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1.  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
2.  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
3.  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
4.  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
5.  Electrocardiographic Spatial QRS-T Angle and Incident Cardiovascular Disease in HIV-Infected Individuals (From the Strategies for the Management of Antiretroviral Therapy [SMART] Study) 
The American journal of cardiology  2012;111(1):118-124.
Widening of the electrocardiographic [ECG] spatial QRS-T angle has been predictive of cardiovascular disease [CVD] events in the general population. However, its prognostic significance in HIV-infected individuals remains unknown. Spatial QRS-T angle was derived from the baseline ECG of 4453 HIV-infected patients aged 43.5 (SD 9.3) years from the Strategies for Management of Antiretroviral Therapy [SMART] trial. CVD events were identified during a median follow up of 28.7 months. Quartiles of spatial QRS-T angle was calculated for males and females separately, and values in the upper quartile were considered as widened angle (values above 74° for women and 93° for men). Multivariable Cox proportional hazards analysis was used to examine the association between widened baseline spatial QRS-T angle and incident CVD events. During 11965 person-years of follow-up, 152 CVD events occurred at a rate of 1.27 events per 100 person-years. The rate of CVD events in individuals with widened spatial QRS-T angle was almost double the rate in those with normal spatial QRS-T angle [Rate ratio (95% CI) of 1.94 (1.40, 2.69); p <0.001]. In a model adjusted for study treatment arm, demographics, CVD risk factors, HIV characteristics, inflammatory markers and other ECG abnormalities, widened spatial QRS-T angle was associated with more than 50% increased risk of CVD events compared to normal spatial QRS-T angle [Hazard ratio (95% CI): 1.53 (1.07, 2.17); p= 0.02]. There was no interaction by SMART trial arms [p-value for interaction 0.37] or by gender [p-value for interaction 0.84]. In Conclusion, widened spatial QRS-T angle is independently predictive of CVD events in HIV-infected patients on antiretroviral therapy. This highlights the potential role of routine ECG as a simple non-invasive CVD risk-screening tool in HIV-infected individuals.
PMCID: PMC3525800  PMID: 23062314
Spatial QRS-T angle; Electrocardiogram; HIV/AIDS
7.  Prolongation of QTc interval and risk of stroke: the REasons for Geographic and Racial Differences in Stroke (REGARDS) 
To examine the association between prolongation of heart rate–corrected QT interval (QTc) with incident stroke.
Unlike cardiovascular morbidity and mortality, little is known about the relationship between QTc and risk of stroke.
A total of 27,411 participants aged ≥ 45 years without prior stroke from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study were included in this analysis. QTc was calculated using Framingham formula (QTcFram). Stroke cases were identified and adjudicated during up to 8.2 years of follow-up (median 5.1 years).
The risk of incident stroke in study participants with prolonged QTcFram was almost three times the risk in those with normal QTcFram [HR (95% CI): 2.88 (2.12, 3.92), p<0.0001]. After adjustment for demographics (age, race, sex), traditional stroke risk factors (antihypertensive medication use, systolic blood pressure, current smoking, diabetes, left ventricular hypertrophy, atrial fibrillation, prior cardiovascular disease), warfarin use, aspirin use, QRS duration and use of QT-prolonging drugs, the risk of stroke remained significantly high [HR (95% CI): 1.67 (1.16, 2.41), p=0.0061)], and was consistent across several subgroups of REGARDS participants. Similar results were obtained when the risk of stroke was estimated per 1-standard deviation increase in QTcFram, [HR (95% CI): 1.12 (1.03, 1.21), p=0.0053 in multivariable-adjusted model], and when other QTc correction formulas including Hodge’s, Bazett’s and Fridericia’s were used.
QTc prolongation is associated with a significantly increased risk of incident stroke independent of traditional stroke risk factors. Examining the risk of stroke associated with QT-prolonging drugs may be warranted.
PMCID: PMC3345207  PMID: 22497826
QTc; stroke; electrocardiogram; QT-prolonging drugs; REGARDS
8.  Protease inhibitors and cardiac autonomic function in HIV-infected patients: a cross-sectional analysis from the Strategies for Management of Antiretroviral Therapy (SMART) Trial 
BMJ Open  2013;3(3):e002523.
