mm Hg, or self-reported antihypertensive medication use) by WC before and after stratification by BMI (normal: 18.5–24.9; overweight: 25–29.9; obese class I: 30–34.9). Logistic regression adjusted associations between WC, BMI, and hypertension prevalence for age, race, sex, region, income, education, cigarette smoking, glomerular filtration rate, alcohol use, and physical activity.
RESULTS
Overall, hypertension prevalence was 44% among those with low WC (n = 8,068), 55% with moderate WC (n = 6,488), and 66% with high WC (n = 9,691). After full adjustment, moderate WC was independently associated with hypertension prevalence among persons with normal BMI, (adjusted odds ratio (aOR), 1.49; 95% confidence interval (CI), 1.31–1.70), overweight BMI (aOR, 1.80; 95% CI, 1.64–1.98), and obese class I BMI (aOR, 2.28; 95%CI, 1.96–2.65) (referent: low WC-normal BMI). The moderate WC–hypertension association was observed in blacks and whites and in men and women.
CONCLUSION
Moderate WC is associated with hypertension prevalence independent of BMI and several hypertension risk factors in middle-aged and older adults.
doi:10.1038/ajh.2010.258
PMCID: PMC3717383  PMID: 21233800
blood pressure; clinical epidemiology; hypertension; obesity; race; waist circumference
13.  The Sensitivity of the Method Used to Detect Atrial Fibrillation in Population Studies Affects Group-Specific Prevalence Estimates: Ethnic and Regional Distribution of Atrial Fibrillation in the REGARDS Study 
Journal of Epidemiology  2009;19(4):177-181.
Background
Among African-Americans, and in southern US states, the rates of stroke are high but the reported prevalences of atrial fibrillation (AF) are low. We hypothesized that the reported ethnic and regional distributions of AF are affected by the sensitivity of the methods that were used to detect AF in previous reports.
Methods
A total of 18 833 black and white participants from the US national REasons For Geographic And Racial Differences In Stroke (REGARDS) study were included in this analysis. Levels of sensitivity to detect AF, from least to most sensitive, were created for combinations of self-report (SR) and ECG methods, as follows: (1) SR plus ECG, (2) ECG alone, (3) SR alone, and (4) SR or ECG. Geographic regions were dichotomized as Stroke Belt (the southern US states) and non-Stroke Belt. Logistic regression analysis estimated the odd ratios of AF associated with the Stroke Belt and black ethnicity for each diagnostic combination.
Results
Residence in the Stroke Belt was significantly associated with AF when diagnosed by SR plus ECG (multivariable-adjusted OR, 0.66; 95% CI, 0.47 to 0.92), but not when diagnosed with SR or ECG (OR, 0.95; 95% CI, 0.85 to 1.06). Similarly, for the 4 methods used to detect AF, the strength of the association between black ethnicity and AF progressively decreased with increasing test sensitivity (ORs: 0.20, 0.40, 0.70, 0.71, respectively).
Conclusions
The association of AF with residence in the Stroke Belt and black ethnicity was inversely related to the sensitivity of the method used to detect AF: as test sensitivity increased, the association became attenuated. This may partially explain the lower reported prevalence of AF in populations and regions with higher stroke rates.
doi:10.2188/jea.JE20081032
PMCID: PMC2750004  PMID: 19561382
atrial fibrillation; race/ethnicity; REGARDS study
14.  Gender Differences Between the Minnesota Code and Novacode Electrocardiographic Prognostication of Coronary Heart Disease in the Cardiovascular Health Study 
The American journal of cardiology  2011;107(6):817-820.e1.
The Minnesota Code (MC) and Novacode (Nova) are the most widely used electrocardiographic (ECG) classification systems. The comparative strengths of their classifications for Q- and ST-T–wave abnormalities in predicting coronary heart disease (CHD) events and total mortality have not been evaluated separately by gender. We studied standard 12-lead electrocardiograms at rest from 4,988 participants in the Cardiovascular Health Study. Average age at baseline was 73 years, 60% of participants were women 85% were white, and 22% had a history of cardiovascular disease or presence of ECG myocardial infarction by MC or Nova. Starting in 1989 with an average 17-year follow-up, 65% of participants died and 33% had incident CHD in a cohort free of cardiovascular disease at baseline. Of these, electrocardiograms with major Q-wave or major ST-T abnormalities by MC or Nova predicted increased risk for CHD events and total mortality with no significant differences in predictability between men and women. The study also found that women had fewer major Q-wave changes but more major ST-T abnormalities than men. However, there were no gender differences in predicting CHD events and total mortality. In conclusion, ECG classification systems for myocardial infarction/ischemia abnormalities by MC or Nova are valuable and useful for men and women in clinical trials and epidemiologic studies.
