@article {1053, title = {Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study.}, journal = {J Am Coll Cardiol}, volume = {52}, year = {2008}, month = {2008 Sep 30}, pages = {1152-9}, abstract = {

OBJECTIVES: The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities.

BACKGROUND: Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited.

METHODS: We studied 3,044 adults>or=65 years of age who initially were free of HF in the Cardiovascular Health Study. We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over the course of 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by thyroid-stimulating hormone [TSH] levels: 4.5 to 9.9, >or=10.0 mU/l), and those with subclinical hyperthyroidism.

RESULTS: Over the course of 12 years, 736 participants developed HF events. Participants with TSH>or=10.0 mU/l had a greater incidence of HF compared with euthyroid participants (41.7 vs. 22.9 per 1,000 person years, p=0.01; adjusted hazard ratio: 1.88; 95\% confidence interval: 1.05 to 3.34). Baseline peak E velocity, which is an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was greater in those patients with TSH>or=10.0 mU/l compared with euthyroid participants (0.80 m/s vs. 0.72 m/s, p=0.002). Over the course of 5 years, left ventricular mass increased among those with TSH>or=10.0 mU/l, but other echocardiographic measurements were unchanged. Those patients with TSH 4.5 to 9.9 mU/l or with subclinical hyperthyroidism had no increase in risk of HF.

CONCLUSIONS: Compared with euthyroid older adults, those adults with TSH>or=10.0 mU/l have a moderately increased risk of HF and alterations in cardiac function but not older adults with TSH<10.0 mU/l. Clinical trials should assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH>or=10.0 mU/l.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Echocardiography, Female, Heart, Heart Failure, Heart Function Tests, Humans, Hyperthyroidism, Hypertrophy, Left Ventricular, Hypothyroidism, Male, Risk Factors, Time Factors}, issn = {1558-3597}, doi = {10.1016/j.jacc.2008.07.009}, author = {Rodondi, Nicolas and Bauer, Douglas C and Cappola, Anne R and Cornuz, Jacques and Robbins, John and Fried, Linda P and Ladenson, Paul W and Vittinghoff, Eric and Gottdiener, John S and Newman, Anne B} } @article {1248, title = {European ancestry as a risk factor for atrial fibrillation in African Americans.}, journal = {Circulation}, volume = {122}, year = {2010}, month = {2010 Nov 16}, pages = {2009-15}, abstract = {

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.

}, keywords = {African Americans, Aged, Atrial Fibrillation, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Risk Factors}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.110.958306}, author = {Marcus, Gregory M and Alonso, Alvaro and Peralta, Carmen A and Lettre, Guillaume and Vittinghoff, Eric and Lubitz, Steven A and Fox, Ervin R and Levitzky, Yamini S and Mehra, Reena and Kerr, Kathleen F and Deo, Rajat and Sotoodehnia, Nona and Akylbekova, Meggie and Ellinor, Patrick T and Paltoo, Dina N and Soliman, Elsayed Z and Benjamin, Emelia J and Heckbert, Susan R} } @article {1231, title = {Subclinical hypothyroidism and the risk of coronary heart disease and mortality.}, journal = {JAMA}, volume = {304}, year = {2010}, month = {2010 Sep 22}, pages = {1365-74}, abstract = {

CONTEXT: Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants{\textquoteright} age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease.

OBJECTIVE: To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism.

DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched.

DATA EXTRACTION: Individual data on 55,287 participants with 542,494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25,977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations.

RESULTS: Among 55,287 adults, 3450 had subclinical hypothyroidism (6.2\%) and 51,837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95\% confidence interval [CI], 0.86-1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95\% CI, 0.96-1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95\% CI, 1.28-2.80) for a TSH level of 10 to 19.9 mIU/L (n = 70 events/235; 38.4/1000 person-years; P <.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95\% CI, 0.91-1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95\% CI, 1.03-1.95; 6.9/1000 person-years), and 1.58 (95\% CI, 1.10-2.27, n = 28 deaths/333; 7.7/1000 person-years; P = .005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease.

