TY - JOUR T1 - Sometimes higher heart rate variability is not better heart rate variability: results of graphical and nonlinear analyses. JF - J Cardiovasc Electrophysiol Y1 - 2005 A1 - Stein, Phyllis K A1 - Domitrovich, Peter P A1 - Hui, Nelson A1 - Rautaharju, Pentti A1 - Gottdiener, John KW - Aged KW - Aged, 80 and over KW - Algorithms KW - Arrhythmia, Sinus KW - Cohort Studies KW - Diagnosis, Computer-Assisted KW - Electrocardiography KW - Female KW - Heart Rate KW - Humans KW - Male KW - Models, Cardiovascular KW - Nonlinear Dynamics KW - Numerical Analysis, Computer-Assisted KW - Prevalence KW - Proportional Hazards Models KW - Reproducibility of Results KW - Risk Assessment KW - Risk Factors KW - Sensitivity and Specificity KW - United States AB -

OBJECTIVE: To determine the prevalence and effect on traditional heart rate variability (HRV) indices of abnormal HRV patterns in the elderly.

METHODS: Hourly Poincaré plots and plots of spectral HRV from normal-to-normal interbeat intervals and hourly nonlinear HRV values were examined in a subset of 290 consecutive participants in the Cardiovascular Health Study. Only subjects in normal sinus rhythm with > or = 18 hours of usable data were included. Eligible subjects were 71 +/- 5 years. During 7 years of follow-up, 21.7% had died. Hours were scored as normal (0), borderline (0.5), or abnormal (1) from a combination of plot appearance and HRV. Summed scores were normalized to 100% to create an abnormality score (ABN). Short-term HRV versus each 5th percentile of ABN was plotted and a cutpoint for markedly increased HRV identified. The t-tests compared HRV for subjects above and below this cutpoint. Cox regression evaluated the association of ABN and mortality.

RESULTS: Of 5,815 eligible hourly plots, 64.4% were normal, 14.5% borderline, and 21.1% abnormal. HR, SDNN, SDNNIDX, ln VLF and LF power, and power law slope did not differ by the cutpoint for increased short-term HRV, while SDANN and ln ULF power were significantly lower for those above the cutpoint. However, many HRV indices including LF/HF ratio and normalized LF and HF power were significantly different between groups (P < 0.001). Increased ABN was significantly associated with mortality (P = 0.019). Despite similar values for many HRV indices, being in the group above the cutpoint was significantly associated with mortality (P = 0.04).

CONCLUSIONS: Abnormal HR patterns that elevate many HRV indices are prevalent among the elderly and associated with higher risk of mortality. Consideration of abnormal HRV may improve HRV-based risk stratification.

VL - 16 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16174015?dopt=Abstract ER - TY - JOUR T1 - Dietary fish and n-3 fatty acid intake and cardiac electrocardiographic parameters in humans. JF - J Am Coll Cardiol Y1 - 2006 A1 - Mozaffarian, Dariush A1 - Prineas, Ronald J A1 - Stein, Phyllis K A1 - Siscovick, David S KW - Aged KW - Animals KW - Atrioventricular Node KW - Cross-Sectional Studies KW - Diet KW - Electrocardiography KW - Fatty Acids, Omega-3 KW - Female KW - Fishes KW - Heart KW - Heart Rate KW - Humans KW - Male KW - Ventricular Function AB -

OBJECTIVES: We evaluated the association between dietary fish intake and several cardiac electrocardiographic parameters in humans relevant to arrhythmic risk.

BACKGROUND: Fish consumption may reduce the incidence of sudden death and atrial fibrillation, possibly related to anti-arrhythmic effects.

METHODS: In a population-based study of 5,096 men and women, we evaluated cross-sectional associations between usual dietary fish intake and electrocardiographic measures of heart rate, atrioventricular conduction (PR interval), ventricular repolarization (QT interval), and ventricular conduction (QRS interval). Multivariate models were adjusted for age, gender, race, education, smoking, body mass index, diabetes, coronary heart disease, physical activity, and intakes of beef or pork, fried fish, fruits, vegetables, alcohol, and total calories.

RESULTS: Consumption of tuna or other broiled or baked fish (comparing the highest to the lowest category of intake) was associated with lower heart rate (-3.2 beats/min, 95% confidence interval [CI] = 1.3 to 5.1; p trend <0.001), slower atrioventricular conduction (PR interval +7.2 ms, 95% CI = 1.4 to 12.9; p trend = 0.03), and substantially lower likelihood of prolonged QT (relative risk = 0.50, 95% CI = 0.27 to 0.95; p trend = 0.03). Tuna/other fish intake was not associated with ventricular conduction (p = 0.60). Findings were similar for estimated intake of marine n-3 fatty acids: a 1 g/day higher intake was associated with 2.3 beats/min lower heart rate (95% CI = 0.9 to 3.7), 7.6 ms longer PR interval (95% CI = 3.3 to 11.9), and 46% lower likelihood of prolonged QT (relative risk = 0.54, 95% CI = 0.33 to 0.88).

CONCLUSIONS: These findings in this large, population-based study suggest that dietary fish intake is associated with cardiac electrophysiology in humans, including heart rate, atrioventricular conduction, and ventricular repolarization, with potential implications for arrhythmic risk.

VL - 48 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16875972?dopt=Abstract ER - TY - JOUR T1 - Dietary fish and omega-3 fatty acid consumption and heart rate variability in US adults. JF - Circulation Y1 - 2008 A1 - Mozaffarian, Dariush A1 - Stein, Phyllis K A1 - Prineas, Ronald J A1 - Siscovick, David S KW - Aged KW - Aged, 80 and over KW - Animals KW - Cardiovascular Diseases KW - Cohort Studies KW - Cross-Sectional Studies KW - Electrocardiography KW - Fatty Acids, Omega-3 KW - Female KW - Fishes KW - Heart Rate KW - Humans KW - Male KW - Risk Factors KW - Seafood KW - Tuna KW - United States AB -

BACKGROUND: Fish and omega-3 fatty acid consumption reduce risk of cardiac death, but mechanisms are not well established. Heart rate variability (HRV) predicts cardiac death and reflects specific electrophysiological pathways and influences. We hypothesized that habitual consumption of fish and marine omega-3 fatty acids would be associated with more favorable HRV, elucidating electrophysiological influences and supporting effects on clinical risk.

METHODS AND RESULTS: In a population-based cohort of older US adults, we evaluated cross-sectional associations of usual dietary fish and omega-3 consumption during the prior year and ECG-derived (n=4263) and 24-hour Holter monitor-derived (n=1152) HRV. After multivariable adjustment, consumption of tuna or other broiled/baked fish was associated with specific HRV components, including indices suggesting greater vagal predominance and moderated baroreceptor responses (eg, higher root mean square successive differences of normal-to-normal intervals [P=0.001]; higher normalized high-frequency power [P=0.008]; and lower low-frequency/high-frequency ratio [P=0.03]) and less erratic sinoatrial node firing (eg, lower Poincaré ratio [P=0.02] and higher short-term fractal scaling exponent [P=0.005]) but not measures of circadian fluctuations (eg, 24-hour standard deviation of normal-to-normal intervals). Findings were similar for estimated dietary consumption of marine omega-3 fatty acids. For magnitudes of observed differences in HRV comparing the highest to lowest category of fish intake, differences in relative risk of cardiac death during 10.8 years of follow-up ranged from 1.1% (for difference in standard deviation of normal-to-normal intervals) to 5.9% and 8.4% (for differences in Poincaré ratio and short-term fractal scaling exponent) lower risk.

CONCLUSIONS: Habitual tuna/other fish and marine omega-3 consumption are associated with specific HRV components in older adults, particularly indices of vagal activity, baroreceptor responses, and sinoatrial node function. Cellular mechanisms and implications for clinical risk deserve further investigation.

VL - 117 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18285566?dopt=Abstract ER - TY - JOUR T1 - Higher levels of inflammation factors and greater insulin resistance are independently associated with higher heart rate and lower heart rate variability in normoglycemic older individuals: the Cardiovascular Health Study. JF - J Am Geriatr Soc Y1 - 2008 A1 - Stein, Phyllis K A1 - Barzilay, Joshua I A1 - Chaves, Paulo H M A1 - Traber, Jennifer A1 - Domitrovich, Peter P A1 - Heckbert, Susan R A1 - Gottdiener, John S KW - Aged KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cross-Sectional Studies KW - Electrocardiography, Ambulatory KW - Female KW - Fibrinogen KW - Heart Rate KW - Humans KW - Inflammation Mediators KW - Insulin Resistance KW - Interleukin-6 KW - Male KW - Risk Factors AB -

OBJECTIVES: To explore the relationship between (1) insulin resistance and inflammation factors with (2) higher heart rate (HR) and lower heart rate variability (HRV) in normoglycemic older adults.

DESIGN: Cross-sectional population-based study.

PARTICIPANTS: Five hundred forty-five adults aged 65 and older with normoglycemia (fasting glucose <100 mg/dL) who participated in the Cardiovascular Health Study.

MEASUREMENTS: Serum levels of three inflammation proteins (C-reactive protein (CRP), interleukin 6 (IL-6), and fibrinogen); insulin resistance, quantified according to the homeostasis assessment model (HOMA-IR); HR; and four representative measures of HRV (the standard deviation of normal beat to beat intervals (SDNN), the root mean square of successive differences (rMSSD), very low frequency power (VLF), and the low- to high-frequency power ratio (LF/HF)) derived from 24-hour Holter recordings.