doi:10.1016/j.amjcard.2010.11.004
PMCID: PMC3673724  PMID: 21247534
15.  Hospital laboratory reporting may be a barrier to detection of ‘microsize’ myocardial infarction in the US: an observational study 
Background
International guidelines recommend that the decision threshold for troponin should be the 99th percentile of a normal population, or, if the laboratory assay is not sufficiently precise at this low level, the level at which the assay achieves a 10% or better coefficient of variation (CV). Our objectives were to examine US hospital laboratory troponin reports to determine whether either the 99th percentile or the 10% CV level were clearly indicated, and whether nonconcordance with these guidelines was a potential barrier to detecting clinically important microscopic or ‘microsize’ myocardial infarctions (MIs). To confirm past reports of the clinical importance of microsize MIs, we also contrasted in-hospital, 28-day and 1-year mortality among those with microsize and nonmicrosize MI.
Methods
In the REasons for Geographic And Racial Differences in Stroke national prospective cohort study (n=30,239), 1029 participants were hospitalized for acute coronary syndrome (ACS) between 2003–2009. For each case, we recorded all thresholds of abnormal troponin on the laboratory report and whether the 99th percentile or 10% CV value were clearly identified. All cases were expert adjudicated for presence of MI. Peak troponin values were used to classify MIs as microsize MI (< five times the lowest listed upper limit of normal) and nonmicrosize MI.
Results
Participants were hospitalized at 649 acute care US hospitals, only 2% of whose lab reports clearly identified the 99th percentile or the 10% CV level; 52% of reports indicated an indeterminate range, a practice that is no longer recommended. There were 183 microsize MIs and 353 nonmicrosize MIs. In-hospital mortality tended to be lower in the microsize than in the nonmicrosize MI group (1.1 vs. 3.6%, p = 0.09), but 28-day and 1-year mortality were similar (2.5% vs. 2.7% [p = 0.93] and 5.2% vs. 4.3% [p = 0.64], respectively).
Conclusions
Current practices in many US hospitals created barriers to the clinical recognition of microsize MI, which was common and clinically important in our study. Improved hospital troponin reporting is warranted.
doi:10.1186/1472-6963-13-162
PMCID: PMC3648433  PMID: 23635044
Acute coronary syndrome; Troponin; Quality control
16.  Health Professional Shortage Areas, Insurance Status, and Cardiovascular Disease Prevention in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Individuals with cardiovascular disease (CVD) living in Health Professional Shortage Areas (HPSA) may receive less preventive care than others. The Reasons for Geographic And Racial Differences in Stroke Study (REGARDS) surveyed 30,221 African American (AA) and White individuals older than 45 years of age between 2003–2007. We compared medication use for CVD prevention by HPSA and insurance status, adjusting for sociodemographic factors, health behaviors, and health status. Individuals residing in partial HPSA counties were excluded. Mean age was 64±9 years, 42% were AA, 55% were women, and 93% had health insurance; 2,545 resided in 340 complete HPSA counties and 17,427 in 1,145 non-HPSA counties. Aspirin, beta-blocker, and ACE-inhibitor use were similar by HPSA and insurance status. Compared with insured individuals living in non-HPSA counties, statin use was lower among uninsured participants living in non-HPSA and HPSA counties. Less medication use for CVD prevention was not associated with HPSA status, but less statin use was associated with lack of insurance.
doi:10.1353/hpu.2011.0127
PMCID: PMC3586412  PMID: 22080702
Health Professional Shortage Areas; cardiovascular disease; prevention; insurance status
17.  LONG-TERM EFFECTS OF CHLORTHALIDONE VS HYDROCHLOROTHIAZIDE ON ELECTROCARDIOGRAPHIC LEFT VENTRICULAR HYPERTROPHY IN THE MULTIPLE RISK FACTOR INTERVENTION TRIAL 
Hypertension  2011;58(6):1001-1007.
