Aerobic Exercise Improves Heart Rate Variability After an Implantable Cardioverter Defibrillator (ICD).

CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT00522340.

Mortality Following Hip Fracture in Older Adults With and Without Coronary Heart Disease.

BACKGROUND: Comorbidities like coronary heart disease are common among older people who sustain an osteoporotic hip fracture. However, their impact on short- and long-term mortality post-hip fracture is not well quantified. METHODS: We examined 4092 and 1173 older adults without and with prevalent coronary heart disease, respectively. Post-hip fracture mortality rates were computed with Poisson models and hazard ratios with Cox regression. For perspective, we compared mortality rates among participants with prevalent coronary heart disease who had either a hip fracture or incident heart failure (but no hip fracture). RESULTS: Among participants without prevalent coronary heart disease, the mortality rate post-hip fracture was 21.83 per 100 participant years, including 49.27 per 100 participant years in the first 6 months following hip fracture. Among participants with prevalent coronary heart disease, the corresponding mortality rates were 32.52 and 79.44 per 100 participant years, respectively. Participants with prevalent coronary heart disease and incident heart failure (but no hip fracture) had corresponding post-incident heart failure mortality rates per 100 participant years of 25.62 overall and 46.4 in the first 6 months. In all 3 groups, the hazard ratio for mortality was similarly elevated: 5- to 7-fold at 6 months and 1.7- to 2.5-fold beyond 5 years. CONCLUSION: As a case study in the absolute effects of a comorbidity on post-hip fracture mortality, hip fracture in a person with coronary heart disease carries an exceedingly high mortality rate, even higher than that following incident heart failure in individuals with coronary heart disease.

The associations of markers of endothelial dysfunction with hip fracture risk.

Endothelial dysfunction underlies the development of atherosclerotic vascular disease, which in turn is associated with osteoporotic fractures. Here, we examined the association of two markers of endothelial dysfunction with incident hip fracture risk in older adults but found no statistically significant associations between them. PURPOSE/INTRODUCTION: Endothelial dysfunction underlies the development of atherosclerotic vascular disease. Vascular disease, in turn, is associated with the risk of osteoporotic fractures, such as hip fractures. Here, we examine whether two measures of endothelial dysfunction are related to hip fracture risk. METHODS: Participants for this study were 2792 individuals (mean age 78.6 years) who had flow-mediated dilation (FMD) measured after ischemia in the forearm and 2255 adults (mean age 73.3 years) with measured soluble intercellular adhesion molecule (siCAM) levels, a constitutive endothelial cell membrane protein associated with the initiation of atherosclerosis. Mean follow-up was 9.7 and 11.7 years, respectively. There were 375 and 265 incident hip fractures, respectively, in each group. RESULTS: In Cox proportional hazards models, there was no significant association between FMD response and incident hip fracture (HR per 1% higher FMD was 0.98 [0.93, 1.04]; p = 0.44). In exploratory analyses, when data were examined dichotomously, participants in the lowest 80% of FMD (≤ 4.5%) had an adjusted 1.29 (0.98, 1.68; p = 0.067) higher hazard of hip fracture compared to participants in the upper 20% of FMD change. There were no significant associations between siCAM and incident hip fracture whether examined as a continuous or dichotomized variable. CONCLUSIONS: Among older adults, two measures of endothelial dysfunction were not significantly associated with hip fracture risk. There was a trend for higher fracture risk with lower FMD.

Neuroimaging Studies of the Neural Correlates of Heart Rate Variability: A Systematic Review.

Direct and indirect links between brain regions and cardiac function have been reported. We performed a systematic literature review to summarize current knowledge regarding the associations of heart rate variability (HRV) and brain region morphology, activity and connectivity involved in autonomic control at rest in healthy subjects. Both positive and negative correlations of cortical thickness and gray matter volumes of brain structures with HRV were observed. The strongest were found for a cluster located within the cingulate cortex. A decline in HRV, as well as cortical thickness with increasing age, especially in the orbitofrontal cortex were noted. When associations of region-specific brain activity with HRV were examined, HRV correlated most strongly with activity in the insula, cingulate cortex, frontal and prefrontal cortices, hippocampus, thalamus, striatum and amygdala. Furthermore, significant correlations, largely positive, between HRV and brain region connectivity (in the amygdala, cingulate cortex and prefrontal cortex) were observed. Notably, right-sided neural structures may be preferentially involved in heart rate and HRV control. However, the evidence for left hemispheric control of cardiac vagal function has also been reported. Our findings provide support for the premise that the brain and the heart are interconnected by both structural and functional networks and indicate complex multi-level interactions. Further studies of brain-heart associations promise to yield insights into their relationship to health and disease.