RESULTS: High CRP and IL-6 levels were associated with higher HR and lower SDNN and VLF after adjustment for multiple covariates, including HOMA-IR and clinical cardiovascular disease. High IL-6 was also associated with lower LF/HF. Significant univariate inverse relationships between HOMA-IR and HR and HRV were also found, but the strengths of these relationships were attenuated after adjustment for inflammation factors.

CONCLUSION: Increased levels of inflammation markers and HOMA-IR are associated with higher HR and lower HRV. These findings suggest that inflammation may contribute to the pathogenesis of cardiovascular autonomic decline in older adults.

VL - 56 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18179502?dopt=Abstract ER - TY - JOUR T1 - Novel measures of heart rate variability predict cardiovascular mortality in older adults independent of traditional cardiovascular risk factors: the Cardiovascular Health Study (CHS). JF - J Cardiovasc Electrophysiol Y1 - 2008 A1 - Stein, Phyllis K A1 - Barzilay, Joshua I A1 - Chaves, Paulo H M A1 - Mistretta, Stephanie Q A1 - Domitrovich, Peter P A1 - Gottdiener, John S A1 - Rich, Michael W A1 - Kleiger, Robert E KW - Aged KW - Aged, 80 and over KW - Arrhythmias, Cardiac KW - Death, Sudden, Cardiac KW - Electrocardiography, Ambulatory KW - Female KW - Heart Rate KW - Humans KW - Male KW - Maryland KW - Reproducibility of Results KW - Risk Assessment KW - Risk Factors KW - Sensitivity and Specificity KW - Survival Analysis KW - Survival Rate AB -

UNLABELLED: Novel HRV Predicts CV Mortality in the Elderly.

BACKGROUND: It is unknown whether abnormal heart rate turbulence (HRT) and abnormal fractal properties of heart rate variability identify older adults at increased risk of cardiovascular death (CVdth).

METHODS: Data from 1,172 community-dwelling adults, ages 72 +/- 5 (65-93) years, who participated in the Cardiovascular Health Study (CHS), a study of risk factors for CV disease in people >or=65 years. HRT and the short-term fractal scaling exponent (DFA1) derived from 24-hour Holter recordings. HRT categorized as: normal (turbulence slope [TS] and turbulence onset [TO] normal) or abnormal (TS and/or TO abnormal). DFA1 categorized as low (1). Cox regression analyses stratified by Framingham Risk Score (FRS) strata (low = <10, mid = 10-20, and high >20) and adjusted for prevalent clinical cardiovascular disease (CVD), diabetes, and quartiles of ventricular premature beat counts (VPCs).

RESULTS: CVdths (N = 172) occurred over a median follow-up of 12.3 years. Within each FRS stratum, low DFA1 + abnormal HRT predicted risk of CVdth (RR = 7.7 for low FRS; 3.6, mid FRS; 2.8, high FRS). Among high FRS stratum participants, low DFA1 alone also predicted CVdth (RR = 2.0). VPCs in the highest quartile predicted CVdth, but only in the high FRS group. Clinical CV disease predicted CVdth at each FRS stratum (RR = 2.9, low; 2.6, mid; and 1.9, high). Diabetes predicted CVdth in the highest FRS group only (RR = 2.2).

CONCLUSIONS: The combination of low DFA1 + abnormal HRT is a strong risk factor for CVdth among older adults even after adjustment for conventional CVD risk measures and the presence of CVD.

VL - 19 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18631274?dopt=Abstract ER - TY - JOUR T1 - Heart rate variability and its changes over 5 years in older adults. JF - Age Ageing Y1 - 2009 A1 - Stein, Phyllis K A1 - Barzilay, Joshua I A1 - Chaves, Paulo H M A1 - Domitrovich, Peter P A1 - Gottdiener, John S KW - Age Distribution KW - Aged KW - Aging KW - Atrial Premature Complexes KW - Autonomic Nervous System KW - Cardiovascular Diseases KW - Cross-Sectional Studies KW - Electrocardiography, Ambulatory KW - Female KW - Heart Rate KW - Humans KW - Hypertension KW - Male KW - Nonlinear Dynamics KW - Prevalence KW - Prospective Studies KW - Risk Factors KW - Ventricular Premature Complexes AB -

PURPOSE: to characterise the association between age, ageing and heart rate variability (HRV) in older individuals, 585 adults age >65 years with two 24-h Holter recordings in the Cardiovascular Health Study were studied.

METHODS: heart rate (HR), ventricular premature contractions (VPCs), atrial premature contractions (APCs), frequency-domain, ratio-based and non-linear HRV and heart rate turbulence (HRT) were examined cross-sectionally by 5-year age groups and prospectively over 5 years. Analyses adjusted for gender, lower versus elevated cardiovascular (CV) risk and for the change in CV risk.

RESULTS: HR declined, and VPCs and APCs increased per 5-year increase in age. Frequency-domain HRV decreased more at 65-69, less at 70-74 and minimally at > or =75 years, independent of CVD risk or change in CVD risk. Ratio and non-linear HRV continued to decline to > or =75 years old. Ratio HRV and HRT slope were more strongly related to CVD risk than frequency-domain HRV.

CONCLUSIONS: cardiac autonomic function, assessed by frequency-domain HRV, declines most at 65-70 and levels off at age >75. The decline is independent of CVD risk or change in CVD risk. Ratio-based and non-linear HRV and HRT slope continued to change with increasing age and were more closely related to CVD risk than frequency-domain HRV.

VL - 38 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19147739?dopt=Abstract ER - TY - JOUR T1 - Association of Holter-based measures including T-wave alternans with risk of sudden cardiac death in the community-dwelling elderly: the Cardiovascular Health Study. JF - J Electrocardiol Y1 - 2010 A1 - Stein, Phyllis K A1 - Sanghavi, Devang A1 - Sotoodehnia, Nona A1 - Siscovick, David S A1 - Gottdiener, John KW - Comorbidity KW - Coronary Artery Disease KW - Death, Sudden, Cardiac KW - Electrocardiography, Ambulatory KW - Female KW - Humans KW - Male KW - Prevalence KW - Prognosis KW - Reproducibility of Results KW - Risk Assessment KW - Risk Factors KW - Sensitivity and Specificity KW - Survival Analysis KW - Survival Rate KW - United States KW - Ventricular Premature Complexes AB -

BACKGROUND: Sudden cardiac death (SCD) can be the first manifestation of cardiovascular disease. Development of screening methods for higher/lower risk is critical.

METHODS: The Cardiovascular Health Study is a population-based study of risk factors for coronary heart disease and stroke those 65 years or older. Forty-nine (of 1649) with usable Holters and in normal sinus rhythm had SCD during follow-up and were matched with 2 controls, alive at the time of death of the case and not experiencing SCD on follow-up. Univariate and multivariate conditional logistic regression determined the association of Holter-based information and SCD.

RESULTS: In univariate models, the upper half of ventricular premature contraction (VPC) counts, abnormal heart rate turbulence, decreased normalized low-frequency power, increased T-wave alternans (TWA), and decreased the short-term fractal scaling exponent (DFA(1)) were associated with SCD, but time domain heart rate variability was not. In multivariate models, the upper half of VPC counts (odds ratio [OR], 6.6) and having TWA of 37 muV or greater on channel 2 (OR, 4.8) were independently associated with SCD. Also, the upper half of VPC counts (OR, 6.9) and having a DFA(1) of less than 1.05 (OR, 5.0) were independently associated with SCD. When additive effects were explored, having both higher VPCs and higher TWA was associated with an OR of 8.2 for SCD compared with 2.6 for having either. Also, having both higher VPCs and lower DFA(1) was associated with an OR of 9.6 for SCD compared with 3.1 for having either.

CONCLUSIONS: Results support a potential role for 24-hour Holter recordings to identify older adults at increased or lower risk of SCD.

VL - 43 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20096853?dopt=Abstract ER - TY - JOUR T1 - Autonomic nervous system dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression. JF - Psychosom Med Y1 - 2010 A1 - Kop, Willem J A1 - Stein, Phyllis K A1 - Tracy, Russell P A1 - Barzilay, Joshua I A1 - Schulz, Richard A1 - Gottdiener, John S KW - Aged KW - Autonomic Nervous System Diseases KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cause of Death KW - Cohort Studies KW - Comorbidity KW - Depressive Disorder KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Heart Rate KW - Humans KW - Inflammation KW - Interleukin-6 KW - Leukocyte Count KW - Male KW - Risk Factors AB -

OBJECTIVE: To investigate prospectively whether autonomic nervous system (ANS) dysfunction and inflammation play a role in the increased cardiovascular disease (CVD)-related mortality risk associated with depression.

METHODS: Participants in the Cardiovascular Health Study (n = 907; mean age, 71.3 ± 4.6 years; 59.1% women) were evaluated for ANS indices derived from heart rate variability (HRV) analysis (frequency and time domain HRV, and nonlinear indices, including detrended fluctuation analysis (DFA(1)) and heart rate turbulence). Inflammation markers included C-reactive protein, interleukin-6, fibrinogen, and white blood cell count). Depressive symptoms were assessed, using the 10-item Centers for Epidemiological Studies Depression scale. Cox proportional hazards models were used to investigate the mortality risk associated with depression, ANS, and inflammation markers, adjusting for demographic and clinical covariates.