CONCLUSIONS: Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Coronary Disease, Female, Humans, Hypothyroidism, Male, Middle Aged, Mortality, Prospective Studies, Risk, Thyrotropin, Young Adult}, issn = {1538-3598}, doi = {10.1001/jama.2010.1361}, author = {Rodondi, Nicolas and den Elzen, Wendy P J and Bauer, Douglas C and Cappola, Anne R and Razvi, Salman and Walsh, John P and Asvold, Bj{\o}rn O and Iervasi, Giorgio and Imaizumi, Misa and Collet, Tinh-Hai and Bremner, Alexandra and Maisonneuve, Patrick and Sgarbi, Jos{\'e} A and Khaw, Kay-Tee and Vanderpump, Mark P J and Newman, Anne B and Cornuz, Jacques and Franklyn, Jayne A and Westendorp, Rudi G J and Vittinghoff, Eric and Gussekloo, Jacobijn} } @article {1545, title = {Subclinical hyperthyroidism and the risk of coronary heart disease and mortality.}, journal = {Arch Intern Med}, volume = {172}, year = {2012}, month = {2012 May 28}, pages = {799-809}, abstract = {

BACKGROUND: Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting.We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts.

METHODS: Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications.

RESULTS: Of 52 674 participants, 2188 (4.2\%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age- and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio[HR], 1.24, 95\% CI, 1.06-1.46), CHD mortality (HR,1.29; 95\% CI, 1.02-1.62), CHD events (HR, 1.21; 95\%CI, 0.99-1.46), and AF (HR, 1.68; 95\% CI, 1.16-2.43).Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5\% for total mortality to 41.5\% forAF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L(for both, P value for trend, .03).

CONCLUSION: Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.

}, keywords = {Adolescent, Adult, Age Distribution, Aged, Aged, 80 and over, Atrial Fibrillation, Cause of Death, Cohort Studies, Coronary Artery Disease, Female, Humans, Hyperthyroidism, Male, Middle Aged, Prognosis, Prospective Studies, Risk Assessment, Severity of Illness Index, Sex Distribution, Survival Analysis, Switzerland, Thyroid Function Tests, Thyrotropin, Young Adult}, issn = {1538-3679}, doi = {10.1001/archinternmed.2012.402}, author = {Collet, Tinh-Hai and Gussekloo, Jacobijn and Bauer, Douglas C and den Elzen, Wendy P J and Cappola, Anne R and Balmer, Philippe and Iervasi, Giorgio and Asvold, Bj{\o}rn O and Sgarbi, Jos{\'e} A and V{\"o}lzke, Henry and Gencer, Bari{\c s} and Maciel, Rui M B and Molinaro, Sabrina and Bremner, Alexandra and Luben, Robert N and Maisonneuve, Patrick and Cornuz, Jacques and Newman, Anne B and Khaw, Kay-Tee and Westendorp, Rudi G J and Franklyn, Jayne A and Vittinghoff, Eric and Walsh, John P and Rodondi, Nicolas} } @article {6087, title = {Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts.}, journal = {Circulation}, volume = {126}, year = {2012}, month = {2012 Aug 28}, pages = {1040-9}, abstract = {

BACKGROUND: American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events.

METHODS AND RESULTS: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1\%) had subclinical hypothyroidism and 648 (2.6\%) had subclinical hyperthyroidism. In age- and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01); the hazard ratio was 1.01 (95\% confidence interval, 0.81-1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95\% confidence interval, 0.84-3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95\% confidence interval, 1.27-2.72) for TSH of 10.0 to 19.9 mIU/L (P for trend <0.01) and 1.31 (95\% confidence interval, 0.88-1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95\% confidence interval, 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors.

CONCLUSION: Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH >=10 and <0.10 mIU/L.