Sex- and race-specific associations of bone mineral density with incident heart failure and its subtypes in older adults.

BACKGROUND: Previous studies have suggested an association between bone mineral density (BMD) and heart failure (HF) risk that may be race-dependent. METHODS: We evaluated the relationship between BMD and incident HF in a cohort of older adults, the Health, Aging, and Body Composition (Health ABC) study (n = 2835), and next performed a pooled analysis involving a second older cohort, the Cardiovascular Health Study (n = 1268). Hip BMD was measured by dual-energy X-ray absorptiometry in both cohorts and spine BMD by computed tomography in a subset from Health ABC. RESULTS: In Health ABC, lower BMD at the total hip was associated with higher incident HF in Black women after multivariable adjustment. Similar associations were found for BMD at the femoral neck and spine. In both cohorts, pooled analysis again revealed an association between lower total hip BMD and increased risk of HF in Black women (HR = 1.41 per 0.1-g/cm2 decrement [95% CI = 1.23-1.62]), and showed the same to be true for White men (HR = 1.12 [1.03-1.21]). There was a decreased risk of HF in Black men (HR 0.80 [0.70-0.91]), but no relationship in White women. The associations were numerically stronger with HFpEF for Black women and White men, and with HFrEF for Black men. Findings were similar for femoral neck BMD. Sensitivity analyses delaying HF follow-up by 2 years eliminated the association in Black men. CONCLUSIONS: Lower BMD was associated with higher risk of HF and especially HFpEF in older Black women and White men, highlighting the need for additional investigation into underlying mechanisms.

The Association of Measures of Cardiovascular Autonomic Function, Heart Rate, and Orthostatic Hypotension With Incident Glucose Disorders: The Cardiovascular Health Study.

OBJECTIVE: The autonomic nervous system (ANS) innervates pancreatic endocrine cells, muscle, and liver, all of which participate in glucose metabolism. We tested whether measures of cardiovascular ANS function are independently associated with incident diabetes and annual change in fasting glucose (FG) levels as well as with insulin secretion and insulin sensitivity in older adults without diabetes. RESEARCH DESIGN AND METHODS: Heart rate (HR) and measures of HR variability (HRV) were derived from 24-h electrocardiographic monitoring. Blood pressure, seated and standing, was measured. Cox proportional hazards models and linear mixed models were used to analyze the associations between HRV, HR, and orthostatic hypotension (SBP >20 mmHg decline) and incident diabetes or longitudinal FG change. RESULTS: The mean annual unadjusted FG change was 1 mg/dL. Higher detrended fluctuation analyses (DFA) values, averaged over 4-11 (DFA1) or 12-20 beats (DFA2)-reflecting greater versus less organization of beat-to-beat intervals-were associated with less FG increase over time (per 1-SD increment: DFA1: -0.49 mg/dL/year [-0.96, -0.03]; DFA2: -0.55 mg/dL/year [-1.02, -0.09]). In mutually adjusted analyses, higher SD of the N-N interval (SDNN) was associated with less FG increase over time (per 1-SD increment: SDNN: -0.62 mg/dL/year [-1.22, -0.03]). Higher values of DFA1, DFA2, and SDNN were each associated with greater insulin secretion and insulin sensitivity but not with incident diabetes. We observed no association of HR or orthostatic hypotension with diabetes or FG change. CONCLUSIONS: Specific measures of cardiac autonomic function are prospectively related to FG level changes and insulin secretion and action.

Impact of Web-Based Cognitive Behavioral Therapy for Insomnia on Stress, Health, Mood, Cognitive, Inflammatory, and Neurodegenerative Outcomes in Rural Dementia Caregivers: Protocol for the NiteCAPP CARES and NiteCAPP SHARES Randomized Controlled Trial.