RESULTS: Depression was associated with ANS dysfunction (DFA(1), p = .018), and increased inflammation markers (white blood cell count, p = .012, fibrinogen p = .043) adjusting for covariates. CVD-related mortality occurred in 121 participants during a median follow-up of 13.3 years. Depression was associated with an increased CVD mortality risk (hazard ratio, 1.88; 95% confidence interval, 1.23-2.86). Multivariable analyses showed that depression was an independent predictor of CVD mortality (hazard ratio, 1.72; 95% confidence interval, 1.05-2.83) when adjusting for independent HRV and inflammation predictors (DFA(1), heart rate turbulence, interleukin-6), attenuating the depression-CVD mortality association by 12.7% (p < .001).

CONCLUSION: Autonomic dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression, but a large portion of the predictive value of depression remains unexplained by these neuroimmunological measures.

VL - 72 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20639389?dopt=Abstract ER - TY - JOUR T1 - Relationship of abnormal heart rate turbulence and elevated CRP to cardiac mortality in low, intermediate, and high-risk older adults. JF - J Cardiovasc Electrophysiol Y1 - 2011 A1 - Stein, Phyllis K A1 - Barzilay, Joshua I KW - Aged KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Comorbidity KW - Electrocardiography, Ambulatory KW - Female KW - Humans KW - Incidence KW - Male KW - Risk Assessment KW - Risk Factors KW - Statistics as Topic KW - Survival Analysis KW - Survival Rate KW - United States KW - Ventricular Premature Complexes AB -

INTRODUCTION: We examined whether heart rate turbulence (HRT) and C-reactive protein (CRP) add to traditional risk factors for cardiac mortality in older adults at low, intermediate, and high risk.

METHODS AND RESULTS: One thousand two hundred and seventy-two individuals, age ≥ 65 years, with 24-hour Holter recordings were studied. HRT, which quantifies heart rate response to ventricular premature contractions, was categorized as: both turbulence onset (TO) and turbulence slope (TS) normal; TO abnormal; TS abnormal; or both abnormal. Independent risks for cardiac mortality associated with HRT or, for comparison, elevated CRP (>3.0 mg/L), were calculated using Cox regression analysis adjusted for traditional cardiovascular disease risk factors and stratified by the presence of no, isolated subclinical (i.e., intermediate risk) or clinical cardiovascular disease. Having TS + TO abnormal compared to both normal was associated with cardiac mortality in the low-risk group [HR 7.9, 95% confidence interval (CI) 2.8-22.5, (P < 0.001)]. In the high and intermediate risk groups, abnormal TS and TS + TO ([HR 2.2, 95% CI 1.5-4.0, P = 0.016] and [HR 2.7, 95% CI 1.2-5.9, P = 0.012]), respectively, were also significantly associated with cardiac mortality. In contrast, elevated CRP was associated with increased cardiac mortality risk only in low-risk individuals [HR 2.5, 95% CI 1.3-5.1, P = 0.009]. Among low risk, the c-statistic was 0.706 for the base model, 0.725 for the base model with CRP, and 0.767 for the base model with HRT.

CONCLUSIONS: Abnormal HRT independently adds to risk stratification of low, intermediate and high-risk individuals, but HRT and CRP appear to both add to stratification of those considered low risk.

VL - 22 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21134026?dopt=Abstract ER - TY - JOUR T1 - Cardiovascular physiology in premotor Parkinson's disease: a neuroepidemiologic study. JF - Mov Disord Y1 - 2012 A1 - Jain, Samay A1 - Ton, Thanh G A1 - Perera, Subashan A1 - Zheng, Yan A1 - Stein, Phyllis K A1 - Thacker, Evan A1 - Strotmeyer, Elsa S A1 - Newman, Anne B A1 - Longstreth, Will T KW - Aged KW - Antiparkinson Agents KW - Cardiovascular Physiological Phenomena KW - Carotid Stenosis KW - Cohort Studies KW - Data Interpretation, Statistical KW - Dizziness KW - Electrocardiography KW - Female KW - Heart Rate KW - Hospitalization KW - Humans KW - Longitudinal Studies KW - Male KW - Movement Disorders KW - Neurologic Examination KW - Parkinson Disease KW - Risk KW - Ultrasonography AB -

Changes in cardiovascular physiology in Parkinson's disease (PD) are common and may occur prior to diagnostic parkinsonian motor signs. We investigated associations of electrocardiographic (ECG) abnormalities, orthostasis, heart rate variability, and carotid stenosis with the risk of PD diagnosis in the Cardiovascular Health Study, a community-based cohort of older adults. ECG abnormality, orthostasis (symptomatic or asymptomatic), heart rate variability (24-hour Holter monitoring), and any carotid stenosis (≥1%) by ultrasound were modeled as primary predictors of incident PD diagnosis using multivariable logistic regression. Incident PD cases were identified by at least 1 of the following: self-report, antiparkinsonian medication use, and ICD-9. If unadjusted models were significant, they were adjusted or stratified by age, sex, and smoking status, and those in which predictors were still significant (P ≤ .05) were also adjusted for race, diabetes, total cholesterol, low-density lipoprotein, blood pressure, body mass index, physical activity, education level, stroke, and C-reactive protein. Of 5888 participants, 154 incident PD cases were identified over 14 years of follow-up. After adjusting models with all covariates, those with any ECG abnormality (odds ratio [OR], 1.45; 95% CI, 1.02-2.07; P = .04) or any carotid stenosis (OR, 2.40; 95% CI, 1.40-4.09; P = .001) at baseline had a higher risk of incident PD diagnosis. Orthostasis and heart rate variability were not significant predictors. This exploratory study suggests that carotid stenosis and ECG abnormalities occur prior to motor signs in PD, thus serving as potential premotor features or risk factors for PD diagnosis. Replication is needed in a population with more thorough ascertainment of PD onset.

VL - 27 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22700356?dopt=Abstract ER - TY - JOUR T1 - Heart rate response to a timed walk and cardiovascular outcomes in older adults: the cardiovascular health study. JF - Cardiology Y1 - 2012 A1 - Girotra, Saket A1 - Kitzman, Dalane W A1 - Kop, Willem J A1 - Stein, Phyllis K A1 - Gottdiener, John S A1 - Mukamal, Kenneth J KW - Aged KW - Cause of Death KW - Coronary Disease KW - Exercise Test KW - Female KW - Heart Rate KW - Humans KW - Male KW - Physical Exertion KW - Prognosis KW - Prospective Studies KW - Risk Factors KW - Time Factors KW - Walking AB -

OBJECTIVES: To determine the relationship between heart rate response during low-grade physical exertion (6-min walk) with mortality and adverse cardiovascular outcomes in the elderly.

METHODS: Participants in the Cardiovascular Health Study who completed a 6-min walk test were included. We used delta heart rate (difference between postwalk heart rate and resting heart rate) as a measure of chronotropic response and examined its association with (1) all-cause mortality and (2) incident coronary heart disease event, using multivariable Cox regression models.

RESULTS: We included 2,224 participants (mean age 77 ± 4 years; 60% women; 85% white). The average delta heart rate was 26 beats/min. Participants in the lowest tertile of delta heart rate (<20 beats/min) had higher risk-adjusted mortality [hazard ratio (HR) 1.18, 95% confidence interval (CI) 1.00-1.40] and incident coronary heart disease (HR 1.37, 95% CI 1.05-1.78) compared to subjects in the highest tertile (≥30 beats/min), with a significant linear trend across tertiles (p for trend <0.05 for both outcomes). This relationship was not significant after adjustment for distance walked.

CONCLUSION: Impaired chronotropic response during a 6-min walk test was associated with an increased risk of mortality and incident coronary heart disease among the elderly. This association was attenuated after adjusting for distance walked.

VL - 122 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22722364?dopt=Abstract ER - TY - JOUR T1 - Trans-fatty acid consumption and heart rate variability in 2 separate cohorts of older and younger adults. JF - Circ Arrhythm Electrophysiol Y1 - 2012 A1 - Soares-Miranda, Luisa A1 - Stein, Phyllis K A1 - Imamura, Fumiaki A1 - Sattelmair, Jacob A1 - Lemaitre, Rozenn N A1 - Siscovick, David S A1 - Mota, Jorge A1 - Mozaffarian, Dariush KW - Adolescent KW - Age Factors KW - Aged KW - Aging KW - Arrhythmias, Cardiac KW - Cohort Studies KW - Cross-Sectional Studies KW - Dietary Fats KW - Electrocardiography, Ambulatory KW - Feeding Behavior KW - Female KW - Heart Rate KW - Humans KW - Linear Models KW - Longitudinal Studies KW - Male KW - Multivariate Analysis KW - Portugal KW - Predictive Value of Tests KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Surveys and Questionnaires KW - Trans Fatty Acids KW - United States KW - Young Adult AB -

BACKGROUND: Trans-fatty acid (TFA) consumption is associated with risk of coronary heart disease, and trans-18:2, but not trans-18:1, in red blood cell membranes has been associated with sudden cardiac arrest. Abnormal heart rate variability (HRV) reflects autonomic dysfunction and predicts cardiac death. Relationships between TFA consumption and HRV remain understudied. We determined whether total TFA consumption, as well as trans-18:1 and trans-18:2 TFA consumption, was independently associated with HRV in 2 independent cohorts in the United States and Portugal.

