Multiple Blood Biomarkers and Stroke Risk in Atrial Fibrillation: The REGARDS Study.

Background Atrial fibrillation is associated with increased stroke risk; available risk prediction tools have modest accuracy. We hypothesized that circulating stroke risk biomarkers may improve stroke risk prediction in atrial fibrillation. Methods and Results The REGARDS (Reasons for Geographic and Racial Differences in Stroke) study is a prospective cohort study of 30 239 Black and White adults age ≥45 years. A nested study of stroke cases and a random sample of the cohort included 175 participants (63% women, 37% Black adults) with baseline atrial fibrillation and available blood biomarker data. There were 81 ischemic strokes over 5.2 years in these participants. Adjusted for demographics, stroke risk factors, and warfarin use, the following biomarkers were associated with stroke risk (hazard ratio [HR]; 95% CI for upper versus lower tertile): cystatin C (3.16; 1.04-9.58), factor VIII antigen (2.77; 1.03-7.48), interleukin-6 (9.35; 1.95-44.78), and NT-proBNP (N-terminal B-type natriuretic peptide) (4.21; 1.24-14.29). A multimarker risk score based on the number of blood biomarkers in the highest tertile was developed; adjusted HRs of stroke for 1, 2, and 3+ elevated blood biomarkers, compared with none, were 1.75 (0.57-5.40), 4.97 (1.20-20.5), and 9.51 (2.22-40.8), respectively. Incorporating the multimarker risk score to the CHA2DS2VASc score resulted in a net reclassification improvement of 0.34 (95% CI, 0.04-0.65). Conclusions Findings in this biracial cohort suggested the possibility of substantial improvement in stroke risk prediction in atrial fibrillation using blood biomarkers or a multimarker risk score.

Prevalence of atrial fibrillation and association with clinical, sociocultural, and ancestral correlates among Hispanic/Latinos: The Hispanic Community Health Study/Study of Latinos.

BACKGROUND: Hispanics/Latinos represent the largest ethnic minority group in the United States. Atrial fibrillation (AF) is the most common cardiac arrhythmia in the United States. OBJECTIVE: The purpose of this study was to provide data on the prevalence of AF and its correlates in a representative Hispanic/Latino population-based sample inclusive of all background groups. METHODS: Hispanic Community Health Study/Study of Latinos participants (n=16,415; 60% women; 59% age >45 years) were enrolled between March 2008 and June 2011, representing individuals of Cuban, Dominican, Mexican, Puerto Rican, Central American, and South American heritage. AF was defined by the 12-lead electrocardiogram and/or participant self-report of a physician diagnosis. Hispanic background-specific AF prevalence rates were determined. Weighted sequential logistic regression models were adjusted for demographic factors (age and sex) and clinical variables (diabetes, hypertension, body mass index, tobacco use, and estimated glomerular filtration rate). RESULTS: The overall weighted prevalence of AF was 1.0% (n=162), with the highest prevalence in Hispanics of Dominican and Puerto Rican backgrounds (1.9% and 2.5% respectively) and the lowest in those of Mexican background (0.3%). Diabetes, hypertension, renal disease, left ventricular hypertrophy determined by the electrocardiogram, alcohol use, and English language preference (greater acculturation) (P < .01 for all) were significantly associated with higher AF prevalence. Multivariate analysis by Hispanic/Latino background group showed that Hispanics of Dominican and Puerto Rican backgrounds were at a 3- to 6-fold higher risk of AF than their Mexican counterparts. CONCLUSION: In a diverse representative population of Hispanics/Latinos, overall AF prevalence was low and varied significantly across Hispanic/Latino background groups independent of clinical or demographic factors.

High-Sensitivity C-Reactive Protein and Risk of Stroke in Atrial Fibrillation (from the Reasons for Geographic and Racial Differences in Stroke Study).

The relation between inflammation and prothrombotic state in atrial fibrillation (AF) is well recognized. This suggests a potential role for high-sensitivity C-reactive protein (hs-CRP), a marker of systemic inflammation, in improving prediction of stroke in participants with AF. Cox proportional hazard analysis was used to examine the risk of stroke in 25,841 participants (40% black and 55% women) with and without AF who were enrolled in the Reasons for Geographic and Racial Differences in Stroke study from 2003 to 2007. Baseline AF (n = 2,132) was ascertained by electrocardiogram and self-reported history of previous physician diagnosis. Stroke events were identified and adjudicated during 8.3 years of follow-up. A total of 655 incident strokes occurred during follow-up. In a model adjusted for sociodemographics, traditional stroke risk factors, and use of aspirin and warfarin, higher levels of hs-CRP were associated with increased overall stroke risk (hazard ratio [HR] 1.30, 95% confidence interval [CI] 1.10 to 1.54, and HR 1.06, 95% CI 1.01 to 1.12 for hs-CRP >3 mg/L and per 1-SD increase, respectively). Higher levels of hs-CRP continued to be associated with incident stroke in participants without AF (HR 1.31, 95% CI 1.09 to 1.57, and HR 1.06, 95% CI 1.01 to 1.12 for hs-CRP >3 mg/L and per 1-SD increase, respectively) but not in those with AF (HR 1.22, 95% CI 0.78 to 1.91, and HR 1.01, 95% CI 0.82 to 1.23 for hs-CRP >3 mg/L and per 1-SD increase, respectively). In conclusion, although hs-CRP was significantly associated with stroke risk in this population, it seems to be limited to those without AF. These findings suggest a limited value of hs-CRP in improving stroke risk stratification in subjects with AF.