BACKGROUND: Chronic insomnia affects up to 63% of family dementia caregivers. Research suggests that chronic insomnia prompts changes in central stress processing that have downstream negative effects on health and mood, as well as on cognitive, inflammatory, and neurodegenerative functioning. We hypothesize that cognitive behavioral therapy for insomnia (CBT-I) will reverse those downstream effects by improving insomnia and restoring healthy central stress processing. Rural caregivers are particularly vulnerable, but they have limited access to CBT-I; therefore, we developed an accessible digital version using community input (NiteCAPP CARES). OBJECTIVE: This trial will evaluate the acceptability, feasibility, and short-term and long-term effects of NiteCAPP CARES on the sleep and stress mechanisms underlying poor caregiver health and functioning. METHODS: Dyads (n=100) consisting of caregivers with chronic insomnia and their coresiding persons with dementia will be recruited from Columbia and surrounding areas in Missouri, United States. Participant dyads will be randomized to 4 weeks (plus 4 bimonthly booster sessions) of NiteCAPP CARES or a web-based sleep hygiene control (NiteCAPP SHARES). Participants will be assessed at baseline, after treatment, and 6- and 12-month follow-ups. The following assessments will be completed by caregivers: 1 week of actigraphy and daily diaries measuring sleep, Insomnia Severity Index, arousal (heart rate variability), inflammation (blood-derived biomarkers: interleukin-6 and C-reactive protein), neurodegeneration (blood-derived biomarkers: plasma amyloid beta [Aß40 and Aß42], total tau, and phosphorylated tau [p-tau181 and p-tau217]), cognition (Joggle battery, NIH Toolbox for Assessment of Neurological and Behavioral Function, and Cognitive Failures Questionnaire), stress and burden, health, and mood (depression and anxiety). Persons with dementia will complete 1 week of actigraphy at each time point. RESULTS: Recruitment procedures started in February 2022. All data are expected to be collected by 2026. Full trial results are planned to be published by 2027. Secondary analyses of baseline data will be subsequently published. CONCLUSIONS: This randomized controlled trial tests NiteCAPP CARES, a web-based CBT-I for rural caregivers. The knowledge obtained will address not only what outcomes improve but also how and why they improve and for how long, which will help us to modify NiteCAPP CARES to optimize treatment potency and support future pragmatic testing and dissemination. TRIAL REGISTRATION: ClinicalTrials.gov NCT04896775; https://clinicaltrials.gov/ct2/show/NCT04896775. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/37874.

Premature ventricular complexes and development of heart failure in a community-based population.

OBJECTIVE: A higher premature ventricular complex (PVC) frequency is associated with incident congestive heart failure (CHF) and death. While certain PVC characteristics may contribute to that risk, the current literature stems from patients in medical settings and is therefore prone to referral bias. This study aims to identify PVC characteristics associated with incident CHF in a community-based setting. METHODS: The Cardiovascular Health Study is a cohort of community-dwelling individuals who underwent prospective evaluation and follow-up. We analysed 24-hour Holter data to assess PVC characteristics and used multivariable logistic and Cox proportional hazards models to identify predictors of a left ventricular ejection fraction (LVEF) decline and incident CHF, respectively. RESULTS: Of 871 analysed participants, 316 participants exhibited at least 10 PVCs during the 24-hour recording. For participants with PVCs, the average age was 72±5 years, 41% were women and 93% were white. Over a median follow-up of 11 years, 34% developed CHF. After adjusting for demographics, cardiovascular comorbidities, antiarrhythmic drug use and PVC frequency, a greater heterogeneity of the PVC coupling interval was associated with an increased risk of LVEF decline and incident CHF. Of note, neither PVC duration nor coupling interval duration exhibited a statistically significant relationship with either outcome. CONCLUSIONS: In this first community-based study to identify Holter-based features of PVCs that are associated with LVEF reduction and incident CHF, the fact that coupling interval heterogeneity was an independent risk factor suggests that the mechanism of PVC generation may influence the risk of heart failure.

Cardiovascular autonomic nervous system function and hip fracture risk: the Cardiovascular Health Study.