METHODS AND RESULTS: In 2 independent cohorts of older US adults (Cardiovascular Health Study [CHS], age 72±5 years, 1989/1995) and young Portuguese adults (Porto, age 19±2 years, 2008/2010), we assessed habitual TFA intake by food frequency questionnaires in CHS (separately estimating trans-18:1 and trans-18:2) and multiple 24-hour recalls in Porto (estimating total TFA only, which in a subset correlated with circulating trans-18:2 but not trans-18:1, suggesting that we captured the former). HRV was assessed using 24-hour Holters in CHS (n=1076) and repeated short-term (5-minute) ECGs in Porto (n=160). We used multivariate-adjusted linear regression to relate TFA consumption to HRV cross-sectionally (CHS, Porto) and longitudinally (CHS). In CHS, higher trans-18:2 consumption was associated with lower 24-hour SD of all normal-to-normal intervals both cross-sectionally (-12%; 95% CI, -19% to -6%; P=0.001) and longitudinally (-15%; 95% CI, -25% to -4%; P= 0.009) and lower 24-hour SD of 5-minute average N-N intervals and mean of the 5-minute SD of N-N intervals calculated over 24 hours (P<0.05 each). Higher trans-18:1 consumption in CHS was associated with more favorable 24-hour HRV in particular time-domain indices (24-hour SD of all normal-to-normal intervals, SD of 5-minute average N-N intervals, mean of the 5-minute SD of N-N intervals calculated over 24 hours; P<0.05 each). In Porto, each higher SD TFA consumption was associated with 4% lower 5-minute 24-hour SD of all normal-to-normal intervals (95% CI, -8% to -1%; P=0.04) and 7% lower 5-minute square root of the mean of the squares of successive N-N differences (95% CI, -13% to -1%; P=0.04).

CONCLUSIONS: Trans-18:2 consumption is associated with specific, less favorable indices of HRV in both older and young adults. Trans-18:1 consumption is associated with more favorable HRV indices in older adults. Our results support the need to investigate potential HRV-related mechanisms, whereby trans-18:2 may increase arrhythmic risk.

VL - 5 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22772898?dopt=Abstract ER - TY - JOUR T1 - Atrial ectopy as a predictor of incident atrial fibrillation: a cohort study. JF - Ann Intern Med Y1 - 2013 A1 - Dewland, Thomas A A1 - Vittinghoff, Eric A1 - Mandyam, Mala C A1 - Heckbert, Susan R A1 - Siscovick, David S A1 - Stein, Phyllis K A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Gottdiener, John S A1 - Marcus, Gregory M KW - Aged KW - Atrial Fibrillation KW - Atrial Function KW - Cause of Death KW - Electrocardiography KW - Female KW - Humans KW - Male KW - Models, Statistical KW - Myocardial Contraction KW - Prospective Studies KW - Risk Assessment AB -

BACKGROUND: Atrial fibrillation (AF) prediction models have unclear clinical utility given the absence of AF prevention therapies and the immutability of many risk factors. Premature atrial contractions (PACs) play a critical role in AF pathogenesis and may be modifiable.

OBJECTIVE: To investigate whether PAC count improves model performance for AF risk.

DESIGN: Prospective cohort study.

SETTING: 4 U.S. communities.

PATIENTS: A random subset of 1260 adults without prevalent AF enrolled in the Cardiovascular Health Study between 1989 and 1990.

MEASUREMENTS: The PAC count was quantified by 24-hour electrocardiography. Participants were followed for the diagnosis of incident AF or death. The Framingham AF risk algorithm was used as the comparator prediction model.

RESULTS: In adjusted analyses, doubling the hourly PAC count was associated with a significant increase in AF risk (hazard ratio, 1.17 [95% CI, 1.13 to 1.22]; P < 0.001) and overall mortality (hazard ratio, 1.06 [CI, 1.03 to 1.09]; P < 0.001). Compared with the Framingham model, PAC count alone resulted in similar AF risk discrimination at 5 and 10 years of follow-up and superior risk discrimination at 15 years. The addition of PAC count to the Framingham model resulted in significant 10-year AF risk discrimination improvement (c-statistic, 0.65 vs. 0.72; P < 0.001), net reclassification improvement (23.2% [CI, 12.8% to 33.6%]; P < 0.001), and integrated discrimination improvement (5.6% [CI, 4.2% to 7.0%]; P < 0.001). The specificity for predicting AF at 15 years exceeded 90% for PAC counts more than 32 beats/h.

LIMITATION: This study does not establish a causal link between PACs and AF.

CONCLUSION: The addition of PAC count to a validated AF risk algorithm provides superior AF risk discrimination and significantly improves risk reclassification. Further study is needed to determine whether PAC modification can prospectively reduce AF risk.

PRIMARY FUNDING SOURCE: American Heart Association, Joseph Drown Foundation, and National Institutes of Health.

VL - 159 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24297188?dopt=Abstract ER - TY - JOUR T1 - Cardiomyocyte injury assessed by a highly sensitive troponin assay and sudden cardiac death in the community: the Cardiovascular Health Study. JF - J Am Coll Cardiol Y1 - 2013 A1 - Hussein, Ayman A A1 - Gottdiener, John S A1 - Bartz, Traci M A1 - Sotoodehnia, Nona A1 - DeFilippi, Christopher A1 - Dickfeld, Timm A1 - Deo, Rajat A1 - Siscovick, David A1 - Stein, Phyllis K A1 - Lloyd-Jones, Donald KW - Aged KW - Ambulatory Care KW - Biomarkers KW - Death, Sudden, Cardiac KW - Female KW - Heart Arrest KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Myocardium KW - Myocytes, Cardiac KW - Proportional Hazards Models KW - Risk Assessment KW - Troponin T AB -

OBJECTIVES: This study sought to determine the association between markers of cardiomyocyte injury in ambulatory subjects and sudden cardiac death (SCD).

BACKGROUND: The pathophysiology of SCD is complex but is believed to be associated with an abnormal cardiac substrate in most cases. The association between biomarkers of cardiomyocyte injury in ambulatory subjects and SCD has not been investigated.

METHODS: Levels of cardiac troponin T, a biomarker of cardiomyocyte injury, were measured by a highly sensitive assay (hsTnT) in 4,431 ambulatory participants in the Cardiovascular Health Study, a longitudinal community-based prospective cohort study. Serial measures were obtained in 3,089 subjects. All deaths, including SCD, were adjudicated by a central events committee.

RESULTS: Over a median follow-up of 13.1 years, 246 participants had SCD. Baseline levels of hsTnT were significantly associated with SCD (hazard ratio [HR] for +1 log(hsTnT): 2.04, 95% confidence interval [CI]: 1.78 to 2.34]. This association persisted in covariate-adjusted Cox analyses accounting for baseline risk factors (HR: 1.30, 95% CI: 1.05 to 1.62), as well as for incident heart failure and myocardial infarction (HR: 1.26, 95% CI: 1.01 to 1.57). The population was also categorized into 3 groups based on baseline hsTnT levels and SCD risk [fully adjusted HR: 1.89 vs. 1.55 vs. 1 (reference group) for hsTnT ≥12.10 vs. 5.01 to 12.09 vs. ≤ 5.00 pg/ml, respectively; p trend = 0.005]. On serial measurements, change in hsTnT levels was also associated with SCD risk (fully adjusted HR for +1 pg/ml per year increase from baseline: 1.03, 95% CI: 1.01 to 1.06).

CONCLUSIONS: The findings suggest an association between cardiomyocyte injury in ambulatory subjects and SCD risk beyond that of traditional risk factors.

VL - 62 IS - 22 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23973690?dopt=Abstract ER - TY - JOUR T1 - Impact of inflammatory biomarkers on relation of high density lipoprotein-cholesterol with incident coronary heart disease: cardiovascular Health Study. JF - Atherosclerosis Y1 - 2013 A1 - Tehrani, David M A1 - Gardin, Julius M A1 - Yanez, David A1 - Hirsch, Calvin H A1 - Lloyd-Jones, Donald M A1 - Stein, Phyllis K A1 - Wong, Nathan D KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - African Americans KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Humans KW - Incidence KW - Inflammation KW - Interleukin-6 KW - Male KW - Middle Aged KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: Inflammatory factors and low HDL-C relate to CHD risk, but whether inflammation attenuates any protective association of high HDL-C is unknown.

OBJECTIVE: Investigate inflammatory markers' individual and collective impact on the association of HDL-C with incident coronary heart disease (CHD).

METHODS: In 3888 older adults without known cardiovascular disease (CVD), we examined if the inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and lipoprotein-associated phospholipase A2 (Lp-PLA₂) modify the relation of HDL-C with CHD. HDL-C, CRP, IL-6, and Lp-PLA₂ values were grouped as using gender-specific tertiles. Also, an inflammation index of z-score sums for CRP, IL-6, and Lp-PLA₂ was categorized into tertiles. We calculated CHD incidence for each HDL-C/inflammation group and performed Cox regression, adjusted for standard CVD risk factors and triglycerides to examine the relationship of combined HDL-C-inflammation groups with incident events.

RESULTS: CHD incidence (per 1000 person years) was higher for higher levels of CRP, IL-6, and the index, and lower for higher levels of HDL-C. Compared to high HDL-C/low-inflammation categories (referent), adjusted HRs for incident CHD were increased for those with high HDL-C and high CRP (HR = 1.50, p < 0.01) or highest IL-6 tertile (HR = 1.40, p < 0.05), but not with highest Lp-PLA₂ tertile. Higher CHD incidence was similarly seen for those with intermediate or low HDL-C accompanied by high CRP, high IL-6, or a high inflammatory index.