To compare cardiac autonomic function as measured by heart rate variability for HIV-infected participants taking protease inhibitors (PIs) with those taking a non-nucleoside reverse transcriptase inhibitor without a PI (NNRTI-no PI) regimen.
Cross-sectional analysis.
Multicentre study.
2998 participants (average age 44 years, 28% females) enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) trial.
Primary outcome measures
Heart rate and two heart rate variability measures (the SD of all filtered RR intervals over the length of the recording (SDNN) and the root mean square of successive differences in normal RR intervals (rMSSD)).
At study entry, 869 participants were taking a boosted PI (PI/r), 579 a non-boosted PI and 1550 an NNRTI-no PI. Median values (IQR) of heart rate, SDNN and rMSSD were: 68 (60–75) beats/min (bpm), 21 (13–33) ms, 22 (13–35) ms in the PI/r group, 68 (60–75) bpm, 21 (13–33) ms and 21 (14–33) ms in the non-boosted PI group and 69 (62–77) bpm, 20 (13–31) ms and 21(13–33) ms in the NNRTI-no PI group. After adjustment for baseline factors, for those given PI/r and non-boosted PI, heart rate was 2.2 and 2.8 bpm, respectively, lower than the NNRTI-no PI group (p<0.001 for both). On the other hand, compared with the NNRTI-no PI group, log SDNN and log rMSSD were significantly greater for those in the non-boosted PI (p values for baseline adjusted differences in log-transformed SDNN and rMSSD were 0.004 and 0.001) but not for those in the PI/r group at the 0.01 α-level.
Compared to an NNRTI-no PI regimen, heart rate was lower for those taking a PI/r or non-boosted PI and heart rate variability was greater, reflecting better cardiac autonomic function, for those taking a non-boosted PI regimen but not PI/r.
PMCID: PMC3612790  PMID: 23471611
Virology; Cardiology; Clinical Pharmacology
9.  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.
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.
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.
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.
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.
PMCID: PMC3060290  PMID: 21145066
HIV/AIDS; ECG; Cardiovascular Disease; SMART Study
10.  Self-reported atrial fibrillation and risk of stroke in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study 
Background and Purpose
We compared the associations of self-reported atrial fibrillation (SR-AF) and electrocardiogram-detected AF (ECG-AF) with incident stroke in the REGARDS study.
27,109 participants aged ≥45 years without prior stroke were included in this analysis. Stroke cases were identified and adjudicated during an average of 4.4 years of follow-up. Cox proportional hazards analysis was used to calculate hazard ratios of SR-AF, ECG-AF, and AF detected by either method with incident stroke. We also examined the predictive ability of the Framingham Stroke Risk Score (FSRS) where the component AF was defined by different methods.
After adjustment for components of the FSRS, SR-AF, ECG-AF, and AF by either method were predictive of incident stroke [HR (95% CI): 1.41 (1.05,1.88), 1.90 (1.10,3.27), 1.53 and (1.16,2.01), respectively]. When self-report, ECG or either method, separately, were considered as the method of AF ascertainment in the FSRS, the Hazard ratios per 1% increase in the FSRS were identical across AF ascertainment methods [1.04 (1.03,1.04); 1.04 (1.04,1.05); 1.04 (1.03,1.04) respectively].
SR-AF is a strong predictor of stroke that can be used interchangeably or in combination with ECG-AF in stroke risk prediction models.
PMCID: PMC3185239  PMID: 21817138
Atrial fibrillation; self-report; Electrocardiogram
11.  Boosted protease inhibitors and the electrocardiographic measures of QT and PR durations 
AIDS (London, England)  2011;25(3):367-377.
There are contradictory reports regarding the effects of protease inhibitors on the ECG measures of QT and PR interval durations. The effect of interrupting use of protease inhibitors on QT and PR progression is also unknown.