Among 1299 older adults with 24-h Holter monitoring data at baseline, followed for approximately 15 years, 190 incident hip fractures occurred. Increased heart rate variability was independently associated with reduced risk of hip fracture among female participants. PURPOSE: Autonomic nervous system function modulates bone remodeling in rodent osteoporosis models. We tested whether cardiovascular autonomic function is associated with hip fracture risk in humans. METHODS: Participants were 1299 subjects from the Cardiovascular Health Study (mean age 72.8 years). Eight heart rate variability (HRV) measures (time and frequency domains, detrended fluctuation analysis variables, and heart rate turbulence) were derived from 24-h Holter monitor scans in sinus rhythm. Median follow-up for incident hip fracture was 14.7 years [IQR 9.1, 20.2]. Cox proportional hazards models were used to calculate hazard ratios (95% confidence intervals, CI). RESULTS: There were 144 hip fractures among 714 women (1.31 [1.06, 1.61] per 100-person years) and 46 among 585 men (0.62 [0.43, 0.90] per 100 person-years). From among HRV variables examined, a one standard deviation (SD) higher variation between normal heart beats over 24 h (the SD of NN intervals [SDNN]) was associated with a multivariable-adjusted lower hip fracture risk (HR [Formula: see text] 0.80; 95% CI 0.65-0.99; p = 0.04) in women. The adjusted association between very low frequency power, and hip fracture was borderline statistically significant in women (HR [Formula: see text] 0.82; 95% CI, 0.66-1.00; p = 0.06). When the 8 HRV variables were considered conjointly and adjusted for each other's association with hip fracture risk, a 1 SD higher SDNN value was significantly associated with reduced hip fracture risk in women (HR 0.74; 95% CI, 0.50-0.99; p = 0.05). No HRV variables were associated with hip fracture in men. CONCLUSIONS: In older women, increased heart rate variation is associated with hip fracture risk.

Short-term deceleration capacity of heart rate: a sensitive marker of cardiac autonomic dysfunction in idiopathic Parkinson's disease.

PURPOSE: Cardiac autonomic dysfunction in idiopathic Parkinson's disease (PD) manifests as reduced heart rate variability (HRV). In the present study, we explored the deceleration capacity of heart rate (DC) in patients with idiopathic PD, an advanced HRV marker that has proven clinical utility. METHODS: Standard and advanced HRV measures derived from 7-min electrocardiograms in 20 idiopathic PD patients and 27 healthy controls were analyzed. HRV measures were compared using regression analysis, controlling for age, sex, and mean heart rate. RESULTS: Significantly reduced HRV was found only in the subcohort of PD patients older than 60 years. Low- frequency power and global HRV measures were lower in patients than in controls, but standard beat-to-beat HRV markers (i.e., rMSSD and high-frequency power) were not significantly different between groups. DC was significantly reduced in the subcohort of PD patients older than 60 years compared to controls. CONCLUSIONS: Deceleration-related oscillations of HRV were significantly reduced in the older PD patients compared to healthy controls, suggesting that short-term DC may be a sensitive marker of cardiac autonomic dysfunction in PD. DC may be complementary to traditional markers of short-term HRV for the evaluation of autonomic modulation in PD. Further study to examine the association between DC and cardiac adverse events in PD is needed to clarify the clinical relevance of DC in this population.

Increased markers of cardiac vagal activity in leucine-rich repeat kinase 2-associated Parkinson's disease.

PURPOSE: Cardiac autonomic dysfunction manifests as reduced heart rate variability (HRV) in idiopathic Parkinson's disease (PD), but no significant reduction has been found in PD patients who carry the LRRK2 mutation. Novel HRV features have not been investigated in these individuals. We aimed to assess cardiac autonomic modulation through standard and novel approaches to HRV analysis in individuals who carry the LRRK2 G2019S mutation. METHODS: Short-term electrocardiograms were recorded in 14 LRRK2-associated PD patients, 25 LRRK2-non-manifesting carriers, 32 related non-carriers, 20 idiopathic PD patients, and 27 healthy controls. HRV measures were compared using regression modeling, controlling for age, sex, mean heart rate, and disease duration. Discriminant analysis highlighted the feature combination that best distinguished LRRK2-associated PD from controls. RESULTS: Beat-to-beat and global HRV measures were significantly increased in LRRK2-associated PD patients compared with controls (e.g., deceleration capacity of heart rate: p = 0.006) and idiopathic PD patients (e.g., 8th standardized moment of the interbeat interval distribution: p = 0.0003), respectively. LRRK2-associated PD patients also showed significantly increased irregularity of heart rate dynamics, as quantified by Rényi entropy, when compared with controls (p = 0.002) and idiopathic PD patients (p = 0.0004). Ordinal pattern statistics permitted the identification of LRRK2-associated PD individuals with 93% sensitivity and 93% specificity. Consistent results were found in a subgroup of LRRK2-non-manifesting carriers when compared with controls. CONCLUSIONS: Increased beat-to-beat HRV in LRRK2 G2019S mutation carriers compared with controls and idiopathic PD patients may indicate augmented cardiac autonomic cholinergic activity, suggesting early impairment of central vagal feedback loops in LRRK2-associated PD.