CONCLUSION: The protective relation of high HDL-C for incident CHD appears to be attenuated by greater inflammation.

VL - 231 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24267235?dopt=Abstract ER - TY - JOUR T1 - Inflammation and sudden cardiac death in a community-based population of older adults: the Cardiovascular Health Study. JF - Heart Rhythm Y1 - 2013 A1 - Hussein, Ayman A A1 - Gottdiener, John S A1 - Bartz, Traci M A1 - Sotoodehnia, Nona A1 - DeFilippi, Christopher A1 - See, Vincent A1 - Deo, Rajat A1 - Siscovick, David A1 - Stein, Phyllis K A1 - Lloyd-Jones, Donald KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - C-Reactive Protein KW - Case-Control Studies KW - Cohort Studies KW - Death, Sudden, Cardiac KW - Female KW - Humans KW - Inflammation KW - Interleukin-6 KW - Male KW - Risk Factors AB -

BACKGROUND: Inflammation is linked to adverse cardiovascular events, but its association with sudden cardiac death (SCD) has been controversial. Older subjects, who are at particular risk for SCD, were underrepresented in previous studies addressing this issue.

OBJECTIVE: The purpose of this study was to study the association between inflammation and SCD in a community-based population of older adults.

METHODS: In the Cardiovascular Health Study, 5806 and 5382 participants had measurements of C-reactive protein (CRP) and interleukin-6 (IL6), respectively, and were followed for up to 17 years. SCD risk as a function of baseline IL-6 and CRP was assessed in the overall population and in a group of participants without known prevalent cardiac disease.

RESULTS: In univariate analyses, both IL-6 (hazard ratio [HR] 1.79 for 1+ log IL-6, 95% confidence interval [CI] 1.50-2.13; 5th vs 1st quintile HR 3.36, 95% CI 2.24-5.05) and CRP (HR 1.31 for 1+ log CRP, 95% CI 1.18-1.45; 5th vs 1st quintile HR 2.00, 95% CI 1.40-2.87) were associated with SCD risk. In covariate-adjusted analyses, accounting for baseline risk factors, incident myocardial infarction, and heart failure, the association with SCD risk persisted for IL-6 (HR 1.26 for 1+ log IL-6, 95% CI 1.02-1.56; 5th vs 1st quintile HR 1.63, 95% CI 1.03-2.56) but was significantly attenuated for CRP (HR 1.13 for 1+ log CRP, 95% CI 1.00-1.28; 5th vs 1st quintile HR 1.34, 95% CI 0.88-2.05). Similar findings were observed in participants without prevalent cardiac disease.

CONCLUSION: Greater burden of inflammation, assessed by IL-6 levels, is associated with SCD risk beyond traditional risk factors, incident myocardial infarction, and heart failure.

VL - 10 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23906927?dopt=Abstract ER - TY - JOUR T1 - Physical activity and heart rate variability in older adults: the Cardiovascular Health Study. JF - Circulation Y1 - 2014 A1 - Soares-Miranda, Luisa A1 - Sattelmair, Jacob A1 - Chaves, Paulo A1 - Duncan, Glen E A1 - Siscovick, David S A1 - Stein, Phyllis K A1 - Mozaffarian, Dariush KW - Aged KW - Cardiovascular Diseases KW - Cross-Sectional Studies KW - Electrocardiography, Ambulatory KW - Female KW - Follow-Up Studies KW - Health Status KW - Heart Rate KW - Humans KW - Leisure Activities KW - Longitudinal Studies KW - Male KW - Motor Activity KW - Prospective Studies KW - Walking AB -

BACKGROUND: Cardiac mortality and electrophysiological dysfunction both increase with age. Heart rate variability (HRV) provides indices of autonomic function and electrophysiology that are associated with cardiac risk. How habitual physical activity among older adults prospectively relates to HRV, including nonlinear indices of erratic sinus patterns, is not established. We hypothesized that increasing the levels of both total leisure-time activity and walking would be prospectively associated with more favorable time-domain, frequency-domain, and nonlinear HRV measures in older adults.

METHODS AND RESULTS: We evaluated serial longitudinal measures of both physical activity and 24-hour Holter HRV over 5 years among 985 older US adults in the community-based Cardiovascular Health Study. After multivariable adjustment, greater total leisure-time activity, walking distance, and walking pace were each prospectively associated with specific, more favorable HRV indices, including higher 24-hour standard deviation of all normal-to-normal intervals (Ptrend=0.009, 0.02, 0.06, respectively) and ultralow-frequency power (Ptrend=0.02, 0.008, 0.16, respectively). Greater walking pace was also associated with a higher short-term fractal scaling exponent (Ptrend=0.003) and lower Poincaré ratio (Ptrend=0.02), markers of less erratic sinus patterns.

CONCLUSIONS: Greater total leisure-time activity, and walking alone, as well, were prospectively associated with more favorable and specific indices of autonomic function in older adults, including several suggestive of more normal circadian fluctuations and less erratic sinoatrial firing. Our results suggest potential mechanisms that might contribute to lower cardiovascular mortality with habitual physical activity later in life.

VL - 129 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24799513?dopt=Abstract ER - TY - JOUR T1 - Association between left atrial abnormality on ECG and vascular brain injury on MRI in the Cardiovascular Health Study. JF - Stroke Y1 - 2015 A1 - Kamel, Hooman A1 - Bartz, Traci M A1 - Longstreth, W T A1 - Okin, Peter M A1 - Thacker, Evan L A1 - Patton, Kristen K A1 - Stein, Phyllis K A1 - Gottesman, Rebecca F A1 - Heckbert, Susan R A1 - Kronmal, Richard A A1 - Elkind, Mitchell S V A1 - Soliman, Elsayed Z KW - Aged KW - Atrial Fibrillation KW - Brain KW - Brain Infarction KW - Cardiovascular Diseases KW - Cerebrovascular Trauma KW - Electrocardiography KW - Female KW - Heart Atria KW - Heart Diseases KW - Humans KW - Linear Models KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Prospective Studies KW - Regression Analysis KW - Risk Factors KW - Treatment Outcome AB -

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 V1 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 V1 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 V1 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 V1 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.

VL - 46 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25677594?dopt=Abstract ER - TY - JOUR T1 - Ventricular Ectopy as a Predictor of Heart Failure and Death. JF - J Am Coll Cardiol Y1 - 2015 A1 - Dukes, Jonathan W A1 - Dewland, Thomas A A1 - Vittinghoff, Eric A1 - Mandyam, Mala C A1 - Heckbert, Susan R A1 - Siscovick, David S A1 - Stein, Phyllis K A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Gottdiener, John S A1 - Marcus, Gregory M KW - Aged KW - Catheter Ablation KW - Echocardiography KW - Electrocardiography, Ambulatory KW - Female KW - Forecasting KW - Heart Failure KW - Humans KW - Male KW - Risk Factors KW - Stroke Volume KW - Ventricular Premature Complexes AB -

BACKGROUND: Studies of patients presenting for catheter ablation suggest that premature ventricular contractions (PVCs) are a modifiable risk factor for congestive heart failure (CHF). The relationship among PVC frequency, incident CHF, and mortality in the general population remains unknown.

OBJECTIVES: The goal of this study was to determine whether PVC frequency ascertained using a 24-h Holter monitor is a predictor of a decrease in the left ventricular ejection fraction (LVEF), incident CHF, and death in a population-based cohort.

METHODS: We studied 1,139 Cardiovascular Health Study (CHS) participants who were randomly assigned to 24-h ambulatory electrocardiography (Holter) monitoring and who had a normal LVEF and no history of CHF. PVC frequency was quantified using Holter studies, and LVEF was measured from baseline and 5-year echocardiograms. Participants were followed for incident CHF and death.

RESULTS: Those in the upper quartile versus the lowest quartile of PVC frequency had a multivariable-adjusted, 3-fold greater odds of a 5-year decrease in LVEF (odds ratio [OR]: 3.10; 95% confidence interval [CI]: 1.42 to 6.77; p = 0.005), a 48% increased risk of incident CHF (HR: 1.48; 95% CI: 1.08 to 2.04; p = 0.02), and a 31% increased risk of death (HR: 1.31; 95% CI: 1.06 to 1.63; p = 0.01) during a median follow-up of >13 years. Similar statistically significant results were observed for PVCs analyzed as a continuous variable. The specificity for the 15-year risk of CHF exceeded 90% when PVCs included at least 0.7% of ventricular beats. The population-level risk for incident CHF attributed to PVCs was 8.1% (95% CI: 1.2% to 14.9%).

CONCLUSIONS: In a population-based sample, a higher frequency of PVCs was associated with a decrease in LVEF, an increase in incident CHF, and increased mortality. Because of the capacity to prevent PVCs through medical or ablation therapy, PVCs may represent a modifiable risk factor for CHF and death.

VL - 66 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26160626?dopt=Abstract ER - TY - JOUR T1 - Consumption of Caffeinated Products and Cardiac Ectopy. JF - J Am Heart Assoc Y1 - 2016 A1 - Dixit, Shalini A1 - Stein, Phyllis K A1 - Dewland, Thomas A A1 - Dukes, Jonathan W A1 - Vittinghoff, Eric A1 - Heckbert, Susan R A1 - Marcus, Gregory M AB -

BACKGROUND: Premature cardiac contractions are associated with increased morbidity and mortality. Though experts associate premature atrial contractions (PACs) and premature ventricular contractions (PVCs) with caffeine, there are no data to support this relationship in the general population. As certain caffeinated products may have cardiovascular benefits, recommendations against them may be detrimental.

