03298nas a2200397 4500008004100000022001400041245008200055210006900137260001600206300001000222490000800232520217800240653000902418653002402427653002002451653001902471653002402490653001102514653001102525653000902536653002402545653002702569653002402596653002002620100002302640700002202663700002102685700002302706700002402729700002202753700002002775700002202795700002402817700002302841856003602864 2013 eng d a1539-370400aAtrial ectopy as a predictor of incident atrial fibrillation: a cohort study.0 aAtrial ectopy as a predictor of incident atrial fibrillation a c c2013 Dec 03 a721-80 v1593 a

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.

10aAged10aAtrial Fibrillation10aAtrial Function10aCause of Death10aElectrocardiography10aFemale10aHumans10aMale10aModels, Statistical10aMyocardial Contraction10aProspective Studies10aRisk Assessment1 aDewland, Thomas, A1 aVittinghoff, Eric1 aMandyam, Mala, C1 aHeckbert, Susan, R1 aSiscovick, David, S1 aStein, Phyllis, K1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aGottdiener, John, S1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/616603017nas a2200493 4500008004100000022001400041245006200055210005700117260001300174300001100187490000700198520168900205653000901894653002401903653001901927653002401946653001101970653001101981653001401992653002102006653000902027653001602036653001702052100002102069700002402090700001902114700002302133700002302156700002202179700002402201700002402225700002502249700001802274700002602292700001902318700001802337700002002355700002202375700002202397700002502419700002002444700002302464856003602487 2013 eng d a1556-387100aThe QT interval and risk of incident atrial fibrillation.0 aQT interval and risk of incident atrial fibrillation c2013 Oct a1562-80 v103 a

BACKGROUND: Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine.

OBJECTIVE: To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF.

METHODS: We examined a prolonged QT interval corrected by using the Framingham formula (QT(Fram)) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas.

RESULTS: Among 14,538 ARIC study participants, a prolonged QT(Fram) predicted a roughly 2-fold increased risk of AF (hazard ratio [HR] 2.05; 95% confidence interval [CI] 1.42-2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QT(Fram) was associated with an increased unadjusted (HR 1.14; 95% CI 1.10-1.17; P < .001) and adjusted (HR 1.11; 95% CI 1.07-1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts.

CONCLUSIONS: A prolonged QT interval is associated with an increased risk of incident AF.

10aAged10aAtrial Fibrillation10aCohort Studies10aElectrocardiography10aFemale10aHumans10aIncidence10aLong QT Syndrome10aMale10aMiddle Aged10aRisk Factors1 aMandyam, Mala, C1 aSoliman, Elsayed, Z1 aAlonso, Alvaro1 aDewland, Thomas, A1 aHeckbert, Susan, R1 aVittinghoff, Eric1 aCummings, Steven, R1 aEllinor, Patrick, T1 aChaitman, Bernard, R1 aStocke, Karen1 aApplegate, William, B1 aArking, Dan, E1 aButler, Javed1 aLoehr, Laura, R1 aMagnani, Jared, W1 aMurphy, Rachel, A1 aSatterfield, Suzanne1 aNewman, Anne, B1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/599803375nas a2200565 4500008004100000022001400041245012200055210006900177260001300246300001200259490000600271520178500277653001602062653000902078653001002087653002402097653001502121653003202136653002402168653002802192653001102220653003802231653001102269653001402280653001502294653000902309653001402318653003602332653002402368653002002392653001702412653001502429653001302444653001702457100002202474700002302496700002002519700002802539700001402567700001602581700001302597700002202610700002002632700002502652700002802677700002202705700002302727700002302750856003602773 2014 eng d a1941-308400aTelomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging.0 aTelomere length and the risk of atrial fibrillation insights int c2014 Dec a1026-320 v73 a

BACKGROUND: Advanced age is the most important risk factor for atrial fibrillation (AF); however, the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length and LTL in cardiac surgery patients.

METHODS AND RESULTS: Mean LTL and the TERT rs2736100 single nucleotide polymorphism were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of atrial cell telomere length versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF before and after adjustment for potential confounders (adjusted hazard ratio, 1.09; 95% confidence interval: 0.92-1.29; P=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the TERT rs2736100 single nucleotide polymorphism and incident AF (adjusted hazard ratio: 0.95; 95% confidence interval: 0.88-1.04; P=0.265). In 35 cardiac surgery patients (26 with AF), atrial cell telomere length was longer than LTL (1.19 ± 0.20 versus 1.02 ± 0.25 [T/S ratio], P<0.001), a finding that remained consistent within the AF subgroup.

