TY - JOUR T1 - European ancestry as a risk factor for atrial fibrillation in African Americans. JF - Circulation Y1 - 2010 A1 - Marcus, Gregory M A1 - Alonso, Alvaro A1 - Peralta, Carmen A A1 - Lettre, Guillaume A1 - Vittinghoff, Eric A1 - Lubitz, Steven A A1 - Fox, Ervin R A1 - Levitzky, Yamini S A1 - Mehra, Reena A1 - Kerr, Kathleen F A1 - Deo, Rajat A1 - Sotoodehnia, Nona A1 - Akylbekova, Meggie A1 - Ellinor, Patrick T A1 - Paltoo, Dina N A1 - Soliman, Elsayed Z A1 - Benjamin, Emelia J A1 - Heckbert, Susan R KW - African Americans KW - Aged KW - Atrial Fibrillation KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Risk Factors AB -

BACKGROUND: Despite a higher burden of standard atrial fibrillation (AF) risk factors, African Americans have a lower risk of AF than whites. It is unknown whether the higher risk is due to genetic or environmental factors. Because African Americans have varying degrees of European ancestry, we sought to test the hypothesis that European ancestry is an independent risk factor for AF.

METHODS AND RESULTS: We studied whites (n=4543) and African Americans (n=822) in the Cardiovascular Health Study (CHS) and whites (n=10 902) and African Americans (n=3517) in the Atherosclerosis Risk in Communities (ARIC) Study (n=3517). Percent European ancestry in African Americans was estimated with 1747 ancestry informative markers from the Illumina custom ITMAT-Broad-CARe array. Among African Americans without baseline AF, 120 of 804 CHS participants and 181 of 3517 ARIC participants developed incident AF. A meta-analysis from the 2 studies revealed that every 10% increase in European ancestry increased the risk of AF by 13% (hazard ratio, 1.13; 95% confidence interval, 1.03 to 1.23; P=0.007). After adjustment for potential confounders, European ancestry remained a predictor of incident AF in each cohort alone, with a combined estimated hazard ratio for each 10% increase in European ancestry of 1.17 (95% confidence interval, 1.07 to 1.29; P=0.001). A second analysis using 3192 ancestry informative markers from a genome-wide Affymetrix 6.0 array in ARIC African Americans yielded similar results.

CONCLUSIONS: European ancestry predicted risk of incident AF. Our study suggests that investigating genetic variants contributing to differential AF risk in individuals of African versus European ancestry will be informative.

VL - 122 IS - 20 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21098467?dopt=Abstract ER - TY - JOUR T1 - Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe) project. JF - Circ Cardiovasc Genet Y1 - 2011 A1 - Schnabel, Renate B A1 - Kerr, Kathleen F A1 - Lubitz, Steven A A1 - Alkylbekova, Ermeg L A1 - Marcus, Gregory M A1 - Sinner, Moritz F A1 - Magnani, Jared W A1 - Wolf, Philip A A1 - Deo, Rajat A1 - Lloyd-Jones, Donald M A1 - Lunetta, Kathryn L A1 - Mehra, Reena A1 - Levy, Daniel A1 - Fox, Ervin R A1 - Arking, Dan E A1 - Mosley, Thomas H A1 - Müller-Nurasyid, Martina A1 - Young, Taylor R A1 - Wichmann, H-Erich A1 - Seshadri, Sudha A1 - Farlow, Deborah N A1 - Rotter, Jerome I A1 - Soliman, Elsayed Z A1 - Glazer, Nicole L A1 - Wilson, James G A1 - Breteler, Monique M B A1 - Sotoodehnia, Nona A1 - Newton-Cheh, Christopher A1 - Kääb, Stefan A1 - Ellinor, Patrick T A1 - Alonso, Alvaro A1 - Benjamin, Emelia J A1 - Heckbert, Susan R KW - African Americans KW - Aged KW - Alleles KW - Atrial Fibrillation KW - Chromosomes, Human, Pair 4 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Middle Aged KW - National Heart, Lung, and Blood Institute (U.S.) KW - Polymorphism, Single Nucleotide KW - Receptors, Interleukin-6 KW - Risk Factors KW - Stroke KW - United States AB -

BACKGROUND: The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated.