Risk of early mortality after placement of a temporary-permanent pacemaker.

BACKGROUND: Temporary-permanent pacemakers [TPPM] are externally placed permanent generators attached to active fixation transvenous leads. TPPM can be used as an alternative to standard temporary pacing leads when placement of a permanent pacemaker is contraindicated. We sought to determine the incidence and risk factors for early (within 6months) mortality after placement of a TPPM. METHODS: Electronic medical records were used to extract baseline characteristics for 152 patients from Wake Forest Baptist Medical Center who had a TPPM placed between the years 2007 and 2012. Multivariable adjusted Cox proportional hazard models were used to estimate hazard ratios [HR] and 95% confidence intervals [C]) for baseline characteristics [age, sex, race, hypertension, diabetes, heart failure, coronary artery disease, smoking, dyslipidemia, chronic kidney disease [CKD], and indication for pacemaker] on early mortality. RESULTS: Of the 152 patients [mean age 68.9years; 57.2% female; 86.8% white], 45 [29.6%] died within the first 6months after TPPM placement. No deaths occurred as a direct result of TPPM placement, and only 1 patient experienced documented non-fatal complications. Maximum time to PPM from the date of insertion of TPPM was 336days. Using a backward multivariable adjusted hazard regression model, independent risk factors for early mortality were pre-existing CKD [HR (95% CI): 2.240 (1.002-5.010) for eGFR 30-59 and 7.645 (3.594-16.263) for eGFR <30 compared to eGFR >60] and history of smoking [HR (95% CI): 2.015 (1.099-3.696)]. Surprisingly, dyslipidemia was protective of early mortality [HR (95%CI): 0.470 (0.240-0.924)]. CONCLUSION: TPPM placement is a safe procedure with rare direct complications. CKD and smoking are predictive of increased risk for early mortality in patients undergoing TPPM placement.

Utility of Nontraditional Risk Markers in Atherosclerotic Cardiovascular Disease Risk Assessment.

BACKGROUND: The improvement in discrimination gained by adding nontraditional cardiovascular risk markers cited in the 2013 American College of Cardiology/American Heart Association cholesterol guidelines to the atherosclerotic cardiovascular disease (ASCVD) risk estimator (pooled cohort equation [PCE]) is untested. OBJECTIVES: This study assessed the predictive accuracy and improvement in reclassification gained by the addition of the coronary artery calcium (CAC) score, the ankle-brachial index (ABI), high-sensitivity C-reactive protein (hsCRP) levels, and family history (FH) of ASCVD to the PCE in participants of MESA (Multi-Ethnic Study of Atherosclerosis). METHODS: The PCE was calibrated (cPCE) and used for this analysis. The Cox proportional hazards survival model, Harrell's C statistics, and net reclassification improvement analyses were used. ASCVD was defined as myocardial infarction, coronary heart disease-related death, or fatal or nonfatal stroke. RESULTS: Of 6,814 MESA participants not prescribed statins at baseline, 5,185 had complete data and were included in this analysis. Their mean age was 61 years; 53.1% were women, 9.8% had diabetes, and 13.6% were current smokers. After 10 years of follow-up, 320 (6.2%) ASCVD events occurred. CAC score, ABI, and FH were independent predictors of ASCVD events in the multivariable Cox models. CAC score modestly improved the Harrell's C statistic (0.74 vs. 0.76; p = 0.04); ABI, hsCRP levels, and FH produced no improvement in Harrell's C statistic when added to the cPCE. CONCLUSIONS: CAC score, ABI, and FH were independent predictors of ASCVD events. CAC score modestly improved the discriminative ability of the cPCE compared with other nontraditional risk markers.

Coronary artery calcium and risk of atrial fibrillation (from the multi-ethnic study of atherosclerosis).

