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Background and Purpose— Emerging evidence suggests that an underlying atrial cardiopathy may result in thromboembolism before atrial fibrillation (AF) develops. We examined the association between various markers of atrial cardiopathy and the risk of ischemic stroke. Methods— The CHS (Cardiovascular Health Study) prospectively enrolled community-dwelling adults ≥65 years of age. For this study, we excluded participants diagnosed with stroke or AF before baseline. Exposures were several markers of atrial cardiopathy: baseline P-wave terminal force in ECG lead V 1 , left atrial dimension on echocardiogram, and N terminal pro B type natriuretic peptide (NT-proBNP), as well as incident AF. Incident AF was ascertained from 12-lead electrocardiograms at annual study visits for the first decade after study enrollment and from inpatient and outpatient Medicare data throughout follow-up. The primary outcome was incident ischemic stroke. We used Cox proportional hazards models that included all 4 atrial cardiopathy markers along with adjustment for demographic characteristics and established vascular risk factors. Results— Among 3723 participants who were free of stroke and AF at baseline and who had data on all atrial cardiopathy markers, 585 participants (15.7%) experienced an incident ischemic stroke during a median 12.9 years of follow-up. When all atrial cardiopathy markers were combined in 1 Cox model, we found significant associations with stroke for P-wave terminal force in ECG lead V 1 (hazard ratio per 1000 μV*ms 1.04; 95% confidence interval, 1.001–1.08), log-transformed NT-proBNP (hazard ratio per doubling of NT-proBNP, 1.09; 95% confidence interval, 1.03–1.16), and incident AF (hazard ratio, 2.04; 95% confidence interval, 1.67–2.48) but not left atrial dimension (hazard ratio per cm, 0.96; 95% confidence interval, 0.84–1.10). Conclusions— In addition to clinically apparent AF, other evidence of abnormal atrial substrate is associated with subsequent ischemic stroke. This finding is consistent with the hypothesis that thromboembolism from the left atrium may occur in the setting of several different manifestations of atrial disease.

Introduction: Several lines of evidence indicate that some cases of cryptogenic stroke may be due to an atrial cardiopathy that forms a nidus for thrombus formation and embolization even in the absence of atrial fibrillation (AF). Hypothesis: We hypothesized that evidence of atrial cardiopathy other than AF is independently associated with stroke. Methods: We examined the association between several markers of atrial cardiopathy and the risk of ischemic stroke among participants in the Cardiovascular Health Study, which prospectively enrolled community-dwelling adults ≥65 years of age. The exposures of interest were P-wave terminal force in electrocardiogram lead V 1 (PTFV 1 ), left atrial dimension on echocardiogram, amino terminal pro-B-type natriuretic peptide (NT-proBNP), and incident AF. The primary outcome was adjudicated ischemic stroke. We used Cox proportional hazards analysis to examine associations with stroke for all four markers together along with adjustment for traditional vascular risk factors. Results: Among 3,723 participants who were free of stroke and AF at baseline and who had data on all atrial cardiopathy markers, 585 patients (15.7%) experienced an incident ischemic stroke during a median 12.9 years of follow-up. When the four atrial cardiopathy markers were combined in one model along with traditional vascular risk factors, we found significant associations with stroke for PTFV 1 (hazard ratio [HR] per 1,000 μV*ms, 1.04; 95% confidence interval [CI], 1.0006-1.08), NT-proBNP (HR per doubling of NT-proBNP, 1.09; 95% CI, 1.03-1.16), and incident AF (HR, 2.04; 95% CI, 1.67-2.48), but not left atrial dimension (HR per cm, 0.96; 95% CI, 0.84-1.10). Conclusions: In a large, prospective, longitudinal study, we found that evidence of abnormal atrial substrate, defined more broadly than just AF, was associated with subsequent ischemic stroke. These findings support the hypothesis that left atrial thromboembolism can occur in the absence of AF.

Background and Purpose— The relative risk of ischemic stroke associated with transient ischemic attack (TIA) is not well defined because most studies of stroke after TIA did not include comparison groups. We sought to estimate short-term and long-term relative risks of ischemic stroke associated with clinically diagnosed TIA. Methods— We used data from a population-based case-control study. Cases were hypertensive men and women and postmenopausal women, ages 30 to 79, with incident ischemic stroke. Control subjects were sampled within strata of age, sex, hypertension status, and calendar year. The index date was the stroke date for cases and a random date for control subjects. Clinically diagnosed TIA was ascertained from medical records. We used logistic regression to calculate ORs. Results— The study included 1914 stroke cases and 9874 control subjects. Clinically diagnosed TIA was present in 215 (11.2%) cases and 252 (2.5%) control subjects. Analyses focused on the most recent TIA before the index date. For TIA 5 years before the index date, it was 1.87 (1.22 to 2.85). Conclusions— The relative risk of ischemic stroke was high for TIA diagnosed within the past 3 months and moderately high for TIA diagnosed >5 years in the past compared with no history of clinically diagnosed TIA.