}, keywords = {Adult, Aged, Aged, 80 and over, Comorbidity, Female, Follow-Up Studies, Heart Failure, Humans, Hypothyroidism, Male, Middle Aged, Prospective Studies, Risk, Risk Factors, Sensitivity and Specificity, Thyrotropin, Thyroxine}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.112.096024}, author = {Gencer, Bari{\c s} and Collet, Tinh-Hai and Virgini, Vanessa and Bauer, Douglas C and Gussekloo, Jacobijn and Cappola, Anne R and Nanchen, David and den Elzen, Wendy P J and Balmer, Philippe and Luben, Robert N and Iacoviello, Massimo and Triggiani, Vincenzo and Cornuz, Jacques and Newman, Anne B and Khaw, Kay-Tee and Jukema, J Wouter and Westendorp, Rudi G J and Vittinghoff, Eric and Aujesky, Drahomir and Rodondi, Nicolas} } @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 {6077, title = {Long-term outcomes of left anterior fascicular block in the absence of overt cardiovascular disease.}, journal = {JAMA}, volume = {309}, year = {2013}, month = {2013 Apr 17}, pages = {1587-8}, keywords = {Aged, Atrial Fibrillation, Biomarkers, Bundle-Branch Block, Cohort Studies, Electrocardiography, Endomyocardial Fibrosis, Female, Heart Failure, Humans, Kaplan-Meier Estimate, Male, Prognosis, Risk}, issn = {1538-3598}, doi = {10.1001/jama.2013.2729}, author = {Mandyam, Mala C and Soliman, Elsayed Z and Heckbert, Susan R and Vittinghoff, Eric 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 {6553, title = {Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis.}, journal = {J Clin Endocrinol Metab}, volume = {99}, year = {2014}, month = {2014 Sep}, pages = {3353-62}, abstract = {

CONTEXT: Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk.

OBJECTIVE: The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs).

DATA SOURCES AND STUDY SELECTION: A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes.

DATA EXTRACTION: Individual data of 38 274 participants from six cohorts for CHD mortality followed up for 460 333 person-years and 33 394 participants from four cohorts for CHD events.

DATA SYNTHESIS: Among 38 274 adults (median age 55 y, 63\% women), 1691 (4.4\%) had subclinical hypothyroidism, of whom 775 (45.8\%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95\% confidence interval (CI) 0.87-1.53 vs HR 1.26, CI 1.01-1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87-1.56 vs HR 1.26, CI 1.02-1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status.

CONCLUSIONS: CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.

}, keywords = {Adult, Aged, Aged, 80 and over, Autoantibodies, Coronary Disease, Female, Humans, Hypothyroidism, Incidence, Male, Middle Aged, Prevalence, Prognosis, Risk Factors, Seroepidemiologic Studies, Severity of Illness Index, Young Adult}, issn = {1945-7197}, doi = {10.1210/jc.2014-1250}, author = {Collet, Tinh-Hai and Bauer, Douglas C and Cappola, Anne R and Asvold, Bj{\o}rn O and Weiler, Stefan and Vittinghoff, Eric and Gussekloo, Jacobijn and Bremner, Alexandra and den Elzen, Wendy P J and Maciel, Rui M B and Vanderpump, Mark P J and Cornuz, Jacques and D{\"o}rr, Marcus and Wallaschofski, Henri and Newman, Anne B and Sgarbi, Jos{\'e} A and Razvi, Salman and V{\"o}lzke, Henry and Walsh, John P and Aujesky, Drahomir and Rodondi, Nicolas} } @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 {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 {7971, title = {Alcohol consumption and leukocyte telomere length.}, journal = {Sci Rep}, volume = {9}, year = {2019}, month = {2019 Feb 05}, pages = {1404}, abstract = {

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.

}, issn = {2045-2322}, doi = {10.1038/s41598-019-38904-0}, author = {Dixit, Shalini and Whooley, Mary A and Vittinghoff, Eric and Roberts, Jason D and Heckbert, Susan R and Fitzpatrick, Annette L and Lin, Jue and Leung, Cindy and Mukamal, Kenneth J 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 {8208, title = {Use of a pooled cohort to impute cardiovascular disease risk factors across the adult life course.}, journal = {Int J Epidemiol}, volume = {48}, year = {2019}, month = {2019 06 01}, pages = {1004-1013}, abstract = {

BACKGROUND: In designing prevention strategies, it may be useful to understand how early and midlife cardiovascular disease risk factor (CVDRF) exposures affect outcomes that primarily occur in mid to late life. Few single US cohorts have followed participants from early adulthood to late life.