METHODS AND RESULTS: We examined a panel of approximately 50,000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genes and AF in 3 cohorts with participants of European (n=18,524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology Stroke Consortium (n=19,602 whites, 1544 incident strokes). SNP rs4845625 in the IL6R gene was associated with AF (relative risk [RR] C allele, 0.90; 95% confidence interval [CI], 0.85-0.95; P=0.0005) in whites but did not reach statistical significance in African Americans (RR, 0.86; 95% CI, 0.72-1.03; P=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95% CI, 0.57-0.89; P=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994; hazard ratio, 1.40; 95% CI, 1.16-1.69; P=0.0005).

CONCLUSIONS: In a community-based cohort meta-analysis, we identified genetic association in IL6R with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.

VL - 4 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21846873?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 - Long-term outcomes of left anterior fascicular block in the absence of overt cardiovascular disease. JF - JAMA Y1 - 2013 A1 - Mandyam, Mala C A1 - Soliman, Elsayed Z A1 - Heckbert, Susan R A1 - Vittinghoff, Eric A1 - Marcus, Gregory M KW - Aged KW - Atrial Fibrillation KW - Biomarkers KW - Bundle-Branch Block KW - Cohort Studies KW - Electrocardiography KW - Endomyocardial Fibrosis KW - Female KW - Heart Failure KW - Humans KW - Kaplan-Meier Estimate KW - Male KW - Prognosis KW - Risk VL - 309 IS - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23592102?dopt=Abstract ER - TY - JOUR T1 - The QT interval and risk of incident atrial fibrillation. JF - Heart Rhythm Y1 - 2013 A1 - Mandyam, Mala C A1 - Soliman, Elsayed Z A1 - Alonso, Alvaro A1 - Dewland, Thomas A A1 - Heckbert, Susan R A1 - Vittinghoff, Eric A1 - Cummings, Steven R A1 - Ellinor, Patrick T A1 - Chaitman, Bernard R A1 - Stocke, Karen A1 - Applegate, William B A1 - Arking, Dan E A1 - Butler, Javed A1 - Loehr, Laura R A1 - Magnani, Jared W A1 - Murphy, Rachel A A1 - Satterfield, Suzanne A1 - Newman, Anne B A1 - Marcus, Gregory M KW - Aged KW - Atrial Fibrillation KW - Cohort Studies KW - Electrocardiography KW - Female KW - Humans KW - Incidence KW - Long QT Syndrome KW - Male KW - Middle Aged KW - Risk Factors AB -

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.

VL - 10 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23872693?dopt=Abstract ER - TY - JOUR T1 - A common SCN5A variant is associated with PR interval and atrial fibrillation among African Americans. JF - J Cardiovasc Electrophysiol Y1 - 2014 A1 - Ilkhanoff, Leonard A1 - Arking, Dan E A1 - Lemaitre, Rozenn N A1 - Alonso, Alvaro A1 - Chen, Lin Y A1 - Durda, Peter A1 - Hesselson, Stephanie E A1 - Kerr, Kathleen F A1 - Magnani, Jared W A1 - Marcus, Gregory M A1 - Schnabel, Renate B A1 - Smith, J Gustav A1 - Soliman, Elsayed Z A1 - Reiner, Alexander P A1 - Sotoodehnia, Nona KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Case-Control Studies KW - Cohort Studies KW - Death, Sudden, Cardiac KW - Female KW - Genetic Variation KW - Humans KW - Male KW - Middle Aged KW - NAV1.5 Voltage-Gated Sodium Channel KW - Prospective Studies KW - Risk Factors KW - Single-Blind Method AB -

OBJECTIVE: We examined the association of rs7626962 (S1103Y) or rs7629265, a variant in high linkage disequilibrium with S1103Y (r(2) = 0.87 - 1), with sudden cardiac death (SCD) and atrial fibrillation (AF) among African Americans.

