Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program.

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV1] and its ratio to forced vital capacity [FEV1/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV1 and FEV1/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p < 2.2 × 10-16 with portability gains ranging from 5% to 28%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.

Persistent albuminuria and chronic kidney disease in adults with sickle cell anaemia: Results from a multicenter natural history study.

Clinical and laboratory correlates of chronic kidney disease (CKD) in sickle cell anaemia remain incompletely defined. In a multicenter cohort study, we evaluated the prevalence of persistent albuminuria (PA) and characteristics associated with PA, albumin-creatinine ratio (ACR) and decreased estimated glomerular filtration rate (eGFR) using logistic, linear and multinomial regression models, respectively. Of 269 participants (median age: 30 years; 57.2% females), the prevalence of PA was 35.7%. Using baseline ACR values of <100 and ≥100 mg/g, the probabilities of PA were 30.0% and 94.6%, respectively. In multivariable logistic regression analyses, male sex (ß = 0.80 [SE = 0.36], p = 0.024) and ACE inhibitors/ARBs use (ß = 1.54 [SE = 0.43], p < 0.001) were associated with higher likelihoods of PA, while higher haemoglobin (ß = -0.33 [SE = 0.13], p = 0.009) and HbF (ß = -0.04 [SE = 0.02], p = 0.041) were associated with lower likelihoods of PA. In multivariable multinomial regression analyses, older age (ß = 0.06 [SE = 0.02], p = 0.004) and higher alkaline phosphatase (ß = 0.01 [SE = 0.00], p = 0.004) were associated with higher odds of having eGFR 60-90 versus eGFR>90 mL/min/1.73 m2 using the cystatin C-based CKD-EPI-2012 equation. Additionally, higher systolic blood pressure (ß = 0.11 [SE = 0.03], p = 0.001) and blood urea nitrogen (ß = 0.45 [SE = 0.12], p < 0.001) were associated with higher odds, while higher haemoglobin (ß = -1.22 [SE = 0.43], p = 0.004) was associated with lower odds of having eGFR<60 versus eGFR>90 mL/min/1.73 m2. PA and decreased eGFR are associated with measures of disease severity and comorbid conditions (Clinicaltrials.gov Identifier: NCT03277547).

Non-cigarette tobacco products, aryl-hydrocarbon receptor repressor gene methylation and smoking-related health outcomes.

INTRODUCTION: Cigarette smoking leads to altered DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) gene. However, it remains unknown whether pipe or cigar smoking is associated with AHRR methylation. We evaluated associations of non-cigarette tobacco use with AHRR methylation and determined if AHRR methylation was associated with smoking-related health outcomes. METHODS: Data were pooled across four population-based cohorts that enrolled participants from 1985 to 2002. Tobacco exposures were evaluated using smoking questionnaires. AHRR cg05575921 methylation was measured in peripheral blood leucocyte DNA. Spirometry and respiratory symptoms were evaluated at the time of methylation measurements and in subsequent visits. Vital status was monitored using the National Death Index. RESULTS: Among 8252 adults (mean age 56.7±10.3 years, 58.1% women, 40.6% black), 4857 (58.9%) participants used cigarettes and 634 (7.7%) used non-cigarette tobacco products. Exclusive use of non-cigarette tobacco products was independently associated with lower AHRR methylation (-2.44 units, 95% CI -4.42 to -0.45), though to a lesser extent than exclusive use of cigarettes (-6.01 units, 95% CI -6.01 to -4.10). Among participants who exclusively used non-cigarette tobacco products, reduced AHRR methylation was associated with increased respiratory symptom burden (OR 1.60, 95% CI 1.03 to 2.68) and higher all-cause mortality (log-rank p=0.02). CONCLUSION: Pipe and cigar smoking were independently associated with lower AHRR methylation in a multiethnic cohort of US adults. Among users of non-cigarette tobacco products, lower AHRR methylation was associated with poor respiratory health outcomes and increased mortality. AHRR methylation may identify non-cigarette tobacco users with an increased risk of adverse smoking-related health outcomes.

Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study.

AIMS: The aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF). METHODS AND RESULTS: Data were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking. CONCLUSION: Lung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.

Rapid decline in estimated glomerular filtration rate in sickle cell anemia: results of a multicenter pooled analysis.

Not available.

Nine-Year Ethanol Intake Trajectories and Their Association With 15-Year Cognitive Decline Among Black and White Adults.

Faster rates of age-related cognitive decline might result in early onset of cognitive impairment and dementia. The relationship between ethanol intake and cognitive decline, although studied extensively, remains poorly understood. Previous studies used single measurements of ethanol, and few were conducted in diverse populations. We assessed the association of 9-year trajectories of ethanol intake (1987-1998) with 15-year rate of decline in cognitive performance from mid- to late life (1996-2013) among 2,169 Black and 8,707 White participants of the US Atherosclerosis Risk in Communities study using multivariable linear regression models. We hypothesized that stable, low to moderate drinking would be associated with lesser 15-year cognitive decline, and stable, heavy drinking with greater 15-year cognitive decline. Stable, low to moderate drinking (for Blacks, adjusted mean difference (MD) = 0.03 (95% confidence interval (CI): -0.13, 0.19); for Whites, adjusted MD = 0.02 (95% CI: -0.05, 0.08)) and stable, heavy drinking (for Blacks, adjusted MD = 0.08 (95% CI: -0.34, 0.50); for Whites, adjusted MD = -0.03 (95% CI: -0.18, 0.11)) in midlife compared with stable never-drinking were not associated with 15-year decline in general cognitive function from mid- to late life. No association was observed for the stable former and "mostly" drinking trajectories with 15-year cognitive decline. Stable low, low to moderate, and stable heavy drinking in midlife are not associated with lesser and greater cognitive decline, respectively, from mid- to late life among Black and White adults.

A Dyadic Growth Modeling Approach for Examining Associations Between Weight Gain and Lung Function Decline.

The relationship between body weight and lung function is complex. Using a dyadic multilevel linear modeling approach, treating body mass index (BMI; weight (kg)/height (m)2) and lung function as paired, within-person outcomes, we tested the hypothesis that persons with more rapid increase in BMI exhibit more rapid decline in lung function, as measured by forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio (FEV1:FVC). Models included random intercepts and slopes and adjusted for sociodemographic and smoking-related factors. A sample of 9,115 adults with paired measurements of BMI and lung function taken at ≥3 visits were selected from a pooled set of 5 US population-based cohort studies (1983-2018; mean age at baseline = 46 years; median follow-up, 19 years). At age 46 years, average annual rates of change in BMI, FEV1, FVC, and FEV1:FVC ratio were 0.22 kg/m2/year, -25.50 mL/year, -21.99 mL/year, and -0.24%/year, respectively. Persons with steeper BMI increases had faster declines in FEV1 (r = -0.16) and FVC (r = -0.26) and slower declines in FEV1:FVC ratio (r = 0.11) (all P values < 0.0001). Results were similar in subgroup analyses. Residual correlations were negative (P < 0.0001), suggesting additional interdependence between BMI and lung function. Results show that greater rates of weight gain are associated with greater rates of lung function loss.

Association of insulin resistance, from mid-life to late-life, with aortic stiffness in late-life: the Atherosclerosis Risk in Communities Study.