Predictors of atrial ectopy and their relationship to atrial fibrillation risk.

AIMS: Premature atrial contractions (PACs) are known to trigger and predict atrial fibrillation (AF). We sought to identify the determinants of PACs and the degree to which PACs mediate the effects of established risk factors for AF. METHODS AND RESULTS: Predictors of baseline PAC frequency were examined using a Holter Study among 1392 participants in the Cardiovascular Health Study, a community-based cohort of individuals aged ≥65 years. Participants were then followed for their first diagnosis of AF. Independent predictors of PACs were identified, and the extent to which PACs might mediate the relationship between those predictors and AF was determined. The median hourly frequency of PACs was 2.7 (interquartile range 0.8-12.1). After multivariable adjustment, increasing age, increasing height, decreasing body mass index, and a history of myocardial infarction were each associated with more PACs. Regarding modifiable predictors, participants using beta-blockers had 21% less [95% confidence interval (95% CI) 9-30%, P = 0.001] and those performing at least moderate intensity exercise vs. lower intensity exercisers had 10% less (95% CI 1-18%, P = 0.03) PACs. Higher PAC frequency explained 34% (95% CI 22-57%, P < 0.0001) of the relationship between increasing age and AF risk and 27% (95% CI 10-75%, P = 0.004) of the relationship between taller height and AF risk. CONCLUSION: Enhancing physical activity and use of beta-blockers may represent fruitful strategies to mitigate PAC frequency. A substantial proportion of the excess risk of AF due to increasing age and taller height may be explained by an increase in PAC frequency.

Neonatal Skin-to-Skin Contact: Implications for Learning and Autonomic Nervous System Function in Infants With Congenital Heart Disease.

BACKGROUND: Infants with complex congenital heart disease (CCHD) often develop neurodevelopmental disabilities. Cognitive abilities are associated with vagally mediated autonomic function. Skin-to-skin contact (SSC) interventions enhance infant neurodevelopment and autonomic function in other high-risk populations. AIM: To examine the effects of a neonatal SSC intervention on learning and autonomic function in 3-month-old infants: infants with CCHD who received neonatal SSC ( n = 10), typically developing (TD) infants ( n = 16), and infants with CCHD without SSC ( n = 10). METHODS: This secondary data analysis measured cognitive function using the mobile paradigm (MP), a classic measure of learning based on operant conditioning. Autonomic function was assessed with heart rate (HR) and HR variability (HRV). Data were analyzed with repeated-measures general linear mixed modeling with α = .10 for this exploratory study. RESULTS: Learning rates were TD = 75%, cardiac-SSC = 70%, and cardiac-control = 40%. Learners demonstrated significant reductions in HRV during the MP; nonlearners exhibited no change. TD and cardiac-SSC groups exhibited increases in HR and reductions in HRV during the MP. No significant changes occurred in the cardiac-control group. Nonlinear HRV during the MP differed only in the TD group. CONCLUSIONS: Findings suggest improvements in cognitive and autonomic development in 3-month-old infants with CCHD who received neonatal SSC. Learning and autonomic function results in infants with CCHD who had not received SSC suggest reduced capacity to muster the physiologic resources to carry out this cognitive task. Findings provide preliminary evidence in support of implementation of SSC with infants with CCHD and support additional research.

Medical Correlates of Chronic Multisymptom Illness in Gulf War Veterans.