CONCLUSIONS: Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.

10aAge Factors10aAged10aAging10aAtrial Fibrillation10aCalifornia10aCardiac Surgical Procedures10aCellular Senescence10aCross-Sectional Studies10aFemale10aGenetic Predisposition to Disease10aHumans10aIncidence10aLeukocytes10aMale10aPhenotype10aPolymorphism, Single Nucleotide10aProspective Studies10aRisk Assessment10aRisk Factors10aTelomerase10aTelomere10aTime Factors1 aRoberts, Jason, D1 aDewland, Thomas, A1 aLongoria, James1 aFitzpatrick, Annette, L1 aZiv, Elad1 aHu, Donglei1 aLin, Jue1 aGlidden, David, V1 aPsaty, Bruce, M1 aBurchard, Esteban, G1 aBlackburn, Elizabeth, H1 aOlgin, Jeffrey, E1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/659403175nas a2200409 4500008004100000022001400041245006600055210006500121260001600186300001000202490000700212520203900219653000902258653002202267653002102289653003602310653001102346653001602357653001802373653001102391653000902402653001702411653001802428653003602446100002302482700002302505700002202528700002102550700002302571700002402594700002202618700002002640700002202660700002402682700002302706856003602729 2015 eng d a1558-359700aVentricular Ectopy as a Predictor of Heart Failure and Death.0 aVentricular Ectopy as a Predictor of Heart Failure and Death c2015 Jul 14 a101-90 v663 a

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.

10aAged10aCatheter Ablation10aEchocardiography10aElectrocardiography, Ambulatory10aFemale10aForecasting10aHeart Failure10aHumans10aMale10aRisk Factors10aStroke Volume10aVentricular Premature Complexes1 aDukes, Jonathan, W1 aDewland, Thomas, A1 aVittinghoff, Eric1 aMandyam, Mala, C1 aHeckbert, Susan, R1 aSiscovick, David, S1 aStein, Phyllis, K1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aGottdiener, John, S1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/676702377nas a2200205 4500008004100000022001400041245006000055210005900115260001300174490000600187520178700193100001901980700002201999700002302021700002302044700002202067700002302089700002302112856003602135 2016 eng d a2047-998000aConsumption of Caffeinated Products and Cardiac Ectopy.0 aConsumption of Caffeinated Products and Cardiac Ectopy c2016 Jan0 v53 a

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.

1 aDixit, Shalini1 aStein, Phyllis, K1 aDewland, Thomas, A1 aDukes, Jonathan, W1 aVittinghoff, Eric1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/699202330nas a2200229 4500008004100000022001400041245006900055210006800124260001500192300001000207490000800217520165900225100002201884700002201906700002301928700002101951700002201972700002401994700002302018700002302041856003602064 2016 eng d a1879-191300aElectrocardiographic Predictors of Incident Atrial Fibrillation.0 aElectrocardiographic Predictors of Incident Atrial Fibrillation c2016 Sep 1 a714-90 v1183 a

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.

1 aNguyen, Kaylin, T1 aVittinghoff, Eric1 aDewland, Thomas, A1 aMandyam, Mala, C1 aStein, Phyllis, K1 aSoliman, Elsayed, Z1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/712903570nas a2200349 4500008004100000022001400041245011100055210006900166260001500235300001100250490000600261520253900267100002202806700001602828700002302844700001902867700002302886700002202909700001702931700002002948700002202968700002202990700002003012700002503032700001903057700002903076700002203105700002003127700001403147700002303161856003603184 2016 eng d a2380-659100aGenetic Investigation Into the Differential Risk of Atrial Fibrillation Among Black and White Individuals.0 aGenetic Investigation Into the Differential Risk of Atrial Fibri c2016 Jul 1 a442-500 v13 a

IMPORTANCE: White persons have a higher risk of atrial fibrillation (AF) compared with black individuals despite a lower prevalence of risk factors. This difference may be due, at least in part, to genetic factors.

OBJECTIVES: To determine whether 9 single-nucleotide polymorphisms (SNPs) associated with AF account for this paradoxical differential racial risk for AF and to use admixture mapping to search genome-wide for loci that may account for this phenomenon.