Chlorthalidone (CTD) reduces 24-hour blood pressure more effectively than hydrochlorothiazide (HCTZ), but whether this influences electrocardiographic left ventricular hypertrophy (LVH) is uncertain. One source of comparative data is the Multiple Risk Factor Intervention Trial (MRFIT), which randomly assigned 8,012 hypertensive men to special intervention (SI) or usual care (UC). SI participants could use CTD or HCTZ initially; previous analyses have grouped clinics by their main diuretic used (C-clinics: CTD; H-clinics: HCTZ). After 48 months, SI participants receiving HCTZ were recommended to switch to CTD, in part, because higher mortality was observed for SI compared to UC participants in H-clinics, while the opposite was found in C-clinics. In this analysis, we examined change in continuous measures of electrocardiographic LVH using both an ecologic analysis by previously-reported C- or H-clinic groupings, and an individual participant analysis where use of CTD or HCTZ by SI participants was considered and updated annually. Through 48 months, differences between SI and UC in LVH were larger for C-clinics compared to H-clinics (Sokolow-Lyon: −93.9 vs −54.9 μV, P=0.049; Cornell voltage: −68.1 vs −35.9 μV, P=0.019; Cornell voltage product: −4.6 vs −2.2 μV/ms, P=0.071; left ventricular mass: −4.4 vs −2.8 gm, P=0.002). At the individual participant level, Sokolow-Lyon and left ventricular mass were significantly lower for SI men receiving CTD compared to HCTZ through 48 months and 84 months of follow-up. Our findings on LVH support the idea that greater blood pressure reduction with CTD than HCTZ may have led to differences in mortality observed in MRFIT.
doi:10.1161/HYPERTENSIONAHA.111.181248
PMCID: PMC3245686  PMID: 22025372
hydrochlorothiazide; chlorthalidone; left ventricular hypertrophy; hypertension; blood pressure; electrocardiography
18.  Prevalence and Prognostic Significance of ECG Abnormalities in HIV-infected Patients: Results from the Strategies for Management of Antiretroviral Therapy (SMART) Study 
Journal of electrocardiology  2010;44(6):779-785.
Background
It remains debated whether to include resting electrocardiogram (ECG) in the routine care of patients infected with Human immunodeficiency virus (HIV). This is largely because data are limited regarding the prevalence and prognostic significance of ECG abnormalities in HIV-infected patients.
Methods
This analysis included 4518 HIV-infected patients (28% females and 29% blacks) from The Strategies for Management of Antiretroviral Therapy (SMART) study, a clinical trial aimed to compare two HIV treatment strategies. ECG abnormalities were classified using the Minnesota Code. Multivariable adjusted Cox proportional hazards analysis was used to examine the association between baseline ECG abnormalities and incident cardiovascular disease.
Results
More than half of the participants (N=2325, 51.5%) had either minor or major ECG abnormalities. Minor ECG abnormalities (48.6%) were more common than major ECG abnormalities (7.7%). During a median follow-up of 28.7 months, 155 (3.4%) participants developed incident cardiovascular disease. After adjusting for the study treatment arms, the presence of major, minor, and either minor or major ECG abnormalities were significantly predictive of incident cardiovascular disease [Hazard ratio (95% Confidence Interval): 2.76 (1.74, 4.39), p<0.001; 1.58 (1.14, 2.20), p=0.006; 1.57 (1.14, 2.18), p=0.006, respectively]. However, after adjusting for demographics, common cardiovascular risk factors and HIV characteristics (full model), presence of major ECG abnormalities was still significantly predictive of cardiovascular disease [1.83 (1.12, 2.97), p=0.015)], but not minor or minor or major abnormalities taken together [1.26 (0.89, 1.79), p=0.18; 1.25 (0.89, 1.76), p=0.20, respectively]. Individual ECG abnormalities that significantly predicted cardiovascular disease in the fully adjusted model included major isolated ST/T abnormalities, major prolongation of QT interval, minor isolated ST/T and minor isolated Q/QS abnormalities.