BACKGROUND: The SCN5A missense variant S1103Y has been associated with SCD among African Americans in small case-control studies, but larger population-based studies are needed to validate these findings. The association of this variant with AF has not been fully explored.

METHODS: Using genotyping data on over 7,000 African Americans from 5 cohorts (Atherosclerosis Risk in Communities [ARIC], Cleveland Family Study [CFS], Jackson Heart Study [JHS], Multi-Ethnic Study of Atherosclerosis [MESA], Cardiovascular Health Study [CHS]), we examined the association of rs7629265 with electrocardiographic PR, QRS, and QT intervals, and with incident AF and SCD. We examined association of S1103Y (rs7626962) with SCD using a population-based case-control study of SCD Cardiac Arrest Blood Study (CABS).

RESULTS: Meta-analyses across 5 cohorts demonstrated that rs7629265 was significantly associated with PR duration (β = -4.1 milliseconds; P = 2.2×10(-6) ), but not significantly associated with QRS or QT intervals. In meta-analyses of prospectively followed ARIC and CHS participants (n = 3,656), rs7629265 was associated with increased AF risk (n = 299 AF cases; HR = 1.74, P = 1.9 × 10(-4) ). By contrast, rs7629265 was not significantly associated with SCD risk in ARIC (n = 83 SCD cases; P = 0.30) or CHS (n = 54 SCD cases; P = 0.47). Similarly, S1103Y was not significantly associated with SCD risk in CABS (n = 225 SCD cases; P = 0.29).

CONCLUSION: The common SCN5A variant, rs7629265, is associated with increased AF risk and shorter PR interval among African Americans. In contrast to prior reports, we found no evidence of association of rs7629265 or rs7626962 (S1103Y) with SCD risk in the general population.

VL - 25 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25065297?dopt=Abstract ER - TY - JOUR T1 - Telomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging. JF - Circ Arrhythm Electrophysiol Y1 - 2014 A1 - Roberts, Jason D A1 - Dewland, Thomas A A1 - Longoria, James A1 - Fitzpatrick, Annette L A1 - Ziv, Elad A1 - Hu, Donglei A1 - Lin, Jue A1 - Glidden, David V A1 - Psaty, Bruce M A1 - Burchard, Esteban G A1 - Blackburn, Elizabeth H A1 - Olgin, Jeffrey E A1 - Heckbert, Susan R A1 - Marcus, Gregory M KW - Age Factors KW - Aged KW - Aging KW - Atrial Fibrillation KW - California KW - Cardiac Surgical Procedures KW - Cellular Senescence KW - Cross-Sectional Studies KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Incidence KW - Leukocytes KW - Male KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Telomerase KW - Telomere KW - Time Factors AB -

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.

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25381796?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 - Genetic Investigation Into the Differential Risk of Atrial Fibrillation Among Black and White Individuals. JF - JAMA Cardiol Y1 - 2016 A1 - Roberts, Jason D A1 - Hu, Donglei A1 - Heckbert, Susan R A1 - Alonso, Alvaro A1 - Dewland, Thomas A A1 - Vittinghoff, Eric A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Olgin, Jeffrey E A1 - Magnani, Jared W A1 - Huntsman, Scott A1 - Burchard, Esteban G A1 - Arking, Dan E A1 - Bibbins-Domingo, Kirsten A1 - Harris, Tamara B A1 - Perez, Marco V A1 - Ziv, Elad A1 - Marcus, Gregory M AB -

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.

VL - 1 IS - 4 ER - TY - JOUR T1 - Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation. JF - Am Heart J Y1 - 2016 A1 - Roberts, Jason D A1 - Dewland, Thomas A A1 - Glidden, David V A1 - Hoffmann, Thomas J A1 - Arking, Dan E A1 - Chen, Lin Y A1 - Psaty, Bruce M A1 - Olgin, Jeffrey E A1 - Alonso, Alvaro A1 - Heckbert, Susan R A1 - Marcus, Gregory M AB -

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.