DESIGN, SETTING, AND PARTICIPANTS: Genome-wide admixture analysis and candidate SNP study involving 3 population-based cohort studies that were initiated between 1987 and 1997, including the Cardiovascular Health Study (CHS) (n = 4173), the Atherosclerosis Risk in Communities (ARIC) (n = 12 341) study, and the Health, Aging, and Body Composition (Health ABC) (n = 1015) study. In all 3 studies, race was self-identified. Cox proportional hazards regression models and the proportion of treatment effect method were used to determine the impact of 9 AF-risk SNPs among participants from CHS and the ARIC study. The present study began July 1, 2012, and was completed in 2015.

MAIN OUTCOMES AND MEASURES: Incident AF systematically ascertained using clinic visit electrocardiograms, hospital discharge diagnosis codes, death certificates, and Medicare claims data.

RESULTS: A single SNP, rs10824026 (chromosome 10: position 73661450), was found to significantly mediate the higher risk for AF in white participants compared with black participants in CHS (11.4%; 95% CI, 2.9%-29.9%) and ARIC (31.7%; 95% CI, 16.0%-53.0%). Admixture mapping was performed in a meta-analysis of black participants within CHS (n = 811), ARIC (n = 3112), and Health ABC (n = 1015). No loci that reached the prespecified statistical threshold for genome-wide significance were identified.

CONCLUSIONS AND RELEVANCE: The rs10824026 SNP on chromosome 10q22 mediates a modest proportion of the increased risk of AF among white individuals compared with black individuals, potentially through an effect on gene expression levels of MYOZ1. No additional genetic variants accounting for a significant portion of the differential racial risk of AF were identified with genome-wide admixture mapping, suggesting that additional genetic or environmental influences beyond single SNPs in isolation may account for the paradoxical racial risk of AF among white individuals and black individuals.

1 aRoberts, Jason, D1 aHu, Donglei1 aHeckbert, Susan, R1 aAlonso, Alvaro1 aDewland, Thomas, A1 aVittinghoff, Eric1 aLiu, Yongmei1 aPsaty, Bruce, M1 aOlgin, Jeffrey, E1 aMagnani, Jared, W1 aHuntsman, Scott1 aBurchard, Esteban, G1 aArking, Dan, E1 aBibbins-Domingo, Kirsten1 aHarris, Tamara, B1 aPerez, Marco, V1 aZiv, Elad1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/716502724nas a2200265 4500008004100000022001400041245013800055210006900193260001300262300000900275490000800284520189600292100002202188700002302210700002202233700002402255700001902279700001702298700002002315700002202335700001902357700002302376700002302399856003602422 2016 eng d a1097-674400aImpact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation.0 aImpact of genetic variants on the upstream efficacy of reninangi c2016 May a9-170 v1753 a

BACKGROUND: Renin-angiotensin system (RAS) inhibition via angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may reduce the risk of developing atrial fibrillation (AF) in certain populations, but the evidence is conflicting. Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with AF, potentially identifying clinically relevant subtypes of the disease. We sought to investigate the impact of carrier status of 9 AF-associated SNPs on the efficacy of RAS inhibition for the primary prevention of AF.

METHODS: We performed SNP-RAS inhibitor interaction testing with unadjusted and adjusted Cox proportional hazards models using a discovery (Cardiovascular Health Study) and a replication (Atherosclerosis Risk in Communities) cohort. Additive genetic models were used for the SNP analyses, and 2-tailed P values <.05 were considered statistically significant.

RESULTS: Among 2,796 Cardiovascular Health Study participants, none of the 9 a priori identified candidate SNPs exhibited a significant SNP-drug interaction. Two of the 9 SNPs, rs2106261 (16q22) and rs6666258 (1q21), revealed interaction relationships that neared statistical significance (with point estimates in the same direction for angiotensin-converting enzyme inhibitor only and angiotensin II receptor blocker only analyses), but neither association could be replicated among 8,604 participants in Atherosclerosis Risk in Communities.

CONCLUSIONS: Our study failed to identify AF-associated SNP genetic subtypes of AF that derive increased benefit from upstream RAS inhibition for AF prevention. Future studies should continue to investigate the impact of genotype on the response to AF treatment strategies in an effort to develop personalized approaches to therapy and prevention.