METHODS: We pooled four prospective cohorts that represent segments of the adult life course, and studied 15~001 White and Black adults aged 18 to 95 years at enrollment. We imputed early and midlife exposure to body mass index (BMI), glucose, lipids and blood pressure (BP). CVDRF trajectories were estimated using linear mixed models. Using the best linear unbiased predictions, we obtained person-specific estimates of CVDRF trajectories beginning at age 20 until each participant{\textquoteright}s end of follow-up. We then calculated for each CVDRF, summary measures of early and midlife exposure as time-weighted averages (TWAs).

RESULTS: In the pooled cohort, 33.7\% were Black and 54.8\% were female. CVDRF summary measures worsened in midlife compared with early life and varied by sex and race. In particular, systolic and diastolic BP were consistently higher over the adult life course among men, and BMI was higher among Blacks, particularly Black women. Simulation studies suggested acceptable imputation accuracy, especially for the younger cohorts. Correlations of true and imputed CVDRF summary measures ranged from 0.53 to 0.99, and agreement ranged from 67\% to 99\%.

CONCLUSIONS: These results suggest that imputed CVDRFs may be accurate enough to be useful in assessing the effects of early and midlife exposures on later life outcomes.

}, issn = {1464-3685}, doi = {10.1093/ije/dyy264}, author = {Zeki Al Hazzouri, Adina and Vittinghoff, Eric and Zhang, Yiyi and Pletcher, Mark J and Moran, Andrew E and Bibbins-Domingo, Kirsten and Golden, Sherita H and Yaffe, Kristine} } @article {8703, title = {Association of Midlife Cardiovascular Risk Factors With the Risk of Heart Failure Subtypes Later in Life.}, journal = {J Card Fail}, volume = {27}, year = {2021}, month = {2021 Apr}, pages = {435-444}, abstract = {

BACKGROUND: Independent associations between cardiovascular risk factor exposures during midlife and later life development of heart failure (HF) with preserved ejection fraction (HFpEF) versus reduced EF (HFrEF) have not been previously studied.

METHODS: We pooled data from 4 US cohort studies (Atherosclerosis Risk in Communities, Cardiovascular Health, Health , Aging and Body Composition, and Multi-Ethnic Study of Atherosclerosis) and imputed annual risk factor trajectories for body mass index, systolic and diastolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, and glucose starting from age 40 years. Time-weighted average exposures to each risk factor during midlife and later life were calculated and analyzed for associations with the development of HFpEF or HFrEF.

RESULTS: A total of 23,861 participants were included (mean age at first in-person visit, 61.8 {\textpm}1 0.2 years; 56.6\% female). During a median follow-up of 12 years, there were 3666 incident HF events, of which 51\% had EF measured, including 934 with HFpEF and 739 with HFrEF. A high midlife systolic blood pressure and low midlife high-density lipoprotein cholesterol were associated with HFrEF, and a high midlife body mass index, systolic blood pressure, pulse pressure, and glucose were associated with HFpEF. After adjusting for later life exposures, only midlife pulse pressure remained independently associated with HFpEF.

CONCLUSIONS: Midlife exposure to cardiovascular risk factors are differentially associated with HFrEF and HFpEF later in life. Having a higher pulse pressure during midlife is associated with a greater risk for HFpEF but not HFrEF, independent of later life exposures.