BACKGROUND: Insulin resistance may contribute to aortic stiffening that leads to end-organ damage. We examined the cross-sectional association and prospective association of insulin resistance and aortic stiffness in older adults without diabetes. METHODS: We analyzed 2571 men and women at Visit 5 (in 2011-2013), and 2350 men and women at repeat examinations from baseline at Visit 1 (in 1987-1989) to Visit 5 (in 2011-2013). Linear regression was used to estimate the difference in aortic stiffness per standard unit of HOMA-IR, TG/HDL-C, and TyG at Visit 5. Linear mixed effects were used to assess if high, as opposed to non-high, aortic stiffness (> 75th percentile) was preceded by a faster annual rate of change in log-HOMA-IR, log-TG/HDL-C, and log-TyG from Visit 1 to Visit 5. RESULTS: The mean age of participants was 75 years, 37% (n = 957) were men, and 17% (n = 433) were African American. At Visit 5, higher HOMA-IR, higher TG/HDL-C, and higher TyG were associated with higher aortic stiffness (16 cm/s per SD (95% CI 6, 27), 29 cm/s per SD (95% CI 18, 40), and 32 cm/s per SD (95% CI 22, 42), respectively). From Visit 1 to Visit 5, high aortic stiffness, compared to non-high aortic stiffness, was not preceded by a faster annual rate of change in log-HOMA-IR from baseline to 9 years (0.030 (95% CI 0.024, 0.035) vs. 0.025 (95% CI 0.021, 0.028); p = 0.15) or 9 years onward (0.011 (95% CI 0.007, 0.015) vs. 0.011 (95% CI 0.009, 0.013); p = 0.31); in log-TG/HDL-C from baseline to 9 years (0.019 (95% CI 0.015, 0.024) vs. 0.024 (95% CI 0.022, 0.026); p = 0.06) or 9 years onward (- 0.007 (95% CI - 0.010, - 0.005) vs. - 0.009 (95% CI - 0.010, - 0.007); p = 0.08); or in log-TyG from baseline to 9 years (0.002 (95% CI 0.002, 0.003) vs. 0.003 (95% CI 0.003, 0.003); p = 0.03) or 9 years onward (0 (95% CI 0, 0) vs. 0 (95% CI 0, 0); p = 0.08). CONCLUSIONS: Among older adults without diabetes, insulin resistance was associated with aortic stiffness, but the putative role of insulin resistance in aortic stiffness over the life course requires further study.

Insulin resistance and reduced cardiac autonomic function in older adults: the Atherosclerosis Risk in Communities study.

BACKGROUND: Prior studies have shown insulin resistance is associated with reduced cardiac autonomic function measured at rest, but few studies have determined whether insulin resistance is associated with reduced cardiac autonomic function measured during daily activities. METHODS: We examined older adults without diabetes with 48-h ambulatory electrocardiography (n = 759) in an ancillary study of the Atherosclerosis Risk in Communities Study. Insulin resistance, the exposure, was defined by quartiles for three indexes: 1) the homeostatic model assessment of insulin resistance (HOMA-IR), 2) the triglyceride and glucose index (TyG), and 3) the triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C). Low heart rate variability, the outcome, was defined by <25th percentile for four measures: 1) standard deviation of normal-to-normal R-R intervals (SDNN), a measure of total variability; 2) root mean square of successive differences in normal-to-normal R-R intervals (RMSSD), a measure of vagal activity; 3) low frequency spectral component (LF), a measure of sympathetic and vagal activity; and 4) high frequency spectral component (HF), a measure of vagal activity. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals weighted for sampling/non-response, adjusted for age at ancillary visit, sex, and race/study-site. Insulin resistance quartiles 4, 3, and 2 were compared to quartile 1; high indexes refer to quartile 4 versus quartile 1. RESULTS: The average age was 78 years, 66% (n = 497) were women, and 58% (n = 438) were African American. Estimates of association were not robust at all levels of HOMA-IR, TyG, and TG/HDL-C, but suggest that high indexes were associated consistently with indicators of vagal activity. High HOMA-IR, high TyG, and high TG/HDL-C were consistently associated with low RMSSD (OR: 1.68 (1.00, 2.81), OR: 2.03 (1.21, 3.39), and OR: 1.73 (1.01, 2.91), respectively). High HOMA-IR, high TyG, and high TG/HDL-C were consistently associated with low HF (OR: 1.90 (1.14, 3.18), OR: 1.98 (1.21, 3.25), and OR: 1.76 (1.07, 2.90), respectively). CONCLUSIONS: In older adults without diabetes, insulin resistance was associated with reduced cardiac autonomic function - specifically and consistently for indicators of vagal activity - measured during daily activities. Primary prevention of insulin resistance may reduce the related risk of cardiac autonomic dysfunction.

