@article {6166, title = {Atrial ectopy as a predictor of incident atrial fibrillation: a cohort study.}, journal = {Ann Intern Med}, volume = {159}, year = {2013}, month = {2013 Dec 03}, pages = {721-8}, abstract = {

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.

}, keywords = {Aged, Atrial Fibrillation, Atrial Function, Cause of Death, Electrocardiography, Female, Humans, Male, Models, Statistical, Myocardial Contraction, Prospective Studies, Risk Assessment}, issn = {1539-3704}, doi = {10.7326/0003-4819-159-11-201312030-00004}, author = {Dewland, Thomas A and Vittinghoff, Eric and Mandyam, Mala C and Heckbert, Susan R and Siscovick, David S and Stein, Phyllis K and Psaty, Bruce M and Sotoodehnia, Nona and Gottdiener, John S and Marcus, Gregory M} } @article {5998, title = {The QT interval and risk of incident atrial fibrillation.}, journal = {Heart Rhythm}, volume = {10}, year = {2013}, month = {2013 Oct}, pages = {1562-8}, abstract = {

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.

}, keywords = {Aged, Atrial Fibrillation, Cohort Studies, Electrocardiography, Female, Humans, Incidence, Long QT Syndrome, Male, Middle Aged, Risk Factors}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2013.07.023}, author = {Mandyam, Mala C and Soliman, Elsayed Z and Alonso, Alvaro and Dewland, Thomas A and Heckbert, Susan R and Vittinghoff, Eric and Cummings, Steven R and Ellinor, Patrick T and Chaitman, Bernard R and Stocke, Karen and Applegate, William B and Arking, Dan E and Butler, Javed and Loehr, Laura R and Magnani, Jared W and Murphy, Rachel A and Satterfield, Suzanne and Newman, Anne B and Marcus, Gregory M} } @article {6594, title = {Telomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging.}, journal = {Circ Arrhythm Electrophysiol}, volume = {7}, year = {2014}, month = {2014 Dec}, pages = {1026-32}, abstract = {

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 {\textpm} 0.20 versus 1.02 {\textpm} 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.

}, keywords = {Age Factors, Aged, Aging, Atrial Fibrillation, California, Cardiac Surgical Procedures, Cellular Senescence, Cross-Sectional Studies, Female, Genetic Predisposition to Disease, Humans, Incidence, Leukocytes, Male, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Risk Assessment, Risk Factors, Telomerase, Telomere, Time Factors}, issn = {1941-3084}, doi = {10.1161/CIRCEP.114.001781}, author = {Roberts, Jason D and Dewland, Thomas A and Longoria, James and Fitzpatrick, Annette L and Ziv, Elad and Hu, Donglei and Lin, Jue and Glidden, David V and Psaty, Bruce M and Burchard, Esteban G and Blackburn, Elizabeth H and Olgin, Jeffrey E and Heckbert, Susan R and Marcus, Gregory M} } @article {6767, title = {Ventricular Ectopy as a Predictor of Heart Failure and Death.}, journal = {J Am Coll Cardiol}, volume = {66}, year = {2015}, month = {2015 Jul 14}, pages = {101-9}, abstract = {

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.

}, keywords = {Aged, Catheter Ablation, Echocardiography, Electrocardiography, Ambulatory, Female, Forecasting, Heart Failure, Humans, Male, Risk Factors, Stroke Volume, Ventricular Premature Complexes}, issn = {1558-3597}, doi = {10.1016/j.jacc.2015.04.062}, author = {Dukes, Jonathan W and Dewland, Thomas A and Vittinghoff, Eric and Mandyam, Mala C and Heckbert, Susan R and Siscovick, David S and Stein, Phyllis K and Psaty, Bruce M and Sotoodehnia, Nona and Gottdiener, John S and Marcus, Gregory M} } @article {6992, title = {Consumption of Caffeinated Products and Cardiac Ectopy.}, journal = {J Am Heart Assoc}, volume = {5}, year = {2016}, month = {2016 Jan}, abstract = {

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.

}, issn = {2047-9980}, doi = {10.1161/JAHA.115.002503}, author = {Dixit, Shalini and Stein, Phyllis K and Dewland, Thomas A and Dukes, Jonathan W and Vittinghoff, Eric and Heckbert, Susan R and Marcus, Gregory M} } @article {7129, title = {Electrocardiographic Predictors of Incident Atrial Fibrillation.}, journal = {Am J Cardiol}, volume = {118}, year = {2016}, month = {2016 Sep 1}, pages = {714-9}, abstract = {

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.

}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2016.06.008}, author = {Nguyen, Kaylin T and Vittinghoff, Eric and Dewland, Thomas A and Mandyam, Mala C and Stein, Phyllis K and Soliman, Elsayed Z and Heckbert, Susan R and Marcus, Gregory M} } @article {7165, title = {Genetic Investigation Into the Differential Risk of Atrial Fibrillation Among Black and White Individuals.}, journal = {JAMA Cardiol}, volume = {1}, year = {2016}, month = {2016 Jul 1}, pages = {442-50}, abstract = {

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.