}, issn = {1532-8414}, doi = {10.1016/j.cardfail.2020.11.008}, author = {Cohen, Laura P and Vittinghoff, Eric and Pletcher, Mark J and Allen, Norrina B and Shah, Sanjiv J and Wilkins, John T and Chang, Patricia P and Ndumele, Chiadi E and Newman, Anne B and Ives, Diane and Maurer, Mathew S and Oelsner, Elizabeth C and Moran, Andrew E and Zhang, Yiyi} } @article {9000, title = {Associations of Body Mass Index and Waist Circumference in Young Adulthood with Later Life Incident Diabetes.}, journal = {J Clin Endocrinol Metab}, volume = {106}, year = {2021}, month = {2021 11 19}, pages = {e5011-e5020}, abstract = {

CONTEXT: The independent contribution of young adult exposure to overweight and obesity to later-life incident diabetes is not well studied.

OBJECTIVE: To assess the associations of exposures to elevated body mass index (BMI) and waist circumference (WC) in young adulthood (ages 18-39 years) with incident diabetes later in life (>=40 years).

DESIGN: Pooled data from 6 US prospective cohorts (Atherosclerosis Risk in Communities Study, Cardiovascular Risk Development in Young Adults Study, Cardiovascular Health Study, (4) Framingham Heart Study Offspring Cohort, (5) Health, Aging and Body Composition Study, and (6) Multi-Ethnic Study of Atherosclerosis.

SETTING: Population-based cohort studies.

PARTICIPANTS: 30 780 participants (56.1\% female, 69.8\% non-Hispanic white) without a diagnosis of diabetes by age 40.

INTERVENTIONS: We imputed BMI and WC trajectories from age 18 for every participant and estimated time-weighted average exposures to BMI or WC during young adulthood and later life.

MAIN OUTCOME MEASURE(S): Incident diabetes defined as fasting glucose >=126 mg/dL, nonfasting glucose >=200 mg/dL, or use of diabetes medications.

RESULTS: During a 9-year median follow-up, 4323 participants developed incident diabetes. Young adult BMI and WC were associated with later-life incident diabetes after controlling for later-life exposures [hazard ratios (HR) 1.99 for BMI >= 30 kg/m2 and 2.13 for WC > 88cm (women)/>102cm (men) compared to normal ranges]. Young adult homeostatic model of insulin resistance mediated 49\% and 44\% of the association between BMI and WC with later-life incident diabetes. High-density lipoproteins and triglycerides mediated a smaller proportion of these associations.

CONCLUSIONS: Elevated BMI and WC during young adulthood were independently associated with later-life incident diabetes. Insulin resistance may be a key mediator.

}, keywords = {Adolescent, Adult, Biomarkers, Body Mass Index, Diabetes Mellitus, Female, Follow-Up Studies, Humans, Male, Obesity, Overweight, Prognosis, Prospective Studies, Risk Factors, United States, Waist Circumference, Young Adult}, issn = {1945-7197}, doi = {10.1210/clinem/dgab551}, author = {Nair, Nandini and Vittinghoff, Eric and Pletcher, Mark J and Oelsner, Elizabeth C and Allen, Norrina B and Ndumele, Chiadi E and West, Nancy A and Strotmeyer, Elsa S and Mukamal, Kenneth J and Siscovick, David S and Biggs, Mary L and Laferr{\`e}re, Blandine and Moran, Andrew E and Zhang, Yiyi} } @article {8793, title = {Body mass index in early adulthood and dementia in late life: Findings from a pooled cohort.}, journal = {Alzheimers Dement}, year = {2021}, month = {2021 May 13}, abstract = {

INTRODUCTION: To examine the independent association of body mass index (BMI) in early adulthood with dementia incidence among men and women.

METHODS: We studied 5104 older adults from the Cardiovascular Health Study (CHS) and the Health, Aging, and Body Composition (Health ABC) study. We imputed early adulthood and midlife BMI using a pooled parent cohort with complete adult lifespan coverage and previously established methods. Dementia was ascertained using criteria such as neuropsychological test battery, medical records, and dementia-related drug use. Pooled logistic regression (PLR) models were used.