Background and Purpose— Emerging evidence suggests that atrial disease is associated with vascular brain injury in the absence of atrial fibrillation. Methods— The Cardiovascular Health Study prospectively enrolled community-dwelling adults aged ≥65 years. Among participants who underwent MRI, we examined associations of ECG left atrial abnormality with brain infarcts and leukoaraiosis. P-wave terminal force in lead V 1 was the primary measure of left atrial abnormality; P-wave area and duration were secondary predictors. We excluded participants with atrial fibrillation before or on their index ECG. Primary outcomes were incident infarcts and worsening leukoaraiosis from initial to follow-up scan ≈5 years later. Secondary outcomes were prevalent infarcts and degree of leukoaraiosis on initial MRI. Relative risk (RR) and linear regression models were adjusted for vascular risk factors. Results— Among 3129 participants with ≥1 scan, each SD increase in P-wave terminal force in lead V 1 was associated with a 0.05-point (95% confidence interval [CI], 0.0003–0.10) higher baseline white matter grade on a 10-point scale. P-wave terminal force in lead V 1 was associated with prevalent infarcts of any type (RR per SD, 1.09; 95% CI, 1.04–1.16) and more so with prevalent nonlacunar infarcts (RR per SD, 1.22; 95% CI, 1.08–1.38). Among 1839 participants with 2 scans, P-wave terminal force in lead V 1 was associated with worsening leukoaraiosis (RR per SD, 1.09; 95% CI, 1.01–1.18), but not with incident infarcts (RR per SD, 1.06; 95% CI, 0.93–1.20). Sensitivity analyses adjusting for incident atrial fibrillation found similar results. P-wave area and duration were not associated with outcomes. Conclusions— ECG left atrial abnormality is associated with vascular brain injury in the absence of documented atrial fibrillation.

Background and Purpose— Insulin resistance is associated with increased stroke risk, but the effect has not been adequately examined separately in white and black populations. Methods— The association of baseline insulin resistance with risk of cerebral infarction (CI) and intracerebral hemorrhage (ICH) was assessed in 12 366 white and 6782 black participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort, recruited between 2003 and 2007 and followed for an average of 5.7 years. Insulin resistance was measured with the homeostasis model assessment-insulin resistance. Results— There were 364 incident CI and 41 incident ICH events. The risk for CI increased with the log of insulin resistance in whites (hazards ratio [HR] ln(IR) =1.17; 95% confidence interval [CI], 1.00–1.38) but was largely attenuated by adjustment for stroke risk factors (HR ln(IR) =1.05; 95% CI, 0.88–1.26). There was no association in blacks (HR ln(IR) =1.01; 95% CI, 0.81–1.25). After adjustment for demographic factors and risk factors, there was a significant difference by race in the association of insulin resistance with risk of ICH ( P =0.07), with a decrease in the risk of ICH in whites (HR ln(IR) =0.61; 95% CI, 0.35–1.04) but a nonsignificant increase in blacks (HR ln(IR) =1.20; 95% CI, 0.60–2.39). Conclusions— These data support the growing evidence that insulin resistance may play a more important role in stroke risk among white than black individuals and suggest a potentially discordant relationship of insulin resistance on CI and ICH among whites.