This analysis included 3719 participants from the Strategies for Management of Antiretroviral Therapy (SMART) study, of whom 1879 were randomized to receive intermittent antiretroviral therapy (ART) (drug conservation group), whereas the rest received these drugs continuously (viral suppression group). Linear regression analysis was used to compare four ritonavir-boosted protease inhibitor (protease inhibitor/r) regimens [saquinavir (SQV/r), lopinavir (LPV/r), atazanavir (ATV/r), and other protease inhibitor/r], and nonboosted protease inhibitor regimens with nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens for Bazett’s (QTcB) and Fredericia’s (QTcF) heart rate corrected QT and PR. Changes in QTcB, QTcF, and PR after 12 and 24 months of randomization were compared in the drug conservation group and viral suppression group.
Average levels of QTcB, QTcF, and PR duration at entry were 415, 406, and 158 ms. At study entry, 49% of participants were taking an NNRTI (no protease inhibitor)-based regimen and 31% were prescribed a boosted protease inhibitor, the most common being LPV/r. After adjustment for baseline factors, QTcB and QTcF levels did not vary by boosted protease inhibitor group (P = 0.26 and P = 0.34, respectively). For those given any of the boosted protease inhibitors, QTcB was 1.5 ms lower than the NNRTI group (P = 0.04). Both boosted and nonboosted protease inhibitor-containing regimens were significantly associated (P <0.01 for each) with longer PR intervals compared to the NNRTI group. After adjustment, the difference between boosted protease inhibitors and the NNRTI group was 5.11 ms (P <0.01); for nonboosted protease inhibitors, this difference was 3.00 ms (P <0.01). Following ART interruption, PR duration declined for both the boosted and nonboosted protease inhibitor groups and compared to the viral suppression group, significant changes in PR interval were observed 24 months after ART interruption of boosted protease inhibitors (P <0.01).
Different protease inhibitor-based regimens have a similar, minimal effect on QT compared to NNRTI-based regimens. All protease inhibitor-based regimens (boosted and nonboosted) were associated with prolongation of PR, and interruption of protease inhibitor regimens reduced the prolonged PR duration. Further research is needed to confirm the findings of this study and assess the clinical relevance of the differences.
PMCID: PMC3111078  PMID: 21150558
electrocardiogram; HIV/AIDS; PR; protease inhibitors; QTc
12.  Chronic Kidney Disease and Prevalent Atrial Fibrillation: The Chronic Renal Insufficiency Cohort (CRIC) 
American heart journal  2010;159(6):1102-1107.
The epidemiology of atrial fibrillation (AF) has been mainly investigated in patients with end-stage renal disease (ESRD), with limited data on less advanced chronic kidney disease (CKD) stages.
A total of 3267 adult participants (50% non-Hispanic blacks, 46% females) with CKD from the Chronic Renal Insufficiency Cohort (CRIC) were included in this study. None of the study participants had been on dialysis. Those with self-identified race/ethnicity other than non-Hispanic black or white (N=323) or those without ECG data (N=22) were excluded. AF was ascertained by a 12-lead electrocardiogram (ECG) and self-report. Age- sex- race/ethnicity-specific prevalence rates of AF were estimated and compared between subgroups. Cross sectional associations and correlates with prevalent AF were examined using unadjusted and multivariable adjusted logistic regression analysis.
The mean estimated glomerular filtration rate (GFR) was 43.6 (±13.0) ml/min/1.73 m2. AF was present in 18% of the study population and in more than 25% of those 70 years or older. In multivariable adjusted models, 1-SD increase in age (11 years) [odds ratio (OR) and CI 95%: 1.27 (1.13, 1.43), P<0.0001], female sex [0.80 (0.65, 0.98), P=0.0303], smoking (former vs. never) [1.34 (1.08, 1.66), P= 0.0081], history of heart failure [3.28 (2.47, 4.36), P<0.001], and history of cardiovascular disease [1.94 (1.56, 2.43), P<0.0001] were significantly associated with AF. Race/ethnicity, hypertension, diabetes, body mass index, physical activity, education, high sensitivity C-reactive protein, total cholesterol, and alcohol intake were not significantly associated with AF. An estimated GFR <45 ml/min/1.73 m2 was associated with AF in an unadjusted model [1.35 (1.13–1.62)); P=0.0010)], but not after multivariable adjustment [1.12 (0.92– 1.35), P=0.2710].