BACKGROUND: Chronic multisymptom illness (CMI) is more prevalent among deployed than nondeployed veterans from the first Gulf War. Objective physiologic markers of CMI are lacking. The purpose of this study is to determine whether measurable abnormalities in the autonomic nervous system or hypothalamic-pituitary adrenal axis would distinguish CMI cases (CMI+) from controls (CMI-) among deployed veterans of the 1990-1991 Gulf War. METHODS: This is a cross-sectional case-control cohort study that examined deployed veterans who participated in the Phase III study: National Health Survey of Gulf War Veterans and Their Families. Autonomic nervous system and hypothalamic-pituitary adrenal axis function-related measures included: 24-hour heart-rate variability, urinary catecholamines and cortisol, hypertension, insulin sensitivity, dyslipidemia, body fat, bone mineral density, and ultrasensitive C-reactive protein. RESULTS: Veterans of the first Gulf War with CMI (n = 73) and without the condition (n = 111) were studied. Sociodemographic characteristics were similar. Veterans with CMI reported poorer mental and physical functioning, greater use of prescription medications, and more nonroutine clinic visits. These veterans were also more likely to have fibromyalgia syndrome, irritable bowel syndrome, metabolic syndrome, and among males, a larger waist-to-hip ratio. Lower values for a nonlinear heart-rate-variability parameter-the short-term fractal scaling exponent (DFA1), reflecting an increased randomness of beat-to-beat changes in heart rate-were observed in veterans with CMI than those veterans without it (1.28±0.16vs 1.35±0.15; p=0.005). Hypothalamic-pituitary-adrenal axis function measures were similar between the two groups. CONCLUSION: In this cohort of deployed veterans from the first Gulf War, we identified abnormal heart-rate variability in veterans with CMI compared to veterans without the condition, which suggests abnormal functioning of the autonomic nervous system and possible long-term cardiovascular effects.

Modifiable Predictors of Ventricular Ectopy in the Community.

Background Premature ventricular contractions (PVCs) predict heart failure and death. Data regarding modifiable risk factors for PVCs are scarce. Methods and Results We studied 1424 Cardiovascular Health Study participants randomly assigned to 24-hour Holter monitoring. Demographics, comorbidities, habits, and echocardiographic measurements were examined as predictors of PVC frequency and, among 845 participants, change in PVC frequency 5 years later. Participants exhibited a median of 0.6 (interquartile range, 0.1-7.1) PVCs per hour. Of the more directly modifiable characteristics and after multivariable adjustment, every SD increase in systolic blood pressure was associated with 9% more PVCs (95% confidence interval [CI], 2%-17%; P=0.01), regularly performing no or low-intensity exercise compared with more physical activity was associated with ≈15% more PVCs (95% CI, 3-25%; P=0.02), and those with a history of smoking exhibited an average of 18% more PVCs (95% CI, 3-36%; P=0.02) than did never smokers. After 5 years, PVC frequency increased from a median of 0.5 (IQR, 0.1-4.7) to 1.2 (IQR, 0.1-13.8) per hour ( P<0.0001). Directly modifiable predictors of 5-year increase in PVCs, described as the odds per each quintile increase in PVCs, included increased diastolic blood pressure (odds ratio per SD increase, 1.16; 95% CI, 1.02-1.31; P=0.02) and a history of smoking (OR, 1.31; 95% CI, 1.02-1.68; P=0.04). Conclusions Enhancing physical activity, smoking cessation, and aggressive control of blood pressure may represent fruitful strategies to mitigate PVC frequency and PVC-associated adverse outcomes.

Obstructive Sleep Apnea in Heart Failure: Review of Prevalence, Treatment with Continuous Positive Airway Pressure, and Prognosis.

Obstructive sleep apnea is a sleep-related breathing disorder that has a major impact on cardiovascular function. It has been associated with hypertension, coronary artery disease, cardiac arrhythmias, sudden cardiac death, and heart failure. This review focuses on the relationship between obstructive sleep apnea and heart failure with either reduced or preserved ejection fraction. We discuss the pathophysiology of obstructive sleep apnea, as well as its prevalence, treatment outcomes with continuous positive airway pressure, and prognosis in these 2 distinct types of heart failure. We also identify areas in which further work is needed to improve our understanding of this association in heart failure patients.

Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study).

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 V1, 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 V1 (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.