RESULTS: Compared to women with normal BMI in early adulthood, the odds of dementia were higher among both overweight (odds ratio [OR]~=~1.8; 95\% confidence interval [CI]~=~1.31 to 2.54) and obese (OR~=~2.45; 95\% CI~=~1.47 to 4.06) women, independent of mid- and late-life BMI. Similar relationship was observed in men.

CONCLUSIONS: With the growing obesity epidemic among US adults, efforts aimed at reducing dementia may need to begin obesity prevention and treatment early in the life course.

}, issn = {1552-5279}, doi = {10.1002/alz.12367}, author = {Zeki Al Hazzouri, Adina and Vittinghoff, Eric and Hoang, Tina and Golden, Sherita H and Fitzpatrick, Annette L and Zhang, Adina and Grasset, Leslie and Yaffe, Kristine} } @article {8792, title = {Cardiovascular Risk Factors Across the Life Course and Cognitive Decline: A Pooled Cohort Study.}, journal = {Neurology}, volume = {96}, year = {2021}, month = {2021 04 27}, pages = {e2212-e2219}, abstract = {

OBJECTIVE: Cardiovascular risk factors (CVRFs) are associated with increased risk of cognitive decline, but little is known about how early adult CVRFs and those across the life course might influence late-life cognition. To test the hypothesis that CVRFs across the adult life course are associated with late-life cognitive changes, we pooled data from 4 prospective cohorts (n = 15,001, ages 18-95).

METHODS: We imputed trajectories of body mass index (BMI), fasting glucose (FG), systolic blood pressure (SBP), and total cholesterol (TC) for older adults. We used linear mixed models to determine the association of early adult, midlife, and late-life CVRFs with late-life decline on global cognition (Modified Mini-Mental State Examination [3MS]) and processing speed (Digit Symbol Substitution Test [DSST]), adjusting for demographics, education, and cohort.

RESULTS: Elevated BMI, FG, and SBP (but not TC) at each time period were associated with greater late-life decline. Early life CVRFs were associated with the greatest change, an approximate doubling of mean 10-year decline (an additional 3-4 points for 3MS or DSST). Late-life CVRFs were associated with declines in early late life (<80 years) but with gains in very late life (>=80 years). After adjusting for CVRF exposures at all time periods, the associations for early adult and late-life CVRFs persisted.

CONCLUSIONS: We found that imputed CVRFs across the life course, especially in early adulthood, were associated with greater late-life cognitive decline. Our results suggest that CVRF treatment in early adulthood could benefit late-life cognition, but that treatment in very late life may not be as helpful for these outcomes.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Aging, Blood Pressure, Cardiovascular Diseases, Cognition, Cognitive Dysfunction, Cohort Studies, Female, Heart Disease Risk Factors, Humans, Hypertension, Male, Middle Aged, Risk Factors, Young Adult}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000011747}, author = {Yaffe, Kristine and Vittinghoff, Eric and Hoang, Tina and Matthews, Karen and Golden, Sherita H and Zeki Al Hazzouri, Adina} } @article {8987, title = {Depressive Symptoms Imputed Across the Life Course Are Associated with Cognitive Impairment and Cognitive Decline.}, journal = {J Alzheimers Dis}, volume = {83}, year = {2021}, month = {2021}, pages = {1379-1389}, abstract = {

BACKGROUND: Depressive symptoms may increase risk for dementia, but findings are controversial because late-life depression may be a prodromal dementia symptom. Life course data on depression and dementia risk may clarify this association; however, data is limited.

OBJECTIVE: To impute adult depressive symptoms trajectories across adult life stages and estimate the association with cognitive impairment and decline.

METHODS: Using a pooled study of 4 prospective cohorts (ages 20-89), we imputed adult life course depressive symptoms trajectories based on Center for Epidemiologic Studies Depression Scale-10 (CESD-10) and calculated time-weighted averages for early adulthood (ages 20-49), mid-life (ages 50-69), and late-life (ages 70-89) for 6,122 older participants. Adjusted pooled logistic and mixed-effects models estimated associations of imputed depressive symptoms with two cognitive outcomes: cognitive impairment defined by established criteria and a composite cognitive score.