METHODS AND RESULTS: We studied Cardiovascular Health Study participants with a baseline food frequency assessment, 24-hour ambulatory electrocardiography (Holter) monitoring, and without persistent atrial fibrillation. Frequencies of habitual coffee, tea, and chocolate consumption were assessed using a picture-sort food frequency survey. The main outcomes were PACs/h and PVCs/hour. Among 1388 participants (46% male, mean age 72 years), 840 (61%) consumed ≥1 caffeinated product per day. The median numbers of PACs and PVCs/h and interquartile ranges were 3 (1-12) and 1 (0-7), respectively. There were no differences in the number of PACs or PVCs/h across levels of coffee, tea, and chocolate consumption. After adjustment for potential confounders, more frequent consumption of these products was not associated with ectopy. In examining combined dietary intake of coffee, tea, and chocolate as a continuous measure, no relationships were observed after multivariable adjustment: 0.48% fewer PACs/h (95% CI -4.60 to 3.64) and 2.87% fewer PVCs/h (95% CI -8.18 to 2.43) per 1-serving/week increase in consumption.

CONCLUSIONS: In the largest study to evaluate dietary patterns and quantify cardiac ectopy using 24-hour Holter monitoring, we found no relationship between chronic consumption of caffeinated products and ectopy.

VL - 5 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26813889?dopt=Abstract ER - TY - JOUR T1 - Electrocardiographic Predictors of Incident Atrial Fibrillation. JF - Am J Cardiol Y1 - 2016 A1 - Nguyen, Kaylin T A1 - Vittinghoff, Eric A1 - Dewland, Thomas A A1 - Mandyam, Mala C A1 - Stein, Phyllis K A1 - Soliman, Elsayed Z A1 - Heckbert, Susan R A1 - Marcus, Gregory M AB -

Atrial fibrillation (AF) is likely secondary to multiple different pathophysiological mechanisms that are increasingly but incompletely understood. Motivated by the hypothesis that 3 previously described electrocardiographic predictors of AF identify distinct AF mechanisms, we sought to determine if these electrocardiographic findings independently predict incident disease. Among Cardiovascular Health Study participants without prevalent AF, we determined whether left anterior fascicular block (LAFB), a prolonged QTC, and atrial premature complexes (APCs) each predicted AF after adjusting for each other. We then calculated the attributable risk in the exposed for each electrocardiographic marker. LAFB and QTC intervals were assessed on baseline 12-lead electrocardiogram (n = 4,696). APC count was determined using 24-hour Holter recordings obtained in a random subsample (n = 1,234). After adjusting for potential confounders and each electrocardiographic marker, LAFB (hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.1 to 3.9, p = 0.023), a prolonged QTC (HR 2.5, 95% CI 1.4 to 4.3, p = 0.002), and every doubling of APC count (HR 1.2, 95% CI 1.1 to 1.3, p <0.001) each remained independently predictive of incident AF. The attributable risk of AF in the exposed was 35% (95% CI 13% to 52%) for LAFB, 25% (95% CI 0.6% to 44%) for a prolonged QTC, and 34% (95% CI 26% to 42%) for APCs. In conclusion, in a community-based cohort, 3 previously established electrocardiogram-derived AF predictors were each independently associated with incident AF, suggesting that they may represent distinct mechanisms underlying the disease.

VL - 118 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27448684?dopt=Abstract ER - TY - JOUR T1 - Addition of 24-Hour Heart Rate Variability Parameters to the Cardiovascular Health Study Stroke Risk Score and Prediction of Incident Stroke: The Cardiovascular Health Study. JF - J Am Heart Assoc Y1 - 2017 A1 - Bodapati, Rohan K A1 - Kizer, Jorge R A1 - Kop, Willem J A1 - Kamel, Hooman A1 - Stein, Phyllis K AB -

BACKGROUND: Heart rate variability (HRV) characterizes cardiac autonomic functioning. The association of HRV with stroke is uncertain. We examined whether 24-hour HRV added predictive value to the Cardiovascular Health Study clinical stroke risk score (CHS-SCORE), previously developed at the baseline examination.

METHODS AND RESULTS: N=884 stroke-free CHS participants (age 75.3±4.6), with 24-hour Holters adequate for HRV analysis at the 1994-1995 examination, had 68 strokes over ≤8 year follow-up (median 7.3 [interquartile range 7.1-7.6] years). The value of adding HRV to the CHS-SCORE was assessed with stepwise Cox regression analysis. The CHS-SCORE predicted incident stroke (HR=1.06 per unit increment, P=0.005). Two HRV parameters, decreased coefficient of variance of NN intervals (CV%, P=0.031) and decreased power law slope (SLOPE, P=0.033) also entered the model, but these did not significantly improve the c-statistic (P=0.47). In a secondary analysis, dichotomization of CV% (LOWCV% ≤12.8%) was found to maximally stratify higher-risk participants after adjustment for CHS-SCORE. Similarly, dichotomizing SLOPE (LOWSLOPE <-1.4) maximally stratified higher-risk participants. When these HRV categories were combined (eg, HIGHCV% with HIGHSLOPE), the c-statistic for the model with the CHS-SCORE and combined HRV categories was 0.68, significantly higher than 0.61 for the CHS-SCORE alone (P=0.02).

CONCLUSIONS: In this sample of older adults, 2 HRV parameters, CV% and power law slope, emerged as significantly associated with incident stroke when added to a validated clinical risk score. After each parameter was dichotomized based on its optimal cut point in this sample, their composite significantly improved prediction of incident stroke during ≤8-year follow-up. These findings will require validation in separate, larger cohorts.

VL - 6 IS - 7 ER - TY - JOUR T1 - Association of Holter-Derived Heart Rate Variability Parameters With the Development of Congestive Heart Failure in the Cardiovascular Health Study. JF - JACC Heart Fail Y1 - 2017 A1 - Patel, Vaiibhav N A1 - Pierce, Brian R A1 - Bodapati, Rohan K A1 - Brown, David L A1 - Ives, Diane G A1 - Stein, Phyllis K AB -

OBJECTIVES: This study sought to determine whether Holter-based parameters of heart rate variability (HRV) are independently associated with incident heart failure among older adults in the CHS (Cardiovascular Health Study) as evidenced by an improvement in the predictive power of the Health Aging and Body Composition Heart Failure (Health ABC) score.

BACKGROUND: Abnormal HRV, a marker of autonomic dysfunction, has been associated with multiple adverse cardiovascular outcomes but not the development of congestive heart failure (CHF).

METHODS: Asymptomatic CHS participants with interpretable 24-h baseline Holter recordings were included (n = 1,401). HRV measures and premature ventricular contraction (PVC) counts were compared between participants with (n = 260) and without (n = 1,141) incident CHF on follow-up. Significantly different parameters between groups were added to the components of the Health ABC score, a validated CHF prediction tool, using stepwise Cox regression.

RESULTS: The final model included components of the Health ABC score, In PVC counts (adjusted hazard ratio [aHR]: 1.12; 95% confidence interval [CI]: 1.07 to 1.19; p < 0.001) and the following HRV measures: abnormal heart rate turbulence onset (aHR: 1.52; 95% CI: 1.11 to 2.08; p = 0.009), short-term fractal scaling exponent (aHR: 0.27; 95% CI: 0.14 to 0.53; p < 0.001), in very low frequency power (aHR: 1.28; 95% CI: 1.02 to 1.60; p = 0.037), and coefficient of variance of N-N intervals (aHR: 0.94; 95% CI: 0.90 to 0.99; p = 0.009). The C-statistic for the final model was significantly improved over the Health ABC model alone (0.77 vs. 0.73; p = 0.0002).

CONCLUSIONS: Abnormal HRV parameters were significantly and independently associated with incident CHF in asymptomatic, older adults. When combined with increased PVCs, HRV improved the predictive power of the Health ABC score.

ER - TY - JOUR T1 - Atrial ectopy as a mediator of the association between race and atrial fibrillation. JF - Heart Rhythm Y1 - 2017 A1 - Christensen, Matthew A A1 - Nguyen, Kaylin T A1 - Stein, Phyllis K A1 - Fohtung, Raymond B A1 - Soliman, Elsayed Z A1 - Dewland, Thomas A A1 - Vittinghoff, Eric A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Marcus, Gregory M AB -

BACKGROUND: Blacks have a lower risk of atrial fibrillation (AF) despite having more AF risk factors, but the mechanism remains unknown. Premature atrial contraction (PAC) burden is a recently identified risk factor for AF.

OBJECTIVE: The purpose of this study was to determine whether the burden of PACs explains racial differences in AF risk.

METHODS: PAC burden (number per hour) was assessed by 24-hour ambulatory electrocardiographic (ECG) monitoring in a randomly selected subset of patients in the Cardiovascular Health Study. Participants were followed prospectively for the development of AF, diagnosed by study ECG and hospital admission records.