Albuminuria, Lung Function Decline, and Risk of Incident Chronic Obstructive Pulmonary Disease. The NHLBI Pooled Cohorts Study.

RATIONALE: Chronic lower respiratory diseases (CLRDs), including chronic obstructive pulmonary disease (COPD) and asthma, are the fourth leading cause of death. Prior studies suggest that albuminuria, a biomarker of endothelial injury, is increased in patients with COPD. OBJECTIVES: To test whether albuminuria was associated with lung function decline and incident CLRDs. METHODS: Six U.S. population-based cohorts were harmonized and pooled. Participants with prevalent clinical lung disease were excluded. Albuminuria (urine albumin-to-creatinine ratio) was measured in spot samples. Lung function was assessed by spirometry. Incident CLRD-related hospitalizations and deaths were classified via adjudication and/or administrative criteria. Mixed and proportional hazards models were used to test individual-level associations adjusted for age, height, weight, sex, race/ethnicity, education, birth year, cohort, smoking status, pack-years of smoking, renal function, hypertension, diabetes, and medications. MEASUREMENTS AND MAIN RESULTS: Among 10,961 participants with preserved lung function, mean age at albuminuria measurement was 60 years, 51% were never-smokers, median albuminuria was 5.6 mg/g, and mean FEV1 decline was 31.5 ml/yr. For each SD increase in log-transformed albuminuria, there was 2.81% greater FEV1 decline (95% confidence interval [CI], 0.86-4.76%; P = 0.0047), 11.02% greater FEV1/FVC decline (95% CI, 4.43-17.62%; P = 0.0011), and 15% increased hazard of incident spirometry-defined moderate-to-severe COPD (95% CI, 2-31%, P = 0.0021). Each SD log-transformed albuminuria increased hazards of incident COPD-related hospitalization/mortality by 26% (95% CI, 18-34%, P < 0.0001) among 14,213 participants followed for events. Asthma events were not significantly associated. Associations persisted in participants without current smoking, diabetes, hypertension, or cardiovascular disease. CONCLUSIONS: Albuminuria was associated with greater lung function decline, incident spirometry-defined COPD, and incident COPD-related events in a U.S. population-based sample.

Trends in Hospitalizations and Survival of Acute Decompensated Heart Failure in Four US Communities (2005-2014): ARIC Study Community Surveillance.

BACKGROUND: Community trends of acute decompensated heart failure (ADHF) in diverse populations may differ by race and sex. METHODS: The ARIC study (Atherosclerosis Risk in Communities) sampled heart failure-related hospitalizations (≥55 years of age) in 4 US communities from 2005 to 2014 using International Classification of Diseases, Ninth Revision, Clinical Modification codes. ADHF hospitalizations were validated by standardized physician review and computer algorithm, yielding 40 173 events after accounting for sampling design (unweighted n=8746). RESULTS: Of the ADHF hospitalizations, 50% had reduced ejection fraction, and 39% had preserved EF (HFpEF). HF with reduced ejection fraction was more common in black men and white men, whereas HFpEF was most common in white women. Average age-adjusted rates of ADHF were highest in blacks (38.1 per 1000 black men, 30.5 per 1000 black women), with rates differing by HF type and sex. ADHF rates increased over the 10 years (average annual percentage change: black women +4.3%, black men +3.7%, white women +1.9%, white men +2.6%), mostly reflecting more acute HFpEF. Age-adjusted 28-day and 1-year case fatality proportions were ≈10% and 30%, respectively, similar across race-sex groups and HF types. Only blacks showed decreased 1-year mortality over time (average annual percentage change: black women -5.4%, black men -4.6%), with rates differing by HF type (average annual percentage change: black women HFpEF -7.1%, black men HF with reduced ejection fraction -4.7%). CONCLUSIONS: Between 2005 and 2014, trends in ADHF hospitalizations increased in 4 US communities, primarily driven by acute HFpEF. Survival at 1 year was poor regardless of EF but improved over time for black women and black men.