Calcified coronary arteries are associated with the development of cardiovascular disease and stroke. It is currently unknown whether coronary artery calcium (CAC) is associated with an increased risk for atrial fibrillation (AF). The aim of this study was to address this question in 6,641 participants (mean age 62 ± 10 years, 53% women, 62% nonwhites) from the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of baseline clinical cardiovascular disease and AF. CAC measurements were assessed by cardiac computed tomography at study baseline. AF was ascertained by review of hospital discharge records and from Medicare claims data until December 31, 2010. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between CAC and AF. During a median follow-up period of 8.5 years, 308 participants (4.6%) developed AF. In a model adjusted for sociodemographics, cardiovascular risk factors, and potential confounders, higher CAC scores were associated with increased risk for AF (CAC = 0: HR 1.0, referent; CAC = 1 to 100: HR 1.4, 95% CI 1.01 to 2.0; CAC = 101 to 300: HR 1.6, 95% CI 1.1 to 2.4; CAC >300: HR 2.1, 95% CI 1.4 to 2.9). The addition of CAC to the Framingham Heart Study and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) AF risk scores yielded integrated discrimination improvement of 0.0033 (95% CI 0.0015 to 0.0066) and 0.0028 (95% CI 0.0012 to 0.0057), with relative integrated discrimination improvement of 0.10 (95% CI 0.061 to 0.15) and 0.077 (95% CI 0.040 to 0.11), respectively. In conclusion, CAC is independently associated with increased risk for AF.

Determinants of developing widened spatial QRS-T angle in HIV-infected individuals: results from the Strategies for Management of Antiretroviral Therapy [SMART] Study.

BACKGROUND: A widened electrocardiographic spatial QRS-T angle has been shown to be predictive of cardiovascular disease in HIV-infected individuals. However, determinants and risk factors of developing widened QRS-T angle over time in this population remain unknown. METHODS AND RESULTS: Spatial QRS-T angle was automatically measured from standard electrocardiogram of 1444 HIV-infected individuals without baseline widened spatial QRS-T angle from the Strategies for Management of Antiretroviral Therapy [SMART], a clinical trial comparing two antiretroviral treatment strategies [Drug Conservation (DC) vs. Viral Suppression (VS)]. Conditional logistic regression analysis was used to examine the association between baseline characteristics and incident widened spatial QRS-T angle (a new angle>93° in males and>74° in females). During 2544 person-years of follow-up, 199 participants developed widened angle at a rate of 7.8 per 100 person-years. In unadjusted models, female sex, black race (vs. white), DC treatment strategy, current and past smokers (vs. never), history of alcohol abuse, greater body mass index, history of diabetes and higher levels of hs-C-reactive protein were associated with incident widened spatial QRS-T angle. When these variables were entered together in the same model with adjustment for demographics and treatment strategy, DC treatment strategy [OR (95% CI): 1.50 (1.09, 2.07)], female gender [1.69 (1.17, 2.45)], current and past smoking (vs. never) [2.49 (1.63, 3.81) and 1.93 (1.21, 3.09), respectively], and diabetes [2.28 (1.33, 3.91)] predicted incident widened spatial QRS-T angle. CONCLUSIONS: Drug conservation treatment strategy, female gender, smoking, and diabetes are independently predictive of incident widened spatial QRS-T angle in HIV-infected individuals.

Atrial fibrillation and the risk of myocardial infarction.

IMPORTANCE: 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. OBJECTIVE: To examine the risk of incident MI associated with AF. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: Expert-adjudicated total MI events (fatal and nonfatal). RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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.

Minor isolated Q waves and cardiovascular events in the MESA study.

BACKGROUND: The significance of minor isolated Q waves in the resting electrocardiograms (ECGs) of apparently healthy individuals is unknown. OBJECTIVE: To examine the association between minor isolated Q waves and incident cardiovascular disease events in the Multi-Ethnic Study of Atherosclerosis (MESA). DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Electrocardiographic spatial QRS-T angle and incident cardiovascular disease in HIV-infected patients (from the Strategies for the Management of Antiretroviral Therapy [SMART] study).

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 human immunodeficiency virus (HIV)-infected patients remains unknown. The spatial QRS-T angle was derived from the baseline resting 12-lead electrocardiogram of 4,453 HIV-infected patients aged 43.5 ± 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 the spatial QRS-T angle was calculated for men and women separately, and values in the upper quartile were considered as a widened angle (values >74° for women and >93° for men). A multivariate Cox proportional hazards analysis was used to examine the association between a widened baseline spatial QRS-T angle and incident CVD events. During 11,965 person-years of follow-up, 152 CVD events occurred at a rate of 1.27 events/100 person-years. The rate of CVD events in those with a widened spatial QRS-T angle was almost double the rate in those with a normal spatial QRS-T angle (rate ratio 1.94, 95% confidence interval 1.40 to 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, a widened spatial QRS-T angle was associated with a >50% increased risk of CVD events compared to a normal spatial QRS-T angle (hazard ratio 1.53, 95% confidence interval 1.07 to 2.17; p = 0.02). No interaction was seen by SMART trial arm (p value for interaction = 0.37) or gender (p value for interaction = 0.84). In conclusion, a widened spatial QRS-T angle was independently predictive of CVD events in HIV-infected patients receiving antiretroviral therapy. This highlights the potential role of routine electrocardiography as a simple noninvasive CVD risk-screening tool in HIV-infected patients.