Background and Purpose— Improved identification of those at risk of stroke might improve prevention. We evaluated the association of the cardiac function biomarker N-terminal pro–B-type natriuretic peptide (NT-proBNP) with stroke risk in the 30 239 black and white participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Methods— During 5.4 years of follow-up after enrollment in 2003 to 2007, NT-proBNP was measured in baseline blood samples of 546 subjects with incident ischemic stroke and 956 without stroke. Results— NT-proBNP was higher with older age and in those with heart disease, kidney disease, atrial fibrillation, and lower low-density lipoprotein-cholesterol. Adjusting for age, race, sex, income, education, and traditional stroke risk factors, there was an increased risk of stroke across quartiles of NT-proBNP; participants with NT-proBNP in the top versus the bottom quartile had a hazard ratio of 2.9 (95% confidence interval, 1.9–4.5). There was no impact of added adjustment for kidney function and heart failure. Among pathogenetic stroke subtypes, the association was largest for cardioembolic stroke, with a hazard ratio of 9.1 (95% confidence interval, 2.9–29.2). Associations did not differ by age, sex, or race, or after excluding those with baseline heart failure or atrial fibrillation. Predicted stroke risk was more accurate in 27% of participants if NT-proBNP was considered after traditional stroke risk factors ( P Conclusions— NT-proBNP was a major independent risk marker for stroke. Considering this and other data for stroke, coronary disease, and atrial fibrillation, the clinical use of NT-proBNP measurement in primary prevention settings should be considered.

Objective: Low scores on tests of learning, memory, and executive function have been associated with subclinical cerebrovascular pathology in the absence of stroke. In a population-based, stroke-free cohort, we hypothesized that lower performance in these cognitive domains would predict incident stroke. Methods: From 2003-2007, REGARDS enrolled black and white adults aged ≥45 throughout the U.S. Participants are followed by phone twice a year for stroke events and biennially for longitudinal cognitive assessments. Word list learning and recall tasks are used to measure learning and memory, and semantic and letter fluency tasks to measure executive function. Included participants were stroke-free at enrollment and remained so prior to their cognitive assessments. We assessed incident stroke risk through September 1, 2012 using standard survival analyses adjusted for age, education, race, and geographic region. Results: Sample sizes up to 20,422 varied by cognitive task, and follow-up time ranged up to 7 years. Adjusted hazard ratios (95% CI) for stroke associated with the lowest versus highest quintiles of pre-stroke cognitive scores were 1.90 (1.24, 2.93) for learning, 2.23 (1.45, 3.42) for memory, and 1.69 (1.10, 2.61) and 1.98 (1.12, 3.52) for executive function as assessed by semantic and letter fluency, respectively (Figure). Conclusions: In a stroke-free, population-based cohort, lower baseline function in each cognitive domain was associated with increased risk of incident stroke. Low scores may signal the progression and severity of stroke risk factors.

Background: Higher NT-Pro-BNP is a biomarker of cardiac dysfunction associated with risk of future heart failure and atrial fibrillation, and as such may be a marker of stroke risk. Methods: REGARDS enrolled 30,239 US participants in 2003-07 (41% black, 59% white, 55% living in the southeastern stroke belt). With 5.4 years follow-up, baseline NT-Pro-BNP was measured in 610 subjects with first-time stroke and a 1017 person cohort random sample free from prebaseline stroke. Cox proportional hazards models were used to calculate hazard ratios (HR) of stroke by quartiles of NT-Pro-BNP. Net reclassification improvement (NRI) was calculated using the category free NRI statistic. Results: Baseline NT-Pro-BNP was higher with older age, in whites, women, and with diabetes, impaired kidney function, atrial fibrillation, prebaseline heart disease, lower body-mass index and left ventricular hypertrophy by ECG. Levels were higher in those who developed incident stroke. Adjusting for age, race and sex there was an increased HR of stroke with increasing quartiles of NT-Pro-BNP (Model 1 in table); subjects in the 4 th versus 1 st quartile had a 3.7-fold increased stroke risk. Adjustment for income, education and traditional stroke risk factors attenuated this HR to 3.0. There was minimal impact of added adjustment for kidney function, BMI and heart failure. Associations did not differ by age, sex, race or kidney disease status. Based on NRI, predicted stroke risk was more accurate in 27% of participants if NT-Pro-BNP was measured with traditional stroke risk factors (p Discussion: NT-Pro-BNP was a major risk marker for stroke and improved risk classification. By comparison, in this cohort the HRs of stroke were 1.5 for atrial fibrillation and 1.8 for hypertension. More work is needed to confirm that measuring NT-Pro-BNP improves clinical prediction scores for stroke.

To the Editor: Reitz and colleagues examined whether 2 important dementia risk factors—cognitive performance and incident stroke—have an interactive effect on subsequent dementia risk or have only independent effects.1 They reported finding no interaction between incident stroke and prestroke cognitive function or decline in predicting the risk of subsequent dementia. Unfortunately, the only statistical measures given to describe the apparent lack of interaction were probability values for the interaction terms between incident stroke and baseline MMSE score ( P =0.7) and between incident stroke and rate of decline in MMSE score over time ( P =0.5). These probability values are …