}, issn = {2380-6591}, doi = {10.1001/jamacardio.2016.1185}, author = {Roberts, Jason D and Hu, Donglei and Heckbert, Susan R and Alonso, Alvaro and Dewland, Thomas A and Vittinghoff, Eric and Liu, Yongmei and Psaty, Bruce M and Olgin, Jeffrey E and Magnani, Jared W and Huntsman, Scott and Burchard, Esteban G and Arking, Dan E and Bibbins-Domingo, Kirsten and Harris, Tamara B and Perez, Marco V and Ziv, Elad and Marcus, Gregory M} } @article {7166, title = {Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation.}, journal = {Am Heart J}, volume = {175}, year = {2016}, month = {2016 May}, pages = {9-17}, abstract = {

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.

}, issn = {1097-6744}, doi = {10.1016/j.ahj.2016.02.002}, author = {Roberts, Jason D and Dewland, Thomas A and Glidden, David V and Hoffmann, Thomas J and Arking, Dan E and Chen, Lin Y and Psaty, Bruce M and Olgin, Jeffrey E and Alonso, Alvaro and Heckbert, Susan R and Marcus, Gregory M} } @article {7555, title = {Atrial ectopy as a mediator of the association between race and atrial fibrillation.}, journal = {Heart Rhythm}, volume = {14}, year = {2017}, month = {2017 Dec}, pages = {1856-1861}, abstract = {

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.

}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2017.09.034}, author = {Christensen, Matthew A and Nguyen, Kaylin T and Stein, Phyllis K and Fohtung, Raymond B and Soliman, Elsayed Z and Dewland, Thomas A and Vittinghoff, Eric and Psaty, Bruce M and Heckbert, Susan R and Marcus, Gregory M} } @article {7489, title = {Ectopy on a Single 12-Lead ECG, Incident Cardiac Myopathy, and Death in the Community.}, journal = {J Am Heart Assoc}, volume = {6}, year = {2017}, month = {2017 Aug 03}, abstract = {

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.

}, issn = {2047-9980}, doi = {10.1161/JAHA.117.006028}, author = {Nguyen, Kaylin T and Vittinghoff, Eric and Dewland, Thomas A and Dukes, Jonathan W and Soliman, Elsayed Z and Stein, Phyllis K and Gottdiener, John S and Alonso, Alvaro and Chen, Lin Y and Psaty, Bruce M and Heckbert, Susan R and Marcus, Gregory M} } @article {7917, title = {Modifiable Predictors of Ventricular Ectopy in the Community.}, journal = {J Am Heart Assoc}, volume = {7}, year = {2018}, month = {2018 Nov 20}, pages = {e010078}, abstract = {

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.

}, issn = {2047-9980}, doi = {10.1161/JAHA.118.010078}, author = {Kerola, Tuomas and Dewland, Thomas A and Vittinghoff, Eric and Heckbert, Susan R and Stein, Phyllis K and Marcus, Gregory M} } @article {7787, title = {Sleep characteristics that predict atrial fibrillation.}, journal = {Heart Rhythm}, volume = {15}, year = {2018}, month = {2018 Sep}, pages = {1289-1295}, abstract = {

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.

}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2018.05.008}, author = {Christensen, Matthew A and Dixit, Shalini and Dewland, Thomas A and Whitman, Isaac R and Nah, Gregory and Vittinghoff, Eric and Mukamal, Kenneth J and Redline, Susan and Robbins, John A and Newman, Anne B and Patel, Sanjay R and Magnani, Jared W and Psaty, Bruce M and Olgin, Jeffrey E and Pletcher, Mark J and Heckbert, Susan R and Marcus, Gregory M} } @article {8008, title = {NT -pro BNP as a Mediator of the Racial Difference in Incident Atrial Fibrillation and Heart Failure.}, journal = {J Am Heart Assoc}, volume = {8}, year = {2019}, month = {2019 Apr 02}, pages = {e010868}, abstract = {

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.

}, issn = {2047-9980}, doi = {10.1161/JAHA.118.010868}, author = {Whitman, Isaac R and Vittinghoff, Eric and deFilippi, Christopher R and Gottdiener, John S and Alonso, Alvaro and Psaty, Bruce M and Heckbert, Susan R and Hoogeveen, Ron C and Arking, Dan E and Selvin, Elizabeth and Chen, Lin Y and Dewland, Thomas A and Marcus, Gregory M} } @article {8006, title = {Predictors of atrial ectopy and their relationship to atrial fibrillation risk.}, journal = {Europace}, year = {2019}, month = {2019 Mar 06}, abstract = {

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.

}, issn = {1532-2092}, doi = {10.1093/europace/euz008}, author = {Kerola, Tuomas and Dewland, Thomas A and Vittinghoff, Eric and Heckbert, Susan R and Stein, Phyllis K and Marcus, Gregory M} } @article {8923, title = {Premature ventricular complexes and development of heart failure in a community-based population.}, journal = {Heart}, year = {2021}, month = {2021 Sep 07}, abstract = {

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{\textpm}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.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2021-319473}, author = {Limpitikul, Worawan B and Dewland, Thomas A and Vittinghoff, Eric and Soliman, Elsayed and Nah, Gregory and Fang, Christina and Siscovick, David S and Psaty, Bruce M and Sotoodehnia, Nona and Heckbert, Susan and Stein, Phyllis K and Gottdiener, John and Hu, Xiao and Hempfling, Ralf and Marcus, Gregory M} }