Nearly one in five participants in CRIC, a national study of CKD, had evidence for AF at study entry, a prevalence similar to that reported among patients with ESRD and 2–3 times of that reported in the general population. Risk factors for AF in this CKD population do not mirror those reported in the general population.
PMCID: PMC2891979  PMID: 20569726
13.  Calculating Cornell Voltage from Nonstandard Chest Electrode Recording site in the Reasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
Journal of electrocardiology  2009;43(3):209-214.
To minimize participants’ burden and the need for disrobing, a 7-lead electrocardiogram (ECG) recording using a single mid-sternal chest lead was recorded at the initial stages of The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study. ECG-detected left ventricular hypertrophy (ECG-LVH) by Cornell voltage (RaVL +SV3) cannot be assessed from this method because of the absence of V3. We examined the possibility that the S wave amplitude in the mid-sternal lead (SV) could be used as a surrogate for SV3.
The REGARDS study is a US national study where 7-lead ECGs were performed in 8,330 (29%) participants and standard 12-lead EGCs were performed in 20,811 (71%). Cornell voltage was calculated as the sum of aVL amplitude + SV (in the 7-lead group) or SV3 (in the 12-lead group). Logistic regression analysis was used to examine and compare the magnitude of the association between the LVH risk factors with ECG-LVH in both groups, and Cox Proportional Hazards analysis was used to examine and compare the hazard ratios of overall mortality and cardiovascular mortality associated with ECG-LVH in both groups.
Regardless of the Cornell voltage calculation method, ECG-LVH was significantly associated with LVH risk factors, and with the exception of sex there was no evidence of a difference in the magnitude of the association. ECG-LVH from both approaches were significantly and similarly associated with both all cause and cardiovascular mortality.
ECG-LVH by Cornell voltage calculated from a 7-lead ECG (using SV in the formula) has demographic and clinical associations that are similar to that calculated from a standard 12-lead ECG (using SV3). In epidemiologic studies recording 7-lead ECG, SV could be used as an alternative to SV3 in the Cornell voltage formula.
PMCID: PMC2856789  PMID: 20004413
14.  Association Between Carotid Intima-Media Thickness and Pericardial Fat in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Carotid intima-media thickness (IMT) is a sub-clinical marker of atherosclerosis and a strong predictor of stroke. Pericardial fat (PF), the fat depot around the heart, has been associated with several atherosclerosis risk factors. We sought to examine the association between carotid IMT and PF, and to examine whether such an association is independent from common atherosclerosis risk factors including measures of overall adiposity.
Unadjusted and multivariable adjusted linear regression analysis was used to examine associations between common (CCA-IMT) and internal (ICA-IMT) carotid IMT with PF in a random sample of 996 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent carotid ultrasound and chest CT at baseline examination.
A significant positive correlation was observed between PF and CCA-IMT (r =0.27, P<0.0001) and ICA-IMT (r =0.17, P<0.0001). In an unadjusted sex-specific linear regression analysis, there was a significant association between PF (1-SD difference) and CCA-IMT (mm) in both women (β coefficient (95% CI): 0.06 (0.04, 0.08), P<0.0001) and men (0.03 (0.01, 0.05), P<0.0002), an association that persisted after further adjusting for age and ethnicity (0.02 (+0.00, 0.04), P=0.0120 for women, and 0.02 (+0.00, 0.03), P=0.0208 for men). However, after additional adjustment for atherosclerosis risk factors and either BMI or waist circumference, these relations were no longer significant in either sex. In similar analyses, PF was significantly associated with ICA-IMT in both men (0.11 (0.06, 0.15), P<0.0001) and women (0.08 (0.02, 0.13), P=041). These relations were no longer significant in women in multivariable adjusted models, but persisted in men in all models except after adjusting for age, ethnicity and waist circumference.
In the general population PF is associated with carotid IMT, an association that possibly not independent from markers of overall adiposity or common atherosclerosis risk factors.