The prevalence of atrial fibrillation on 48-hour ambulatory electrocardiography in African Americans compared to Whites: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: A lower prevalence of atrial fibrillation (AF), but paradoxically higher burden of cardiovascular disease risk factors, has been observed among African Americans compared to Whites in studies of AF identified by mostly 12-lead electrocardiograms (ECGs) and clinically. METHODS: We performed 48-hour ambulatory electrocardiography (aECG) in a biracial sample of 1,193 participants in the Atherosclerosis Risk in Communities (ARIC) (mean age = 78 years, 62% African Americans, 64% female). Atrial fibrillation was identified from aECG, study visit ECGs, and discharge codes from cohort hospitalizations. We used covariate-adjusted logistic regression to estimate prevalence odds ratios (ORs) for AF in African Americans versus Whites, with adjustment for sampling and nonresponse. RESULTS: African Americans were more likely than Whites to have hypertension and diabetes but less likely to have coronary heart disease. The prevalence of AF detected by aECG or ARIC study ECG (adjusted for age and coronary heart disease) was lower in African Americans than Whites (2.7% vs 5.0%). White men had a higher (although not significant) AF prevalence of 7.8% compared to the other race and gender groups at 2.3%-2.8%. The adjusted OR for AF was 0.49 (0.24-0.99) comparing African Americans to Whites. Findings were similar when AF was defined to include prior AF hospitalizations (OR = 0.42, 0.25-0.72). There were no significant differences by race for asymptomatic or paroxysmal AF. CONCLUSIONS: Atrial fibrillation was less prevalent in African American than white older adults, regardless of detection method. Although overall detection of new AF cases with aECG was low, future studies should consider longer-term monitoring to characterize AF by race.

Heart Failure Stages Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study.

BACKGROUND: Although heart failure (HF) disproportionately affects older adults, little data exist regarding the prevalence of American College of Cardiology/American Heart Association HF stages among older individuals in the community. Additionally, the role of contemporary measures of longitudinal strain and diastolic dysfunction in defining HF stages is unclear. METHODS: HF stages were classified in 6118 participants in the Atherosclerosis Risk in Communities study (67-91 years of age) at the fifth study visit as follows: A (asymptomatic with HF risk factors but no cardiac structural or functional abnormalities), B (asymptomatic with structural abnormalities, defined as left ventricular hypertrophy, dilation or dysfunction, or significant valvular disease), C1 (clinical HF without prior hospitalization), and C2 (clinical HF with earlier hospitalization). RESULTS: Using the traditional definitions of HF stages, only 5% of examined participants were free of HF risk factors or structural heart disease (Stage 0), 52% were categorized as Stage A, 30% Stage B, 7% Stage C1, and 6% Stage C2. Worse HF stage was associated with a greater risk of incident HF hospitalization or death at a median follow-up of 608 days. Left ventricular (LV) ejection fraction was preserved in 77% and 65% in Stages C1 and C2, respectively. Incorporation of longitudinal strain and diastolic dysfunction into the Stage B definition reclassified 14% of the sample from Stage A to B and improved the net reclassification index (P=0.028) and integrated discrimination index (P=0.016). Abnormal LV structure, systolic function (based on LV ejection fraction and longitudinal strain), and diastolic function (based on e', E/e', and left atrial volume index) were each independently and additively associated with risk of incident HF hospitalization or death in Stage A and B participants. CONCLUSIONS: The majority of older adults in the community are at risk for HF (Stages A or B), appreciably more compared with previous reports in younger community-based samples. LV ejection fraction is robustly preserved in at least two-thirds of older adults with prevalent HF (Stage C), highlighting the burden of HF with preserved LV ejection fraction in the elderly. LV diastolic function and longitudinal strain provide incremental prognostic value beyond conventional measures of LV structure and LV ejection fraction in identifying persons at risk for HF hospitalization or death.