RESULTS: Among 938 participants (median age 73 years; 34% black; 58% female), 206 (22%) developed AF over a median follow-up of 11.0 years (interquartile range 6.1-13.4). After adjusting for age, sex, body mass index, coronary disease, congestive heart failure, diabetes, hypertension, alcohol consumption, smoking status, and study site, black race was associated with a 42% lower risk of AF (hazard ratio 0.58, 95% confidence interval [CI] 0.40-0.85; P = .005). The baseline PAC burden was 2.10 times (95% CI 1.57-2.83; P <.001) higher in whites than blacks. There was no detectable difference in premature ventricular contraction (PVC) burden by race. PAC burden mediated 19.5% (95% CI 6.3-52.5) of the adjusted association between race and AF.

CONCLUSION: On average, whites exhibited more PACs than blacks, and this difference statistically explains a modest proportion of the differential risk of AF by race. The differential PAC burden, without differences in PVCs, by race suggests that identifiable common exposures or genetic influences might be important to atrial pathophysiology.

VL - 14 IS - 12 ER - TY - JOUR T1 - Bone Mineral Density and Risk of Heart Failure in Older Adults: The Cardiovascular Health Study. JF - J Am Heart Assoc Y1 - 2017 A1 - Fohtung, Raymond B A1 - Brown, David L A1 - Koh, William J H A1 - Bartz, Traci M A1 - Carbone, Laura D A1 - Civitelli, Roberto A1 - Stein, Phyllis K A1 - Chaves, Paulo H M A1 - Kestenbaum, Bryan R A1 - Kizer, Jorge R AB -

BACKGROUND: Despite increasing evidence of a common link between bone and heart health, the relationship between bone mineral density (BMD) and heart failure (HF) risk remains insufficiently studied.

METHODS AND RESULTS: We investigated whether BMD measured by dual-energy x-ray absorptiometry was associated with incident HF in an older cohort. Cox models were stratified by sex and interactions of BMD with race assessed. BMD was examined at the total hip and femoral neck separately, both continuously and by World Health Organization categories. Of 1250 participants, 442 (55% women) developed HF during the median follow-up of 10.5 years. In both black and nonblack women, neither total hip nor femoral neck BMD was significantly associated with HF; there was no significant interaction by race. In black and nonblack men, total hip, but not femoral neck, BMD was significantly associated with HF, with evidence of an interaction by race. In nonblack men, lower total hip BMD was associated with higher HF risk (hazard ratio, 1.13 [95% CI, 1.01-1.26] per 0.1 g/cm(2) decrement), whereas in black men, lower total hip BMD was associated with lower HF risk (hazard ratio, 0.74 [95% CI, 0.59-0.94]). There were no black men with total hip osteoporosis. Among nonblack men, total hip osteoporosis was associated with higher HF risk (hazard ratio, 2.83 [95% CI, 1.39-5.74]) compared with normal BMD.

CONCLUSIONS: Among older adults, lower total hip BMD was associated with higher HF risk in nonblack men but lower risk in black men, with no evidence of an association in women. Further research is needed to replicate these findings and to study potential underlying pathways.

VL - 6 IS - 3 ER - TY - JOUR T1 - Ectopy on a Single 12-Lead ECG, Incident Cardiac Myopathy, and Death in the Community. JF - J Am Heart Assoc Y1 - 2017 A1 - Nguyen, Kaylin T A1 - Vittinghoff, Eric A1 - Dewland, Thomas A A1 - Dukes, Jonathan W A1 - Soliman, Elsayed Z A1 - Stein, Phyllis K A1 - Gottdiener, John S A1 - Alonso, Alvaro A1 - Chen, Lin Y A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Marcus, Gregory M AB -

BACKGROUND: Atrial fibrillation and heart failure are 2 of the most common diseases, yet ready means to identify individuals at risk are lacking. The 12-lead ECG is one of the most accessible tests in medicine. Our objective was to determine whether a premature atrial contraction observed on a standard 12-lead ECG would predict atrial fibrillation and mortality and whether a premature ventricular contraction would predict heart failure and mortality.

METHODS AND RESULTS: We utilized the CHS (Cardiovascular Health) Study, which followed 5577 participants for a median of 12 years, as the primary cohort. The ARIC (Atherosclerosis Risk in Communities Study), the replication cohort, captured data from 15 792 participants over a median of 22 years. In the CHS, multivariable analyses revealed that a baseline 12-lead ECG premature atrial contraction predicted a 60% increased risk of atrial fibrillation (hazard ratio, 1.6; 95% CI, 1.3-2.0; P<0.001) and a premature ventricular contraction predicted a 30% increased risk of heart failure (hazard ratio, 1.3; 95% CI, 1.0-1.6; P=0.021). In the negative control analyses, neither predicted incident myocardial infarction. A premature atrial contraction was associated with a 30% increased risk of death (hazard ratio, 1.3; 95% CI, 1.1-1.5; P=0.008) and a premature ventricular contraction was associated with a 20% increased risk of death (hazard ratio, 1.2; 95% CI, 1.0-1.3; P=0.044). Similarly statistically significant results for each analysis were also observed in ARIC.

CONCLUSIONS: Based on a single standard ECG, a premature atrial contraction predicted incident atrial fibrillation and death and a premature ventricular contraction predicted incident heart failure and death, suggesting that this commonly used test may predict future disease.

VL - 6 IS - 8 ER - TY - JOUR T1 - Genetic loci associated with heart rate variability and their effects on cardiac disease risk. JF - Nat Commun Y1 - 2017 A1 - Nolte, Ilja M A1 - Munoz, M Loretto A1 - Tragante, Vinicius A1 - Amare, Azmeraw T A1 - Jansen, Rick A1 - Vaez, Ahmad A1 - von der Heyde, Benedikt A1 - Avery, Christy L A1 - Bis, Joshua C A1 - Dierckx, Bram A1 - van Dongen, Jenny A1 - Gogarten, Stephanie M A1 - Goyette, Philippe A1 - Hernesniemi, Jussi A1 - Huikari, Ville A1 - Hwang, Shih-Jen A1 - Jaju, Deepali A1 - Kerr, Kathleen F A1 - Kluttig, Alexander A1 - Krijthe, Bouwe P A1 - Kumar, Jitender A1 - van der Laan, Sander W A1 - Lyytikäinen, Leo-Pekka A1 - Maihofer, Adam X A1 - Minassian, Arpi A1 - van der Most, Peter J A1 - Müller-Nurasyid, Martina A1 - Nivard, Michel A1 - Salvi, Erika A1 - Stewart, James D A1 - Thayer, Julian F A1 - Verweij, Niek A1 - Wong, Andrew A1 - Zabaneh, Delilah A1 - Zafarmand, Mohammad H A1 - Abdellaoui, Abdel A1 - Albarwani, Sulayma A1 - Albert, Christine A1 - Alonso, Alvaro A1 - Ashar, Foram A1 - Auvinen, Juha A1 - Axelsson, Tomas A1 - Baker, Dewleen G A1 - de Bakker, Paul I W A1 - Barcella, Matteo A1 - Bayoumi, Riad A1 - Bieringa, Rob J A1 - Boomsma, Dorret A1 - Boucher, Gabrielle A1 - Britton, Annie R A1 - Christophersen, Ingrid A1 - Dietrich, Andrea A1 - Ehret, George B A1 - Ellinor, Patrick T A1 - Eskola, Markku A1 - Felix, Janine F A1 - Floras, John S A1 - Franco, Oscar H A1 - Friberg, Peter A1 - Gademan, Maaike G J A1 - Geyer, Mark A A1 - Giedraitis, Vilmantas A1 - Hartman, Catharina A A1 - Hemerich, Daiane A1 - Hofman, Albert A1 - Hottenga, Jouke-Jan A1 - Huikuri, Heikki A1 - Hutri-Kähönen, Nina A1 - Jouven, Xavier A1 - Junttila, Juhani A1 - Juonala, Markus A1 - Kiviniemi, Antti M A1 - Kors, Jan A A1 - Kumari, Meena A1 - Kuznetsova, Tatiana A1 - Laurie, Cathy C A1 - Lefrandt, Joop D A1 - Li, Yong A1 - Li, Yun A1 - Liao, Duanping A1 - Limacher, Marian C A1 - Lin, Henry J A1 - Lindgren, Cecilia M A1 - Lubitz, Steven A A1 - Mahajan, Anubha A1 - McKnight, Barbara A1 - Zu Schwabedissen, Henriette Meyer A1 - Milaneschi, Yuri A1 - Mononen, Nina A1 - Morris, Andrew P A1 - Nalls, Mike A A1 - Navis, Gerjan A1 - Neijts, Melanie A1 - Nikus, Kjell A1 - North, Kari E A1 - O'Connor, Daniel T A1 - Ormel, Johan A1 - Perz, Siegfried A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Risbrough, Victoria B A1 - Sinner, Moritz F A1 - Siscovick, David A1 - Smit, Johannes H A1 - Smith, Nicholas L A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Staessen, Jan A A1 - Stein, Phyllis K A1 - Stilp, Adrienne M A1 - Stolarz-Skrzypek, Katarzyna A1 - Strauch, Konstantin A1 - Sundström, Johan A1 - Swenne, Cees A A1 - Syvänen, Ann-Christine A1 - Tardif, Jean-Claude A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thornton, Timothy A A1 - Tinker, Lesley E A1 - Uitterlinden, André G A1 - van Setten, Jessica A1 - Voss, Andreas A1 - Waldenberger, Melanie A1 - Wilhelmsen, Kirk C A1 - Willemsen, Gonneke A1 - Wong, Quenna A1 - Zhang, Zhu-Ming A1 - Zonderman, Alan B A1 - Cusi, Daniele A1 - Evans, Michele K A1 - Greiser, Halina K A1 - van der Harst, Pim A1 - Hassan, Mohammad A1 - Ingelsson, Erik A1 - Jarvelin, Marjo-Riitta A1 - Kääb, Stefan A1 - Kähönen, Mika A1 - Kivimaki, Mika A1 - Kooperberg, Charles A1 - Kuh, Diana A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Nievergelt, Caroline M A1 - O'Donnell, Chris J A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda A1 - Reiner, Alexander P A1 - Riese, Harriëtte A1 - van Roon, Arie M A1 - Rioux, John D A1 - Rotter, Jerome I A1 - Sofer, Tamar A1 - Stricker, Bruno H A1 - Tiemeier, Henning A1 - Vrijkotte, Tanja G M A1 - Asselbergs, Folkert W A1 - Brundel, Bianca J J M A1 - Heckbert, Susan R A1 - Whitsel, Eric A A1 - den Hoed, Marcel A1 - Snieder, Harold A1 - de Geus, Eco J C AB -