PMCID: PMC2817960  PMID: 20123228
15.  Ethnic Distribution of ECG Predictors of Atrial Fibrillation and Its Impact on Understanding the Ethnic Distribution of Ischemic Stroke in the Atherosclerosis Risk in Communities (ARIC) Study 
Background and Purpose
The paradox of the reported low prevalence of atrial fibrillation (AF) in blacks compared with whites despite higher stroke rates in the former could be related to limitations in the current methods used to diagnose AF in population-based studies. Hence, this study aimed to use the ethnic distribution of ECG predictors of AF as measures of AF propensity in different ethnic groups.
The distribution of baseline measures of P-wave terminal force, P-wave duration, P-wave area, and PR duration (referred to as AF predictors) were compared by ethnicity in 15 429 participants (27% black) from the Atherosclerosis Risk in Communities (ARIC) study by unpaired t test, χ2, and logistic-regression analysis, as appropriate. Cox proportional-hazards analysis was used to separately examine the association of AF predictors with incident AF and ischemic stroke.
Whereas AF was significantly less common in blacks compared with whites (0.24% vs 0.95%, P<0.0001), similar to what has been reported in previous studies, blacks had significantly higher and more abnormal values of AF predictors (P<0.0001 for all comparisons). Black ethnicity was significantly associated with abnormal AF predictors compared with whites; odds ratios for different AF predictors ranged from 2.1 to 3.1. AF predictors were significantly and independently associated with AF and ischemic stroke with no significant interaction between ethnicity and AF predictors, findings that further justify using AF predictors as an earlier indicator of future risk of AF and stroke.
There is a disconnect between the ethnic distribution of AF predictors and the ethnic distribution of AF, probably because the former, unlike the latter, do not suffer from low sensitivity. These results raise the possibility that blacks might actually have a higher prevalence of AF that might have been missed by previous studies owing to limited methodology, a difference that could partially explain the greater stroke risk in blacks.
PMCID: PMC2685189  PMID: 19213946
atrial fibrillation; ischemic stroke; electrocardiogram; ethnicity
17.  Subclinical Myocardial Injury Identified by Cardiac Infarction/Injury Score and the Risk of Mortality in Men and Women Free of Cardiovascular Disease 
The American journal of cardiology  2014;114(7):1018-1023.
Previous studies have explored the ability of the Cardiac Infarction/Injury Score (CIIS) to identify individuals who are high-risk for cardiovascular disease (CVD) mortality. However, its prognostic significance among those without CVD in the United States general population has not been established. This analysis included 6,298 participants (mean age: 59 ± 13 years; 53% female; 51% non-whites) from the Third National Health and Nutrition Examination Survey (NHANES III), excluding participants with a history of CVD or electrocardiographic evidence of old myocardial infarction or ischemic ST depression at baseline. Subclinical myocardial injury was defined as CIIS ≥10. Mortality data were ascertained using the National Death Index. Cox proportional-hazards regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for association between subclinical myocardial injury with CVD and all-cause mortalities. Subclinical myocardial injury was detected in 1,376 (22%) participants. A total of 1,928 deaths occurred during a median of 14 years follow-up, of which 765 (40%) were due to CVD. In a multivariable model adjusted for demographics, traditional CVD risk factors, and other medical comorbidities, subclinical myocardial injury was associated with an increased risk of CVD (HR=1.26, 95%CI=1.02, 1.56) and all-cause (HR=1.42, 95%CI=1.23, 1.63) mortalities. In conclusion, subclinical myocardial injury in persons without manifestations of CVD is associated with an increased risk of CVD and all-cause mortalities. These findings highlight the important role of CIIS to identify subclinical myocardial injury and its association with mortality among men and women in the United States.