Harmonization of Respiratory Data From 9 US Population-Based Cohorts: The NHLBI Pooled Cohorts Study.

Chronic lower respiratory diseases (CLRDs) are the fourth leading cause of death in the United States. To support investigations into CLRD risk determinants and new approaches to primary prevention, we aimed to harmonize and pool respiratory data from US general population-based cohorts. Data were obtained from prospective cohorts that performed prebronchodilator spirometry and were harmonized following 2005 ATS/ERS standards. In cohorts conducting follow-up for noncardiovascular events, CLRD events were defined as hospitalizations/deaths adjudicated as CLRD-related or assigned relevant administrative codes. Coding and variable names were applied uniformly. The pooled sample included 65,251 adults in 9 cohorts followed-up for CLRD-related mortality over 653,380 person-years during 1983-2016. Average baseline age was 52 years; 56% were female; 49% were never-smokers; and racial/ethnic composition was 44% white, 22% black, 28% Hispanic/Latino, and 5% American Indian. Over 96% had complete data on smoking, clinical CLRD diagnoses, and dyspnea. After excluding invalid spirometry examinations (13%), there were 105,696 valid examinations (median, 2 per participant). Of 29,351 participants followed for CLRD hospitalizations, median follow-up was 14 years; only 5% were lost to follow-up at 10 years. The NHLBI Pooled Cohorts Study provides a harmonization standard applied to a large, US population-based sample that may be used to advance epidemiologic research on CLRD.

Feasibility of a healthcare system-based tetralogy of Fallot patient registry.

BACKGROUND: Patient-reported outcomes and epidemiological studies in adults with tetralogy of Fallot are lacking. Recruitment and longitudinal follow-up investigation across institutions is particularly challenging. Objectives of this study were to assess the feasibility of recruiting adult patients with tetralogy of Fallot for a patient-reported outcomes study, describe challenges for recruitment, and create an interactive, online tetralogy of Fallot registry. METHODS: Adult patients living with tetralogy of Fallot, aged 18-58 years, at the University of North Carolina were identified using diagnosis code query. A survey was designed to collect demographics, symptoms, history, and birth mother information. Recruitment was attempted by phone (Part I, n=20) or by email (Part II, n=20). Data analysis included thematic grouping of recruitment challenges and descriptive statistics. Feasibility threshold was 75% for recruitment and for data fields completed per patient. RESULTS: In Part I, 60% (12/20) were successfully contacted and eight (40%) were enrolled. Demographics and birth mother information were obtained for all enrolled patients. In Part II, 70% (14/20) were successfully contacted; 30% (6/20) enrolled and completed all data fields linked to REDCap database; the median time for survey completion was 8 minutes. Half of the patients had cardiac operations/procedures performed at more than one hospital. Automatic electronic data entry from the online survey was uncomplicated. CONCLUSIONS: Although recruitment (54%) fell below our feasibility threshold, enrolled individuals were willing to complete phone or online surveys. Incorrect contact information, privacy concerns, and patient-reported time constraints were challenges for recruitment. Creating an online survey and linked database is technically feasible and efficient for patient-reported outcomes research.