Conclusion
Nearly one in two of the HIV-infected patients in SMART study had ECG abnormalities; one in thirteen had major ECG abnormalities. Presence of ECG abnormalities, especially major ECG abnormalities was independently predictive of incident cardiovascular disease. These results suggest that the ECG could provide a convenient risk screening tool in HIV-infected patients.
doi:10.1016/j.jelectrocard.2010.10.027
PMCID: PMC3060290  PMID: 21145066
HIV/AIDS; ECG; Cardiovascular Disease; SMART Study
19.  Inflammation, Coagulation and Cardiovascular Disease in HIV-Infected Individuals 
PLoS ONE  2012;7(9):e44454.
Background
The SMART study was a trial of intermittent use of antiretroviral therapy (ART) (drug conservation [DC]) versus continuous use of ART (viral suppression [VS]) as a strategy to reduce toxicities, including cardiovascular disease (CVD) risk. We studied the predictive value of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer with CVD morbidity and mortality in HIV-infected patients who were enrolled in SMART beyond other measured CVD risk factors.
Methods
A blood sample was available in 5098 participants who were enrolled in the SMART study for the measurement of IL-6, hsCRP and D-dimer. Hazard ratios (HR) with 95% CI for CVD events were estimated for each quartile (Q) for each biomarker vs the 1st quartile and for 1 SD higher levels. For both treatment groups combined, unadjusted and adjusted HRs were determined using Cox regression models.
Results
There were 252 participants who had a CVD event over a median follow-up of 29 months. Adjusted HRs (95% CI) for CVD for Q4 vs Q1 were 4.65 (2.61, 8.29), 2.10 (1.40, 3.16), and 2.14 (1.38, 3.33) for IL-6, hsCRP and D-dimer, respectively. Associations were similar for the DC and VS treatment groups (interaction p-values were >0.30). The addition of the three biomarkers to a model that included baseline covariates significantly improved model fit (p<0.001). Area under the curve (AUC) estimates improved with inclusion of the three biomarkers in a model that included baseline covariates corresponding to other CVD risk factors and HIV factors (0.741 to 0.771; p<0.001 for difference).
Conclusions
In HIV-infected individuals, IL-6, hsCRP and D-dimer are associated with an increased risk of CVD independent of other CVD risk factors. Further research is needed to determine whether these biomarkers can be used to improve CVD risk prediction among HIV positive individuals.
doi:10.1371/journal.pone.0044454
PMCID: PMC3438173  PMID: 22970224
20.  Awareness and management of chronic disease, insurance status, and health professional shortage areas in the REasons for Geographic And Racial Differences in Stroke (REGARDS): a cross-sectional study 
Background
Limited financial and geographic access to primary care can adversely influence chronic disease outcomes. We examined variation in awareness, treatment, and control of hypertension, diabetes, and hyperlipidemia according to both geographic and financial access to care.
Methods
We analyzed data on 17,458 participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study with either hypertension, hyperlipidemia, or diabetes and living in either complete Health Professional Shortage Area (HPSA) counties or non-HPSA counties in the U.S. All analyses were stratified by insurance status and adjusted for sociodemographics and health behaviors.
Results
2,261 residents lived in HPSA counties and 15,197 in non-HPSA counties. Among the uninsured, HPSA residents had higher awareness of both hypertension (adjusted OR 2.30, 95% CI 1.08, 4.89) and hyperlipidemia (adjusted OR 1.50, 95% CI 1.01, 2.22) compared to non-HPSA residents. Also among the uninsured, HPSA residents with hypertension had lower blood pressure control (adjusted OR 0.45, 95% CI 0.29, 0.71) compared with non-HPSA residents. Similar differences in awareness and control according to HPSA residence were absent among the insured.
Conclusions
Despite similar or higher awareness of some chronic diseases, uninsured HPSA residents may achieve control of hypertension at lower rates compared to uninsured non-HPSA residents. Federal allocations in HPSAs should target improved quality of care as well as increasing the number of available physicians.
doi:10.1186/1472-6963-12-208
PMCID: PMC3571909  PMID: 22818296
21.  Myocardial Infarction after Carotid Stenting and Endarterectomy: Results from the Carotid Revascularization Endarterectomy versus Stenting Trial 
Circulation  2011;123(22):2571-2578.
BACKGROUND
The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) found a higher risk of stroke after carotid artery stenting and a higher risk of myocardial infarction (MI) after carotid endarterectomy.