PMCID: PMC4336466  PMID: 25129878
electrocardiography; mortality; epidemiology
18.  Long Term Mortality Risk in Individuals with Atrial or Ventricular Premature Complexes– Results From The Third National Health And Nutrition Examination Survey (NHANES III) 
Premature ectopic beats are frequently detected on routine 12-lead screening-electrocardiogram (ECG). However, their prognostic importance in individuals without known cardiovascular disease (CVD) is not well established. We evaluated prognostic value of atrial premature complexes (APC’s) and ventricular premature complexes (VPC’s) detected by a single 12-lead-ECG. A prospective cohort of 7504 participants selected from nationally-representative, community-dwelling individuals living in United States, enrolled in the Third Health and Nutrition Examination Survey (NHANES-III) from 1988 – 94 with follow up through December 2006 without known CVD. The main outcomes were all – cause mortality, CVD related mortality and IHD related mortality. Out of 7504 participants (mean age 60 ± 14 years, 47% women, 49% whites), 89 (1.2%) had APC’s and 110 (1.5%) had VPC’s on 12 – lead ECG. During a follow up of up to 18 years, 2386 deaths occurred, of which 963 were due to CVD and 511 were due to IHD. In a multivariable adjusted for demographics, clinical variables and ECG measures, APC’s were significantly associated with all-cause mortality [HR, 1.41 (95% CI, 1.08–1.80)], CVD death [HR, 1.78 (95% CI, 1.26–2.44)] and IHD death [HR, 2.40 (95% CI, 1.59–3.47)]. For VPCs, however, there were no significant associations with all – cause mortality [HR, 1.05 (95% CI, 0.80–1.36)], CVD death [HR, 0.96 (95% CI, 0.62–1.43)] and IHD death [HR, 0.89 (95% CI, 0.47–1.52)]. In conclusion, APC’s, but not VPC’s, on routine screening ECG are predictive of adverse events in community-dwelling individuals without known CVD.
PMCID: PMC4334655  PMID: 24819898
Ventricular premature complex; atrial premature complex; mortality; cardiovascular disease mortality; ischemic heart disease mortality
19.  Prognostic Value of Frontal QRS-T Angle in Patients without Clinical Evidence of Cardiovascular Disease (From the Multi-Ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2013;112(12):10.1016/j.amjcard.2013.08.017.
Abnormal frontal QRS-T angle on a 12 lead electrocardiogram (ECG) is associated with incident coronary heart disease and total mortality in a biracial cohort but there have been no studies to date examining QRS-T angle’s prognostic value across multiple ethnicities. We studied 6,814 participants (52.7% women, mean age 62) from MESA; a multi-ethnic cohort aged 45–84 free of clinical cardiovascular disease (CVD) at enrollment. Baseline examination included measurement of traditional risk factors and 12-lead ECG’s. Frontal QRS-T axis was defined as normal (<75th percentile), borderline (75–95th percentile) or abnormal (≥ 95th percentile) and participants were followed for the composite endpoint of incident CVD events: cardiovascular death, myocardial infarction, angina pectoris or heart failure. After 7.6 years of follow up there were 444 total events. Borderline ((HR 1.37 95% Confidence Interval (CI) (1.10,1.70)) and abnormal QRS-T angle (HR 2.2 95% CI (1.63, 2.97)) was associated with incident CVD events in multivariable-adjusted models. However, after adjusting for T wave abnormalities there was no statistically significant association of either borderline (HR 1.12 95% CI (0.90, 1.41)) or abnormal (HR 1.31 95% CI (0.93, 1.84)) QRS-T angle with incident CVD events. Abnormal frontal QRS-T angle predicts incident CVD events in a multiethnic population and this increased risk is primarily mediated through T wave abnormalities. QRS-T angle provides an easily interpretable, continuous marker of abnormal ventricular repolarization that can aid the everyday clinician in risk prediction.
PMCID: PMC3863114  PMID: 24063831
Electrocardiography; risk assessment; cardiovascular disease
20.  Heart Rate Variability is a Predictor of Mortality in CKD - A Report from the CRIC Study 
American journal of nephrology  2013;38(6):517-528.
Low heart rate variability (HRV) is a risk factor for adverse outcomes in the general population. We aimed to determine the factors associated with HRV and evaluate the association between low HRV and clinical outcomes in patients with chronic kidney disease (CKD).
A 10 second electrocardiogram was obtained at baseline in the Chronic Renal Insufficiency Cohort (CRIC) Study. HRV was measured by the standard deviation of all R-R intervals (SDNN) and the root mean square of successive differences between R-R intervals (RMSSD).