RESULTS: In separate models, elevated depressive symptoms in each life stage were associated with cognitive outcomes: early adulthood OR for cognitive impairment = 1.59 (95\%CI: 1.35,1.87); mid-life OR = 1.94 (95\%CI:1.16, 3.26); and late-life OR = 1.77 (95\%CI:1.42, 2.21). When adjusted for depressive symptoms in the other life-stages, elevated depressive symptoms in early adulthood (OR = 1.73; 95\%CI: 1.42,2.11) and late-life (OR = 1.43; 95\%CI: 1.08,1.89) remained associated with cognitive impairment and were also associated with faster rates of cognitive decline (p < 0.05).

CONCLUSION: Imputing depressive symptom trajectories from pooled cohorts may help expand data across the life course. Our findings suggest early adulthood depressive symptoms may be a risk factor for cognitive impairment independent of mid- or late-life depressive symptoms.

}, keywords = {Adult, Aged, Aged, 80 and over, Aging, Cognitive Dysfunction, Cohort Studies, Dementia, Depression, Female, Humans, Male, Middle Aged, Prodromal Symptoms, Risk Factors}, issn = {1875-8908}, doi = {10.3233/JAD-210588}, author = {Brenowitz, Willa D and Zeki Al Hazzouri, Adina and Vittinghoff, Eric and Golden, Sherita H and Fitzpatrick, Annette L and Yaffe, Kristine} } @article {9001, title = {Epigenetic Age and the Risk of Incident Atrial Fibrillation.}, journal = {Circulation}, volume = {144}, year = {2021}, month = {2021 12 14}, pages = {1899-1911}, abstract = {

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.

}, keywords = {Aged, Aging, Atrial Fibrillation, DNA Methylation, Epigenesis, Genetic, Epigenomics, Female, Follow-Up Studies, Humans, Incidence, Male, Mendelian Randomization Analysis, Middle Aged, Models, Cardiovascular, Models, Genetic}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.121.056456}, author = {Roberts, Jason D and Vittinghoff, Eric and Lu, Ake T and Alonso, Alvaro and Wang, Biqi and Sitlani, Colleen M and Mohammadi-Shemirani, Pedrum and Fornage, Myriam and Kornej, Jelena and Brody, Jennifer A and Arking, Dan E and Lin, Honghuang and Heckbert, Susan R and Prokic, Ivana and Ghanbari, Mohsen and Skanes, Allan C and Bartz, Traci M and Perez, Marco V and Taylor, Kent D and Lubitz, Steven A and Ellinor, Patrick T and Lunetta, Kathryn L and Pankow, James S and Par{\'e}, Guillaume and Sotoodehnia, Nona and Benjamin, Emelia J and Horvath, Steve 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} } @article {9237, title = {Inflammation and Incident Conduction Disease.}, journal = {J Am Heart Assoc}, volume = {12}, year = {2023}, month = {2023 Jan 03}, pages = {e027247}, keywords = {Cardiac Conduction System Disease, Electrocardiography, Heart Block, Humans, Inflammation}, issn = {2047-9980}, doi = {10.1161/JAHA.122.027247}, author = {Frimodt-M{\o}ller, Emilie K and Gottdiener, John S and Soliman, Elsayed Z and Kizer, Jorge R and Vittinghoff, Eric and Psaty, Bruce M and Biering-S{\o}rensen, Tor and Marcus, Gregory M} } @article {9288, title = {Lifestyle habits associated with cardiac conduction disease.}, journal = {Eur Heart J}, year = {2023}, month = {2023 Jan 20}, abstract = {

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 {\textpm} 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.

}, issn = {1522-9645}, doi = {10.1093/eurheartj/ehac799}, author = {Frimodt-M{\o}ller, Emilie K and Soliman, Elsayed Z and Kizer, Jorge R and Vittinghoff, Eric and Psaty, Bruce M and Biering-S{\o}rensen, Tor and Gottdiener, John S and Marcus, Gregory M} }