METHODS AND RESULTS
Cardiac biomarkers and ECGs were performed before and 6 to 8 hours after either procedure and if there was clinical evidence of ischemia. In CREST, MI was defined as biomarker elevation plus either chest pain or ECG evidence of ischemia. An additional category of biomarker elevation with neither chest pain nor ECG abnormality was prespecified (biomarker+ only). Crude mortality and risk-adjusted mortality for MI and biomarker+ only were assessed during follow-up. Among 2502 patients, 14 MIs occurred in carotid artery stenting and 28 MIs in carotid endarterectomy (hazard ratio, 0.50; 95% confidence interval, 0.26 to 0.94; P=0.032) with a median biomarker ratio of 40 times the upper limit of normal. An additional 8 carotid artery stenting and 12 carotid endarterectomy patients had biomarker+ only (hazard ratio, 0.66; 95% confidence interval, 0.27 to 1.61; P=0.36), and their median biomarker ratio was 14 times the upper limit of normal. Compared with patients without biomarker elevation, mortality was higher over 4 years for those with MI (hazard ratio, 3.40; 95% confidence interval, 1.67 to 6.92) or biomarker+ only (hazard ratio, 3.57; 95% confidence interval, 1.46 to 8.68). After adjustment for baseline risk factors, both MI and biomarker+ only remained independently associated with increased mortality.
CONCLUSIONS
In patients randomized to carotid endarterectomy versus carotid artery stenting, both MI and biomarker+ only were more common with carotid endarterectomy. Although the levels of biomarker elevation were modest, both events were independently associated with increased future mortality and remain an important consideration in choosing the mode of carotid revascularization or medical therapy.
CLINICAL TRIAL REGISTRATION INFORMATION
ClinicalTrials.gov number NCT00004732
doi:10.1161/CIRCULATIONAHA.110.008250
PMCID: PMC3173718  PMID: 21606394
Carotid arteries; carotid artery stenting; carotid endarterectomy; myocardial infarction; prognosis
22.  Agreement on Cause of Death Between Proxies, Death Certificates, and Clinician Adjudicators in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
American Journal of Epidemiology  2011;173(11):1319-1326.
Death certificates may lack accuracy and misclassify the cause of death. The validity of proxy-reported cause of death is not well established. The authors examined death records on 336 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study, a national cohort study of 30,239 community-dwelling US adults (2003–2010). Trained experts used study data, medical records, death certificates, and proxy reports to adjudicate causes of death. The authors computed agreement on cause of death from the death certificate, proxy, and adjudication, as well as sensitivity and specificity for certain diseases. Adjudicated cause of death had a higher rate of agreement with proxy reports (73%; Cohen's kappa (κ) statistic = 0.69) than with death certificates (61%; κ = 0.54). The agreement between proxy reports and adjudicators was better than agreement with death certificates for all disease-specific causes of death. Using the adjudicator assessments as the “gold standard,” for disease-specific causes of death, proxy reports had similar or higher specificity and higher sensitivity (sensitivity = 50%–89%) than death certificates (sensitivity = 31%–81%). Proxy reports may be more concordant with adjudicated causes of death than with the causes of death listed on death certificates. In many settings, proxy reports may represent a better strategy for determining cause of death than reliance on death certificates.
doi:10.1093/aje/kwr033
PMCID: PMC3101067  PMID: 21540327
cause of death; death certificates; epidemiologic methods; prospective studies; proxy
23.  Relation of Cardiac Ventricular Repolarization and Global Cognitive Performance in a Community Population 
The American journal of cardiology  2010;106(8):1169-1173.
Atherosclerosis is a risk factor for dementia. Yet little is known about the association between cognitive performance and a widely used indicator of coronary heart disease, the resting electrocardiogram (ECG). We identified 839 older residents (mean age 81; 58% black) from a geographically defined biracial community in Chicago, Illinois, who underwent extensive cognitive performance testing and met ECG eligibility criteria, including a QRS duration less than 120 msec. We then examined multivariable regression coefficients that describe associations between global cognitive performance and 4 novel descriptors of ventricular repolarization waveforms. All analyses were adjusted for age, sex, education, and race. T wave non-dipolar voltage had a significant association with global cognitive performance (p = 0.01), and this association largely remained after adjustment for cardiovascular disease risk factors (p = 0.03). In contrast, global cognitive performance was not significantly associated with the rate-adjusted QT interval, the voltage change from beginning to end of the ST segment in lead V5, or the spatial angle between mean QRS and T wave vectors. In conclusion, strengths of associations varied between novel ECG descriptors of ventricular repolarization and global cognitive performance. Nevertheless, the significant association observed with T wave non-dipolar voltage suggests that the cardiac effects of heart disease are associated with cognitive decline.