VL - 175 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 - 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 - 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 - Multi-ethnic genome-wide association study for atrial fibrillation. JF - Nat Genet Y1 - 2018 A1 - Roselli, Carolina A1 - Chaffin, Mark D A1 - Weng, Lu-Chen A1 - Aeschbacher, Stefanie A1 - Ahlberg, Gustav A1 - Albert, Christine M A1 - Almgren, Peter A1 - Alonso, Alvaro A1 - Anderson, Christopher D A1 - Aragam, Krishna G A1 - Arking, Dan E A1 - Barnard, John A1 - Bartz, Traci M A1 - Benjamin, Emelia J A1 - Bihlmeyer, Nathan A A1 - Bis, Joshua C A1 - Bloom, Heather L A1 - Boerwinkle, Eric A1 - Bottinger, Erwin B A1 - Brody, Jennifer A A1 - Calkins, Hugh A1 - Campbell, Archie A1 - Cappola, Thomas P A1 - Carlquist, John A1 - Chasman, Daniel I A1 - Chen, Lin Y A1 - Chen, Yii-Der Ida A1 - Choi, Eue-Keun A1 - Choi, Seung Hoan A1 - Christophersen, Ingrid E A1 - Chung, Mina K A1 - Cole, John W A1 - Conen, David A1 - Cook, James A1 - Crijns, Harry J A1 - Cutler, Michael J A1 - Damrauer, Scott M A1 - Daniels, Brian R A1 - Darbar, Dawood A1 - Delgado, Graciela A1 - Denny, Joshua C A1 - Dichgans, Martin A1 - Dörr, Marcus A1 - Dudink, Elton A A1 - Dudley, Samuel C A1 - Esa, Nada A1 - Esko, Tõnu A1 - Eskola, Markku A1 - Fatkin, Diane A1 - Felix, Stephan B A1 - Ford, Ian A1 - Franco, Oscar H A1 - Geelhoed, Bastiaan A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Guo, Xiuqing A1 - Gupta, Namrata A1 - Gustafsson, Stefan A1 - Gutmann, Rebecca A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Hernesniemi, Jussi A1 - Hocking, Lynne J A1 - Hofman, Albert A1 - Horimoto, Andrea R V R A1 - Huang, Jie A1 - Huang, Paul L A1 - Huffman, Jennifer A1 - Ingelsson, Erik A1 - Ipek, Esra Gucuk A1 - Ito, Kaoru A1 - Jimenez-Conde, Jordi A1 - Johnson, Renee A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kane, John P A1 - Kastrati, Adnan A1 - Kathiresan, Sekar A1 - Katschnig-Winter, Petra A1 - Kavousi, Maryam A1 - Kessler, Thorsten A1 - Kietselaer, Bas L A1 - Kirchhof, Paulus A1 - Kleber, Marcus E A1 - Knight, Stacey A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Launer, Lenore J A1 - Laurikka, Jari A1 - Lehtimäki, Terho A1 - Leineweber, Kirsten A1 - Lemaitre, Rozenn N A1 - Li, Man A1 - Lim, Hong Euy A1 - Lin, Henry J A1 - Lin, Honghuang A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lokki, Marja-Liisa A1 - London, Barry A1 - Loos, Ruth J F A1 - Low, Siew-Kee