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 VL - 8 ER - TY - JOUR T1 - Association of Alcohol Consumption After Development of Heart Failure With Survival Among Older Adults in the Cardiovascular Health Study. JF - JAMA Netw Open Y1 - 2018 A1 - Sadhu, Justin S A1 - Novak, Eric A1 - Mukamal, Kenneth J A1 - Kizer, Jorge R A1 - Psaty, Bruce M A1 - Stein, Phyllis K A1 - Brown, David L AB -

Importance: More than 1 million older adults develop heart failure annually. The association of alcohol consumption with survival among these individuals after diagnosis is unknown.

Objective: To determine whether alcohol use is associated with increased survival among older adults with incident heart failure.

Design, Setting, and Participants: This prospective cohort study included 5888 community-dwelling adults aged 65 years or older who were recruited to participate in the Cardiovascular Health Study between June 12, 1989, and June 1993, from 4 US sites. Of the total participants, 393 individuals had a new diagnosis of heart failure within the first 9 years of follow-up through June 2013. The study analysis was performed between January 19, 2016, and September 22, 2016.

Exposures: Alcohol consumption was divided into 4 categories: abstainers (never drinkers), former drinkers, 7 or fewer alcoholic drinks per week, and more than 7 drinks per week.

Primary Outcomes and Measures: Participant survival after the diagnosis of incident heart failure.

Results: Among the 393 adults diagnosed with incident heart failure, 213 (54.2%) were female, 339 (86.3%) were white, and the mean (SD) age was 78.7 (6.0) years. Alcohol consumption after diagnosis was reported in 129 (32.8%) of the participants. Across alcohol consumption categories of long-term abstainers, former drinkers, consumers of 1-7 drinks weekly and consumers of more than 7 drinks weekly, the percentage of men (32.1%, 49.0%, 58.0%, and 82.4%, respectively; P < .001 for trend), white individuals (78.0%, 92.7%, 92.0%, and 94.1%, respectively, P <. 001 for trend), and high-income participants (22.0%, 43.8%, 47.3%, and 64.7%, respectively; P < .001 for trend) increased with increasing alcohol consumption. Across the 4 categories, participants who consumed more alcohol had more years of education (mean, 12 years [interquartile range (IQR), 8.0-10.0 years], 12 years [IQR, 11.0-14.0 years], 13 years [IQR, 12.0-15.0 years], and 13 years [IQR, 12.0-14.0 years]; P < .001 for trend). Diabetes was less common across the alcohol consumption categories (32.1%, 26.0%, 22.3%, and 5.9%, respectively; P = .01 for trend). Across alcohol consumption categories, there were fewer never smokers (58.3%, 44.8%, 35.7%, and 29.4%, respectively; P < .001 for trend) and more former smokers (34.5%, 38.5%, 50.0%, and 52.9%, respectively; P = .006 for trend). After controlling for other factors, consumption of 7 or fewer alcoholic drinks per week was associated with additional mean survival of 383 days (95% CI, 17-748 days; P = .04) compared with abstinence from alcohol. Although the robustness was limited by the small number of individuals who consumed more than 7 drinks per week, a significant inverted U-shaped association between alcohol consumption and survival was observed. Multivariable model estimates of mean time from heart failure diagnosis to death were 2640 days (95% CI, 1967-3313 days) for never drinkers, 3046 days (95% CI, 2372-3719 days) for consumers of 0 to 7 drinks per week, and 2806 (95% CI, 1879-3734 days) for consumers of more than 7 drinks per week (P = .02). Consumption of 10 drinks per week was associated with the longest survival, a mean of 3381 days (95% CI, 2806-3956 days) after heart failure diagnosis.

Conclusions and Relevance: These findings suggest that limited alcohol consumption among older adults with incident heart failure is associated with survival benefit compared with long-term abstinence. These findings suggest that older adults who develop heart failure may not need to abstain from moderate levels of alcohol consumption.

VL - 1 IS - 8 ER - TY - JOUR T1 - Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study). JF - Stroke Y1 - 2018 A1 - Kamel, Hooman A1 - Bartz, Traci M A1 - Elkind, Mitchell S V A1 - Okin, Peter M A1 - Thacker, Evan L A1 - Patton, Kristen K A1 - Stein, Phyllis K A1 - deFilippi, Christopher R A1 - Gottesman, Rebecca F A1 - Heckbert, Susan R A1 - Kronmal, Richard A A1 - Soliman, Elsayed Z A1 - Longstreth, W T AB -

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, 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 (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.

VL - 49 IS - 4 ER - TY - JOUR T1 - Modifiable Predictors of Ventricular Ectopy in the Community. JF - J Am Heart Assoc Y1 - 2018 A1 - Kerola, Tuomas A1 - Dewland, Thomas A A1 - Vittinghoff, Eric A1 - Heckbert, Susan R A1 - Stein, Phyllis K A1 - Marcus, Gregory M AB -

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.

VL - 7 IS - 22 ER - TY - JOUR T1 - Predictors of atrial ectopy and their relationship to atrial fibrillation risk. JF - Europace Y1 - 2019 A1 - Kerola, Tuomas A1 - Dewland, Thomas A A1 - Vittinghoff, Eric A1 - Heckbert, Susan R A1 - Stein, Phyllis K A1 - Marcus, Gregory M AB -

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.

ER - TY - JOUR T1 - Cardiovascular autonomic nervous system function and hip fracture risk: the Cardiovascular Health Study. JF - Arch Osteoporos Y1 - 2021 A1 - Stein, Phyllis K A1 - Bůzková, Petra A1 - Fink, Howard A A1 - Robbins, John A A1 - Mukamal, Kenneth J A1 - Cauley, Jane A A1 - Carbone, Laura A1 - Elam, Rachel A1 - McMillan, David W A1 - Valderrabano, Rodrigo A1 - Barzilay, Joshua I KW - Aged KW - Autonomic Nervous System KW - Female KW - Heart Rate KW - Hip Fractures KW - Humans KW - Osteoporosis KW - Proportional Hazards Models AB -

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.

VL - 16 IS - 1 ER - TY - JOUR T1 - Premature ventricular complexes and development of heart failure in a community-based population. JF - Heart Y1 - 2021 A1 - Limpitikul, Worawan B A1 - Dewland, Thomas A A1 - Vittinghoff, Eric A1 - Soliman, Elsayed A1 - Nah, Gregory A1 - Fang, Christina A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Heckbert, Susan A1 - Stein, Phyllis K A1 - Gottdiener, John A1 - Hu, Xiao A1 - Hempfling, Ralf A1 - Marcus, Gregory M AB -

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.

ER - TY - JOUR T1 - The Association of Measures of Cardiovascular Autonomic Function, Heart Rate, and Orthostatic Hypotension With Incident Glucose Disorders: The Cardiovascular Health Study. JF - Diabetes Care Y1 - 2022 A1 - Barzilay, Joshua I A1 - Tressel, William A1 - Biggs, Mary L A1 - Stein, Phyllis K A1 - Kizer, Jorge R A1 - Shitole, Sanyog G A1 - Bene-Alhasan, Yakubu A1 - Mukamal, Kenneth J KW - Aged KW - Autonomic Nervous System KW - Blood Glucose KW - Diabetes Mellitus KW - Glucose KW - Heart Rate KW - Humans KW - Hypotension, Orthostatic KW - Insulin Resistance AB -

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.

VL - 45 IS - 10 ER - TY - JOUR T1 - Sex- and race-specific associations of bone mineral density with incident heart failure and its subtypes in older adults. JF - J Am Geriatr Soc Y1 - 2022 A1 - Gao, Hans A1 - Patel, Sheena A1 - Fohtung, Raymond B A1 - Cawthon, Peggy M A1 - Newman, Anne B A1 - Cauley, Jane A A1 - Carbone, Laura A1 - Chaves, Paulo H M A1 - Stein, Phyllis K A1 - Civitelli, Roberto A1 - Kizer, Jorge R AB -

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/cm 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.

ER - TY - JOUR T1 - Mortality Following Hip Fracture in Older Adults With and Without Coronary Heart Disease. JF - Am J Med Y1 - 2023 A1 - Robbins, John A A1 - Bůzková, Petra A1 - Barzilay, Joshua I A1 - Cauley, Jane A A1 - Fink, Howard A A1 - Carbone, Laura D A1 - Chen, Zhao A1 - Stein, Phyllis K A1 - Elam, Rachel A1 - Sheets, Kerry A1 - Mukamal, Kenneth J AB -

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.

ER -