1 aRoberts, Jason, D1 aDewland, Thomas, A1 aGlidden, David, V1 aHoffmann, Thomas, J1 aArking, Dan, E1 aChen, Lin, Y1 aPsaty, Bruce, M1 aOlgin, Jeffrey, E1 aAlonso, Alvaro1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/716602588nas a2200253 4500008004100000022001400041245008900055210006900144260001300213300001400226490000700240520182000247100002802067700002202095700002202117700002402139700002402163700002302187700002202210700002002232700002302252700002302275856003602298 2017 eng d a1556-387100aAtrial ectopy as a mediator of the association between race and atrial fibrillation.0 aAtrial ectopy as a mediator of the association between race and  c2017 Dec a1856-18610 v143 a

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.

1 aChristensen, Matthew, A1 aNguyen, Kaylin, T1 aStein, Phyllis, K1 aFohtung, Raymond, B1 aSoliman, Elsayed, Z1 aDewland, Thomas, A1 aVittinghoff, Eric1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/755502652nas a2200265 4500008004100000022001400041245009100055210006900146260001600215490000600231520185100237100002202088700002202110700002302132700002302155700002402178700002202202700002402224700001902248700001702267700002002284700002302304700002302327856003602350 2017 eng d a2047-998000aEctopy on a Single 12-Lead ECG, Incident Cardiac Myopathy, and Death in the Community.0 aEctopy on a Single 12Lead ECG Incident Cardiac Myopathy and Deat c2017 Aug 030 v63 a

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.

1 aNguyen, Kaylin, T1 aVittinghoff, Eric1 aDewland, Thomas, A1 aDukes, Jonathan, W1 aSoliman, Elsayed, Z1 aStein, Phyllis, K1 aGottdiener, John, S1 aAlonso, Alvaro1 aChen, Lin, Y1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/748902234nas a2200205 4500008004100000022001400041245006600055210006500121260001600186300001200202490000600214520164000220100001901860700002301879700002201902700002301924700002201947700002301969856003601992 2018 eng d a2047-998000aModifiable Predictors of Ventricular Ectopy in the Community.0 aModifiable Predictors of Ventricular Ectopy in the Community c2018 Nov 20 ae0100780 v73 a

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.

1 aKerola, Tuomas1 aDewland, Thomas, A1 aVittinghoff, Eric1 aHeckbert, Susan, R1 aStein, Phyllis, K1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/791702716nas a2200337 4500008004100000022001400041245006000055210005900115260001300174300001400187490000700201520176600208100002801974700001902002700002302021700002202044700001702066700002202083700002402105700001902129700002102148700002002169700002102189700002202210700002002232700002202252700002202274700002302296700002302319856003602342 2018 eng d a1556-387100aSleep characteristics that predict atrial fibrillation.0 aSleep characteristics that predict atrial fibrillation c2018 Sep a1289-12950 v153 a

BACKGROUND: The relationship between sleep disruption, independent of obstructive sleep apnea (OSA), and atrial fibrillation (AF) is unknown.

OBJECTIVE: The purpose of this study was to determine whether poor sleep itself is a risk factor for AF.

METHODS: We first performed an analysis of participants in the Health eHeart Study and validated those findings in the longitudinal Cardiovascular Health Study, including a subset of patients undergoing polysomnography. To determine whether the observed relationships readily translated to medical practice, we examined 2005-2009 data from the California Healthcare Cost and Utilization Project.

RESULTS: Among 4553 Health eHeart participants, the 526 with AF exhibited more frequent nighttime awakening (odd ratio [OR] 1.47; 95% confidence interval [CI] 1.14-1.89; P = .003). In 5703 Cardiovascular Health Study participants followed for a median 11.6 years, frequent nighttime awakening predicted a 33% greater risk of AF (hazard ratio [HR] 1.33; 95% CI 1.17-1.51; P <.001). In patients with polysomnography (N = 1127), every standard deviation percentage decrease in rapid eye movement (REM) sleep was associated with a 18% higher risk of developing AF (HR 1.18; 95% CI 1.00-1.38; P = .047). Among 14,330,651 California residents followed for a median 3.9 years, an insomnia diagnosis predicted a 36% increased risk of new AF (HR 1.36; 95% CI 1.30-1.42; P <.001).

CONCLUSION: Sleep disruption consistently predicted AF before and after adjustment for OSA and other potential confounders across several different populations. Sleep quality itself may be important in the pathogenesis of AF, potentially representing a novel target for prevention.