A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Macfarlane, Peter W A1 - Magnusson, Patrik K A1 - Mahajan, Anubha A1 - Malik, Rainer A1 - Mansur, Alfredo J A1 - Marcus, Gregory M A1 - Margolin, Lauren A1 - Margulies, Kenneth B A1 - März, Winfried A1 - McManus, David D A1 - Melander, Olle A1 - Mohanty, Sanghamitra A1 - Montgomery, Jay A A1 - Morley, Michael P A1 - Morris, Andrew P A1 - Müller-Nurasyid, Martina A1 - Natale, Andrea A1 - Nazarian, Saman A1 - Neumann, Benjamin A1 - Newton-Cheh, Christopher A1 - Niemeijer, Maartje N A1 - Nikus, Kjell A1 - Nilsson, Peter A1 - Noordam, Raymond A1 - Oellers, Heidi A1 - Olesen, Morten S A1 - Orho-Melander, Marju A1 - Padmanabhan, Sandosh A1 - Pak, Hui-Nam A1 - Paré, Guillaume A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Pereira, Alexandre A1 - Porteous, David A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Pullinger, Clive R A1 - Rader, Daniel J A1 - Refsgaard, Lena A1 - Ribasés, Marta A1 - Ridker, Paul M A1 - Rienstra, Michiel A1 - Risch, Lorenz A1 - Roden, Dan M A1 - Rosand, Jonathan A1 - Rosenberg, Michael A A1 - Rost, Natalia A1 - Rotter, Jerome I A1 - Saba, Samir A1 - Sandhu, Roopinder K A1 - Schnabel, Renate B A1 - Schramm, Katharina A1 - Schunkert, Heribert A1 - Schurman, Claudia A1 - Scott, Stuart A A1 - Seppälä, Ilkka A1 - Shaffer, Christian A1 - Shah, Svati A1 - Shalaby, Alaa A A1 - Shim, Jaemin A1 - Shoemaker, M Benjamin A1 - Siland, Joylene E A1 - Sinisalo, Juha A1 - Sinner, Moritz F A1 - Slowik, Agnieszka A1 - Smith, Albert V A1 - Smith, Blair H A1 - Smith, J Gustav A1 - Smith, Jonathan D A1 - Smith, Nicholas L A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Stricker, Bruno H A1 - Sun, Albert A1 - Sun, Han A1 - Svendsen, Jesper H A1 - Tanaka, Toshihiro A1 - Tanriverdi, Kahraman A1 - Taylor, Kent D A1 - Teder-Laving, Maris A1 - Teumer, Alexander A1 - Thériault, Sébastien A1 - Trompet, Stella A1 - Tucker, Nathan R A1 - Tveit, Arnljot A1 - Uitterlinden, André G A1 - van der Harst, Pim A1 - Van Gelder, Isabelle C A1 - Van Wagoner, David R A1 - Verweij, Niek A1 - Vlachopoulou, Efthymia A1 - Völker, Uwe A1 - Wang, Biqi A1 - Weeke, Peter E A1 - Weijs, Bob A1 - Weiss, Raul A1 - Weiss, Stefan A1 - Wells, Quinn S A1 - Wiggins, Kerri L A1 - Wong, Jorge A A1 - Woo, Daniel A1 - Worrall, Bradford B A1 - Yang, Pil-Sung A1 - Yao, Jie A1 - Yoneda, Zachary T A1 - Zeller, Tanja A1 - Zeng, Lingyao A1 - Lubitz, Steven A A1 - Lunetta, Kathryn L A1 - Ellinor, Patrick T AB -