doi:10.1016/j.amjcard.2010.06.031
PMCID: PMC2955511  PMID: 20920659
cognitive performance; ventricular repolarization; T wave non-dipolar voltage
24.  Genome-wide association analysis identifies multiple loci related to resting heart rate 
Eijgelsheim, Mark | Newton-Cheh, Christopher | Sotoodehnia, Nona | de Bakker, Paul I.W. | Müller, Martina | Morrison, Alanna C. | Smith, Albert V. | Isaacs, Aaron | Sanna, Serena | Dörr, Marcus | Navarro, Pau | Fuchsberger, Christian | Nolte, Ilja M. | de Geus, Eco J.C. | Estrada, Karol | Hwang, Shih-Jen | Bis, Joshua C. | Rückert, Ina-Maria | Alonso, Alvaro | Launer, Lenore J. | Hottenga, Jouke Jan | Rivadeneira, Fernando | Noseworthy, Peter A. | Rice, Kenneth M. | Perz, Siegfried | Arking, Dan E. | Spector, Tim D. | Kors, Jan A. | Aulchenko, Yurii S. | Tarasov, Kirill V. | Homuth, Georg | Wild, Sarah H. | Marroni, Fabio | Gieger, Christian | Licht, Carmilla M. | Prineas, Ronald J. | Hofman, Albert | Rotter, Jerome I. | Hicks, Andrew A. | Ernst, Florian | Najjar, Samer S. | Wright, Alan F. | Peters, Annette | Fox, Ervin R. | Oostra, Ben A. | Kroemer, Heyo K. | Couper, David | Völzke, Henry | Campbell, Harry | Meitinger, Thomas | Uda, Manuela | Witteman, Jacqueline C.M. | Psaty, Bruce M. | Wichmann, H-Erich | Harris, Tamara B. | Kääb, Stefan | Siscovick, David S. | Jamshidi, Yalda | Uitterlinden, André G. | Folsom, Aaron R. | Larson, Martin G. | Wilson, James F. | Penninx, Brenda W. | Snieder, Harold | Pramstaller, Peter P. | van Duijn, Cornelia M. | Lakatta, Edward G. | Felix, Stephan B. | Gudnason, Vilmundur | Pfeufer, Arne | Heckbert, Susan R. | Stricker, Bruno H.Ch. | Boerwinkle, Eric | O'Donnell, Christopher J.
Human Molecular Genetics  2010;19(19):3885-3894.
Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38 991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and ∼2.5 million markers. Results with P < 5 × 10−8 were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain ∼0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10−5 increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.
doi:10.1093/hmg/ddq303
PMCID: PMC3657480  PMID: 20639392
25.  Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals 
PLoS Genetics  2011;7(6):e1002158.
Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).
Author Summary
Family studies have clearly demonstrated a role for genes in modifying risk for sudden cardiac death (SCD), however genetic studies have been limited by available samples. Here we have assembled over 4,400 SCD cases with >30,000 controls, all of European ancestry, and utilize a two-stage study design. In the first stage, we conducted an unbiased genome-wide scan in 1,283 SCD cases and >20,000 controls, and then performed follow-up genotyping in the remainder of the samples. We demonstrate strong association to a region of the genome not previously implicated in SCD, the BAZ2B locus, which contains 3 genes not previously known to play a role in cardiac biology. In addition, we used the genome-wide scan data to test a focused hypothesis that genetic variants that modulate ECG traits associated with SCD (QT, QRS, and RR intervals) also modify risk for SCD, and we demonstrate that QT- and QRS-prolonging alleles are, as a group, associated with increased risk of SCD. Taken together, these findings begin to elucidate the genetic contribution to SCD susceptibility and provide important targets for functional studies to investigate the etiology and pathogenesis of SCD.
doi:10.1371/journal.pgen.1002158
PMCID: PMC3128111  PMID: 21738491

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