1 aChristensen, Matthew, A1 aDixit, Shalini1 aDewland, Thomas, A1 aWhitman, Isaac, R1 aNah, Gregory1 aVittinghoff, Eric1 aMukamal, Kenneth, J1 aRedline, Susan1 aRobbins, John, A1 aNewman, Anne, B1 aPatel, Sanjay, R1 aMagnani, Jared, W1 aPsaty, Bruce, M1 aOlgin, Jeffrey, E1 aPletcher, Mark, J1 aHeckbert, Susan, R1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/778702786nas a2200289 4500008004100000022001400041245010600055210006900161260001600230300001200246490000600258520191000264100002202174700002202196700003002218700002402248700001902272700002002291700002302311700002202334700001902356700002202375700001702397700002302414700002302437856003602460 2019 eng d a2047-998000aNT -pro BNP as a Mediator of the Racial Difference in Incident Atrial Fibrillation and Heart Failure.0 aNT pro BNP as a Mediator of the Racial Difference in Incident At c2019 Apr 02 ae0108680 v83 a

Background Blacks harbor more cardiovascular risk factors than whites, but experience less atrial fibrillation ( AF ). Conversely, whites may have a lower risk of heart failure ( CHF ). N-terminal pro-B-type natriuretic peptide ( NT -pro BNP) levels are higher in whites, predict incident AF , and have diuretic effects in the setting of increased ventricular diastolic pressures, potentially providing a unifying explanation for these racial differences. Methods and Results We used data from the CHS (Cardiovascular Health Study) to determine the degree to which baseline NT -pro BNP levels mediate the relationships between race and incident AF and CHF by comparing beta estimates between models with and without NT -pro BNP . The ARIC (Atherosclerosis Risk in Communities) study was used to assess reproducibility. Among 4731 CHS (770 black) and 12 418 ARIC (3091 black) participants, there were 1277 and 1253 incident AF events, respectively. Whites had higher baseline NT -pro BNP ( CHS : 40% higher than blacks; 95% CI , 29-53; ARIC : 39% higher; 95% CI , 33-46) and had a greater risk of incident AF compared with blacks ( CHS : adjusted hazard ratio, 1.60; 95% CI , 1.31-1.93; ARIC : hazard ratio, 1.93; 95% CI , 1.57-2.27). NT -pro BNP levels explained a significant proportion of the racial difference in AF risk ( CHS : 36.2%; 95% CI , 23.2-69.2%; ARIC : 24.6%; 95% CI , 14.8-39.6%). Contrary to our hypothesis, given an increased risk of CHF among whites in CHS (adjusted hazard ratio, 1.20; 95% CI , 1.05-1.47) and the absence of a significant association between race and CHF in ARIC (adjusted hazard ratio, 1.07; 95% CI , 0.94-1.23), CHF -related mediation analyses were not performed. Conclusions A substantial portion of the relationship between race and AF was statistically explained by baseline NT -pro BNP levels. No consistent relationship between race and CHF was observed.

1 aWhitman, Isaac, R1 aVittinghoff, Eric1 adeFilippi, Christopher, R1 aGottdiener, John, S1 aAlonso, Alvaro1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aHoogeveen, Ron, C1 aArking, Dan, E1 aSelvin, Elizabeth1 aChen, Lin, Y1 aDewland, Thomas, A1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/800802287nas a2200181 4500008004100000022001400041245008400055210006900139260001600208520171300224100001901937700002301956700002201979700002302001700002202024700002302046856003602069 2019 eng d a1532-209200aPredictors of atrial ectopy and their relationship to atrial fibrillation risk.0 aPredictors of atrial ectopy and their relationship to atrial fib c2019 Mar 063 a

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.

1 aKerola, Tuomas1 aDewland, Thomas, A1 aVittinghoff, Eric1 aHeckbert, Susan, R1 aStein, Phyllis, K1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/800602672nas a2200289 4500008004100000022001400041245010200055210006900157260001600226520178900242100002702031700002302058700002202081700002102103700001702124700002002141700002402161700002002185700002202205700002002227700002202247700002102269700001302290700002002303700002302323856003602346 2021 eng d a1468-201X00aPremature ventricular complexes and development of heart failure in a community-based population.0 aPremature ventricular complexes and development of heart failure c2021 Sep 073 a

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.

1 aLimpitikul, Worawan, B1 aDewland, Thomas, A1 aVittinghoff, Eric1 aSoliman, Elsayed1 aNah, Gregory1 aFang, Christina1 aSiscovick, David, S1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aHeckbert, Susan1 aStein, Phyllis, K1 aGottdiener, John1 aHu, Xiao1 aHempfling, Ralf1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/8923