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

VL - 50 IS - 9 ER - TY - JOUR T1 - Sleep characteristics that predict atrial fibrillation. JF - Heart Rhythm Y1 - 2018 A1 - Christensen, Matthew A A1 - Dixit, Shalini A1 - Dewland, Thomas A A1 - Whitman, Isaac R A1 - Nah, Gregory A1 - Vittinghoff, Eric A1 - Mukamal, Kenneth J A1 - Redline, Susan A1 - Robbins, John A A1 - Newman, Anne B A1 - Patel, Sanjay R A1 - Magnani, Jared W A1 - Psaty, Bruce M A1 - Olgin, Jeffrey E A1 - Pletcher, Mark J A1 - Heckbert, Susan R A1 - Marcus, Gregory M AB -

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.

VL - 15 IS - 9 ER - TY - JOUR T1 - Alcohol consumption and leukocyte telomere length. JF - Sci Rep Y1 - 2019 A1 - Dixit, Shalini A1 - Whooley, Mary A A1 - Vittinghoff, Eric A1 - Roberts, Jason D A1 - Heckbert, Susan R A1 - Fitzpatrick, Annette L A1 - Lin, Jue A1 - Leung, Cindy A1 - Mukamal, Kenneth J A1 - Marcus, Gregory M AB -

The relationship between alcohol consumption and mortality generally exhibits a U-shaped curve. The longevity observed with moderate alcohol consumption may be explained by other confounding factors, and, if such a relationship is present, the mechanism is not well understood. Indeed, the optimal amount of alcohol consumption for health has yet to be determined. Leukocyte telomere length is an emerging quantifiable marker of biological age and health, and a shorter telomere length is a predictor of increased mortality. Because leukocyte telomere length is a quantifiable and objectively measurable biomarker of aging, we sought to identify the amount of alcohol consumption associated with the longest telomere length and least telomere length attrition. Among over 2,000 participants from two distinct cohort studies, we found no pattern of alcohol consumption that was associated with longer telomere length or less telomere length attrition over time. Binge drinking may reduce telomere length. Using telomere length as a marker of age and health, these data fail to demonstrate any benefits of alcohol consumption, even when consumed in moderation.

VL - 9 IS - 1 ER - TY - JOUR T1 - NT -pro BNP as a Mediator of the Racial Difference in Incident Atrial Fibrillation and Heart Failure. JF - J Am Heart Assoc Y1 - 2019 A1 - Whitman, Isaac R A1 - Vittinghoff, Eric A1 - deFilippi, Christopher R A1 - Gottdiener, John S A1 - Alonso, Alvaro A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Hoogeveen, Ron C A1 - Arking, Dan E A1 - Selvin, Elizabeth A1 - Chen, Lin Y A1 - Dewland, Thomas A A1 - Marcus, Gregory M AB -

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.

VL - 8 IS - 7 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 - Characterization of cardiac mechanics and incident atrial fibrillation in participants of the Cardiovascular Health Study. JF - JCI Insight Y1 - 2020 A1 - Patel, Ravi B A1 - Delaney, Joseph A A1 - Hu, Mo A1 - Patel, Harnish A1 - Cheng, Jeanette A1 - Gottdiener, John A1 - Kizer, Jorge R A1 - Marcus, Gregory M A1 - Turakhia, Mintu P A1 - Deo, Rajat A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Shah, Sanjiv J AB -

BACKGROUND: Left atrial (LA) and left ventricular (LV) remodeling are associated with atrial fibrillation (AF). The prospective associations of impairment in cardiac mechanical function, as assessed by speckle-tracking echocardiography, with incident AF are less clear.

METHODS: In the Cardiovascular Health Study, a community-based cohort of older adults, participants free of AF with echocardiograms of adequate quality for speckle tracking were included. We evaluated the associations of indices of cardiac mechanics (LA reservoir strain, LV longitudinal strain, and LV early diastolic strain rate) with incident AF.

RESULTS: Of 4341 participants with strain imaging, participants with lower LA reservoir strain were older, had more cardiometabolic risk factors, and had lower renal function at baseline. Over a median follow-up of 10 years, 497 (11.4%) participants developed AF. Compared with the highest quartile of LA reservoir strain, the lowest quartile of LA reservoir strain was associated with higher risk of AF after covariate adjustment, including LA volume and LV longitudinal strain (heart rate [HR], 1.80; 95% CI, 1.31-2.45; P < 0.001). The association of LA reservoir strain and AF was stronger in subgroups with higher blood pressure, NT-proBNP, and LA volumes. There were no associations of LV longitudinal strain and LV early diastolic strain rate with incident AF after adjustment for LA reservoir strain.

CONCLUSION: Lower LA reservoir strain was associated with incident AF, independent of LV mechanics, and with stronger associations in high-risk subgroups. These findings suggest that LA mechanical dysfunction precedes the development of AF. Therapies targeting LA mechanical dysfunction may prevent progression to AF.

FUNDING: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grants KL2TR001424, R01HL107577, U01HL080295, and U01HL130114 from the NIH's National Center for Advancing Translational Sciences, and National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org.