In 3245 CRIC participants with available baseline SDNN and RMSSD, lower HRV was associated with older age, lack of exercise, heart failure, elevated phosphorus and hemoglobin A1c, and low estimated glomerular filtration rate. After a median follow-up of 4.2 years, in fully adjusted models, lower HRV was not associated with renal (SDNN: HR=0.96 (95% CI 0.88–1.05); RMSSD: HR=0.97 (95% CI 0.88–1.07)) or cardiovascular outcomes (SDNN: HR=1.02 (95% CI 0.92–1.13); RMSSD: HR=1.00 (95% CI 0.90–1.10)). There was a non-linear relationship between RMSSD and all-cause mortality with increased risk with both low and high RMSSD (P=0.04).
In a large cohort of participants with CKD, multiple risk factors for renal and cardiovascular disease were associated with lower HRV. Lower HRV was not associated with increased risk for renal or cardiovascular outcomes, but both low and high RMSSD were associated with increased risk for all-cause mortality. In conclusion, HRV as measured by RMSSD may be a novel and independent risk factor for mortality in CKD patients.
PMCID: PMC3920657  PMID: 24356377
electrocardiography; autonomic nervous system; chronic renal insufficiency; cardiovascular diseases; mortality
21.  Serum and dietary magnesium and the incidence of atrial fibrillation in whites and African Americans: the Atherosclerosis Risk in Communities (ARIC) Study 
Low serum magnesium (Mg) has been associated with an increased risk of cardiovascular disease (CVD), including ventricular arrhythmias. However, the association between serum or dietary Mg and AF has not been investigated.
Methods and Results
We studied 14,290 men and women (75% white, 53% women, mean age 54) free of AF at baseline participating in the Atherosclerosis Risk in Communities study in the United States. Incident AF cases through 2009 were ascertained from electrocardiograms, hospital discharge codes, and death certificates. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for AF associated with serum and dietary Mg quintiles. Over a median follow-up time of 20.6 years, 1,755 incident AF cases were identified. In multivariable models, lower serum Mg was associated with higher AF risk: compared to individuals in the middle quintile (≥1.60–1.65 mEq/L), the HR (95% CI) of AF in quintiles 1, 2, 4, and 5 were 1.34 (1.16–1.54), 0.99 (0.85–1.16), 1.04 (0.90–1.22), and 1.06 (0.91–1.23), respectively. There was no evidence of significant interactions between serum Mg and sex or race. No association between dietary Mg and AF risk was observed.
Lower serum Mg was associated with a higher AF risk, and this association was not different between whites and African Americans. Dietary Mg was not associated with AF risk.
PMCID: PMC4228988  PMID: 23047297
atrial fibrillation; serum magnesium; dietary magnesium
22.  Normal Standards for Computer-ECG Programs for Prognostically and Diagnostically important ECG variables Derived from a Large Ethnically Diverse Female Cohort: The Women's Health Initiative (WHI)† 
Journal of electrocardiology  2013;46(6):10.1016/j.jelectrocard.2013.05.136.
Substantial new information has emerged recently about the prognostic value for a variety of new ECG variables. The objective of the present study was to establish reference standards for these novel risk predictors in a large, ethnically diverse cohort of healthy women from the Women's Health Initiative (WHI) study.
Methods and results
The study population consisted of 36,299 healthy racially diverse women. Racial differences in rate-adjusted QT end (QTea) and QT peak (QTpa) intervals as linear functions of RR were small, leading to the conclusion that 450 ms and 390 ms are applicable as thresholds for prolonged and shortened QTea and similarly, 365 ms and 295 for prolonged and shortened QTpa, respectively. As a threshold for increased dispersion of global repolarization (TpeakTend interval), 110 ms was established for white and Hispanic women and 120 ms for African-American and Asian women. Normal standards were derived using lead transformation matrix computed from 116 lead body surface potential maps to derive normal standards for ST monitoring with limb electrodes in Mason-Likar positions and chest leads V3-V6 at the level of V1-V2 and for bipolar vessel-specific left anterior descending (LAD), left circumflex (LCX) and right coronary artery (RCA) leads. The results support the choice 150 μV as a tentative threshold for abnormal ST onset elevation for all monitoring leads. Body mass index (BMI) had a profound effect on Cornell voltage and Sokolow-Lyon voltage in all racial groups and their utility for left ventricular hypertrophy classification remains open.