VL - 5 IS - 19 ER - TY - JOUR T1 - Epigenetic Age and the Risk of Incident Atrial Fibrillation. JF - Circulation Y1 - 2021 A1 - Roberts, Jason D A1 - Vittinghoff, Eric A1 - Lu, Ake T A1 - Alonso, Alvaro A1 - Wang, Biqi A1 - Sitlani, Colleen M A1 - Mohammadi-Shemirani, Pedrum A1 - Fornage, Myriam A1 - Kornej, Jelena A1 - Brody, Jennifer A A1 - Arking, Dan E A1 - Lin, Honghuang A1 - Heckbert, Susan R A1 - Prokic, Ivana A1 - Ghanbari, Mohsen A1 - Skanes, Allan C A1 - Bartz, Traci M A1 - Perez, Marco V A1 - Taylor, Kent D A1 - Lubitz, Steven A A1 - Ellinor, Patrick T A1 - Lunetta, Kathryn L A1 - Pankow, James S A1 - Paré, Guillaume A1 - Sotoodehnia, Nona A1 - Benjamin, Emelia J A1 - Horvath, Steve A1 - Marcus, Gregory M KW - Aged KW - Aging KW - Atrial Fibrillation KW - DNA Methylation KW - Epigenesis, Genetic KW - Epigenomics KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Models, Cardiovascular KW - Models, Genetic AB -

BACKGROUND: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF.

METHODS: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF.

RESULTS: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; <0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; <0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF.

CONCLUSIONS: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.

VL - 144 IS - 24 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 - Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. JF - Nature Y1 - 2023 A1 - Weinstock, Joshua S A1 - Gopakumar, Jayakrishnan A1 - Burugula, Bala Bharathi A1 - Uddin, Md Mesbah A1 - Jahn, Nikolaus A1 - Belk, Julia A A1 - Bouzid, Hind A1 - Daniel, Bence A1 - Miao, Zhuang A1 - Ly, Nghi A1 - Mack, Taralynn M A1 - Luna, Sofia E A1 - Prothro, Katherine P A1 - Mitchell, Shaneice R A1 - Laurie, Cecelia A A1 - Broome, Jai G A1 - Taylor, Kent D A1 - Guo, Xiuqing A1 - Sinner, Moritz F A1 - von Falkenhausen, Aenne S A1 - Kääb, Stefan A1 - Shuldiner, Alan R A1 - O'Connell, Jeffrey R A1 - Lewis, Joshua P A1 - Boerwinkle, Eric A1 - Barnes, Kathleen C A1 - Chami, Nathalie A1 - Kenny, Eimear E A1 - Loos, Ruth J F A1 - Fornage, Myriam A1 - Hou, Lifang A1 - Lloyd-Jones, Donald M A1 - Redline, Susan A1 - Cade, Brian E A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Silverman, Edwin K A1 - Yun, Jeong H A1 - Qiao, Dandi A1 - Palmer, Nicholette D A1 - Freedman, Barry I A1 - Bowden, Donald W A1 - Cho, Michael H A1 - DeMeo, Dawn L A1 - Vasan, Ramachandran S A1 - Yanek, Lisa R A1 - Becker, Lewis C A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - He, Jiang A1 - Rienstra, Michiel A1 - van der Harst, Pim A1 - Kaplan, Robert A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Arnett, Donna K A1 - Irvin, Marguerite R A1 - Tiwari, Hemant A1 - Cutler, Michael J A1 - Knight, Stacey A1 - Muhlestein, J Brent A1 - Correa, Adolfo A1 - Raffield, Laura M A1 - Gao, Yan A1 - de Andrade, Mariza A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Konkle, Barbara A A1 - Johnsen, Jill M A1 - Wheeler, Marsha M A1 - Smith, J Gustav A1 - Melander, Olle A1 - Nilsson, Peter M A1 - Custer, Brian S A1 - Duggirala, Ravindranath A1 - Curran, Joanne E A1 - Blangero, John A1 - McGarvey, Stephen A1 - Williams, L Keoki A1 - Xiao, Shujie A1 - Yang, Mao A1 - Gu, C Charles A1 - Chen, Yii-Der Ida A1 - Lee, Wen-Jane A1 - Marcus, Gregory M A1 - Kane, John P A1 - Pullinger, Clive R A1 - Shoemaker, M Benjamin A1 - Darbar, Dawood A1 - Roden, Dan M A1 - Albert, Christine A1 - Kooperberg, Charles A1 - Zhou, Ying A1 - Manson, JoAnn E A1 - Desai, Pinkal A1 - Johnson, Andrew D A1 - Mathias, Rasika A A1 - Blackwell, Thomas W A1 - Abecasis, Goncalo R A1 - Smith, Albert V A1 - Kang, Hyun M A1 - Satpathy, Ansuman T A1 - Natarajan, Pradeep A1 - Kitzman, Jacob O A1 - Whitsel, Eric A A1 - Reiner, Alexander P A1 - Bick, Alexander G A1 - Jaiswal, Siddhartha KW - Alleles KW - Animals KW - Clonal Hematopoiesis KW - Genome-Wide Association Study KW - Hematopoiesis KW - Hematopoietic Stem Cells KW - Humans KW - Mice KW - Mutation KW - Promoter Regions, Genetic AB -

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

VL - 616 IS - 7958 ER - TY - JOUR T1 - Inflammation and Incident Conduction Disease. JF - J Am Heart Assoc Y1 - 2023 A1 - Frimodt-Møller, Emilie K A1 - Gottdiener, John S A1 - Soliman, Elsayed Z A1 - Kizer, Jorge R A1 - Vittinghoff, Eric A1 - Psaty, Bruce M A1 - Biering-Sørensen, Tor A1 - Marcus, Gregory M KW - Cardiac Conduction System Disease KW - Electrocardiography KW - Heart Block KW - Humans KW - Inflammation VL - 12 IS - 1 ER - TY - JOUR T1 - Lifestyle habits associated with cardiac conduction disease. JF - Eur Heart J Y1 - 2023 A1 - Frimodt-Møller, Emilie K A1 - Soliman, Elsayed Z A1 - Kizer, Jorge R A1 - Vittinghoff, Eric A1 - Psaty, Bruce M A1 - Biering-Sørensen, Tor A1 - Gottdiener, John S A1 - Marcus, Gregory M AB -

AIMS: Cardiac conduction disease can lead to syncope, heart failure, and death. The only available therapy is pacemaker implantation, with no established prevention strategies. Research to identify modifiable risk factors has been scant.

METHODS AND RESULTS: Data from the Cardiovascular Health Study, a population-based cohort study of adults ≥ 65 years with annual 12-lead electrocardiograms obtained over 10 years, were utilized to examine relationships between baseline characteristics, including lifestyle habits, and conduction disease. Of 5050 participants (mean age 73 ± 6 years; 52% women), prevalent conduction disease included 257 with first-degree atrioventricular block, 99 with left anterior fascicular block, 9 with left posterior fascicular block, 193 with right bundle branch block (BBB), 76 with left BBB, and 102 with intraventricular block at baseline. After multivariable adjustment, older age, male sex, a larger body mass index, hypertension, and coronary heart disease were associated with a higher prevalence of conduction disease, whereas White race and more physical activity were associated with a lower prevalence. Over a median follow-up on 7 (interquartile range 1-9) years, 1036 developed incident conduction disease. Older age, male sex, a larger BMI, and diabetes were each associated with incident conduction disease. Of lifestyle habits, more physical activity (hazard ratio 0.91, 95% confidence interval 0.84-0.98, P = 0.017) was associated with a reduced risk, while smoking and alcohol did not exhibit a significant association.

CONCLUSION: While some difficult to control comorbidities were associated with conduction disease as expected, a readily modifiable lifestyle factor, physical activity, was associated with a lower risk.

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