Common thresholds for all racial groups are applicable for QTea, and QTpa intervals and ST elevation. Race-specific normal standards are required for many other ECG parameters.
PMCID: PMC3825808  PMID: 23809992
electrocardiogram; normal standards; QT; TpTe; ST; monitoring
23.  Echocardiographic Measures of Cardiac Structure and Function Are Associated with Risk of Atrial Fibrillation in Blacks: The Atherosclerosis Risk in Communities (ARIC) Study 
PLoS ONE  2014;9(10):e110111.
Several studies have examined the link between atrial fibrillation (AF) and various echocardiographic measures of cardiac structure and function in whites and other racial groups but not in blacks. Exploring AF risk factors in blacks is important given that the lower incidence of AF in this racial group despite higher risk factors, is not completely explained.
We examined the association of echocardiographic measures with AF incidence in 2283 blacks (64.5% women, mean age 58.8 years) free of diagnosed AF and enrolled in the Jackson cohort of Atherosclerosis Risk in Communities (ARIC) study, a prospective study of cardiovascular disease. Echocardiography was performed in 1993–1995, and incident AF was determined by electrocardiograms at a follow-up study exam, hospitalization discharge codes and death certificates through the end of 2009. Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals for AF associated with the echocardiographic measures, adjusting for age, sex, and known AF risk factors.
During an average follow-up of 13.5 years, 191 (8.4%) individuals developed AF. Left ventricular (LV) internal diameter 2-D (diastole) and percent fractional shortening of LV diameter displayed a U-shaped relationship with risk of AF, while left atrial diameter displayed a J-shaped nonlinear association. LV mass index was associated positively with AF. E/A ratio <0.7 or >1.5 and ejection fraction (EF <50%) were also associated with higher AF risk. These measures improved risk stratification for AF in addition to traditional risk factors, although not significantly {C-statistic of 0.767 (0.714–0.819) vs. 0.744 (0.691–0.797)}.
In a community-based population of blacks, echocardiographic measures of cardiac structure and function are significantly associated with an increased risk of AF.
PMCID: PMC4199625  PMID: 25330035
24.  The QT Interval and Risk of Incident Atrial Fibrillation 
Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine.
To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF.
We examined a prolonged QT corrected by the Framingham formula (QTFram) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (Health ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by other formulae.
Among 14,538 ARIC participants, a prolonged QTFram predicted a roughly two-fold increased risk of AF (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.42–2.96, p<0.001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in CHS and Health ABC and were similar across various QT correction methods. Also in ARIC, each 10-ms increase in QTFram was associated with an increased unadjusted (HR 1.14, 95%CI 1.10–1.17, p<0.001) and adjusted (HR 1.11, 95%CI 1.07–1.14, p<0.001) risk of AF. Findings regarding a short QT were inconsistent across cohorts.
A prolonged QT interval is associated with an increased risk of incident AF.
PMCID: PMC3787974  PMID: 23872693
atrial fibrillation; epidemiology; risk; QT interval; electrocardiography; ECG
25.  Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction 
The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to further characterize the contribution of rare and common coding variation in SCN5A to cardiac conduction.
Methods and Results
In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study (CHARGE), we performed targeted exonic sequencing of SCN5A (n=3699, European-ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, NHLBI’s Exome Sequencing Project (ESP, n=607) and the UK10K (n=1275) and by examining ESP African-ancestry participants (N=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African-ancestry participants (P=1.3×10−3). Three common variants were associated with PR and/or QRS interval duration among European-ancestry participants and one among African-ancestry participants. These included two well-known missense variants; rs1805124 (H558R) was associated with PR and QRS shortening in European-ancestry participants (P=6.25×10−4 and P=5.2×10−3 respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10−3). Among European-ancestry participants, two novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10−7 and P=2.69×10−4 respectively), and rs6599230 was associated with PR shortening (P=2.67×10−5).
By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.
PMCID: PMC4177904  PMID: 24951663
PR interval; QRS interval; genetics; sequencing; cohort

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