Race and Sex Differences in the Incidence and Prognostic Significance of Silent Myocardial Infarction in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Race and sex differences in silent myocardial infarction (SMI) are not well established. METHODS AND RESULTS: The analysis included 9498 participants from the Atherosclerosis Risk in Communities (ARIC) study who were free of cardiovascular disease at baseline (visit 1, 1987-1989). Incident SMI was defined as ECG evidence of MI without clinically documented MI (CMI) after the baseline until ARIC visit 4 (1996-1998). Coronary heart disease and all-cause deaths were ascertained starting from ARIC visit 4 until 2010. During a median follow-up of 8.9 years, 317 participants (3.3%) developed SMI and 386 (4.1%) developed CMI. The incidence rates of both SMI and CMI were higher in men (5.08 and 7.96 per 1000-person years, respectively) than in women (2.93 and 2.25 per 1000-person years, respectively; P<0.0001 for both). Blacks had a nonsignificantly higher rate of SMI than whites (4.45 versus 3.69 per 1000-person years; P=0.217), but whites had higher rate of CMI than blacks (5.04 versus 3.24 per 1000-person years; P=0.002). SMI and CMI (compared with no MI) were associated with increased risk of coronary heart disease death (hazard ratio, 3.06 [95% confidence interval, 1.88-4.99] and 4.74 [95% confidence interval, 3.26-6.90], respectively) and all-cause mortality (hazard ratio, 1.34 [95% confidence interval, 1.09-1.65] and 1.55 [95% confidence interval, 1.30-1.85], respectively). However, SMI and CMI were associated with increased mortality among both men and women, with potentially greater increased risk among women (interaction P=0.089 and 0.051, respectively). No significant interactions by race were detected. CONCLUSIONS: SMI represents >45% of incident MIs and is associated with poor prognosis. Race and sex differences in the incidence and prognostic significance of SMI exist that may warrant considering SMI in personalized assessments of coronary heart disease risk.

Trajectories of Cardiovascular Risk Factors and Incidence of Atrial Fibrillation Over a 25-Year Follow-Up: The ARIC Study (Atherosclerosis Risk in Communities).

BACKGROUND: Timing and trajectories of cardiovascular risk factor (CVRF) development in relation to atrial fibrillation (AF) have not been described previously. We assessed trajectories of CVRF and incidence of AF over 25 years in the ARIC study (Atherosclerosis Risk in Communities). METHODS: We assessed trajectories of CVRF in 2456 individuals with incident AF and 6414 matched control subjects. Subsequently, we determined the association of CVRF trajectories with the incidence of AF among 10 559 AF-free individuals (mean age, 67 years; 52% men; 20% blacks). Risk factors were measured during 5 examinations between 1987 and 2013. Cardiovascular events, including incident AF, were ascertained continuously. We modeled the prevalence of risk factors and cardiovascular outcomes in the period before and after AF diagnosis and the corresponding index date for control subjects using generalized estimating equations. Trajectories in risk factors were identified with latent mixture modeling. The risk of incident AF by trajectory group was examined with Cox models. RESULTS: The prevalence of stroke, myocardial infarction, and heart failure increased steeply during the time close to AF diagnosis. All CVRFs were elevated in AF cases compared with controls >15 years before diagnosis. We identified distinct trajectories for all the assessed CVRFs. In general, individuals with trajectories denoting long-term exposure to CVRFs had increased AF risk even after adjustment for single measurements of the CVRFs. CONCLUSIONS: AF patients have increased prevalence of CVRF many years before disease diagnosis. This analysis identified diverse trajectories in the prevalence of these risk factors, highlighting their different roles in AF pathogenesis.

Accuracy of Self-Reported Heart Failure. The Atherosclerosis Risk in Communities (ARIC) Study.

OBJECTIVE: The aim of this work was to estimate agreement of self-reported heart failure (HF) with physician-diagnosed HF and compare the prevalence of HF according to method of ascertainment. METHODS AND RESULTS: ARIC cohort members (60-83 years of age) were asked annually whether a physician indicated that they have HF. For those self-reporting HF, physicians were asked to confirm their patients' HF status. Physician-diagnosed HF included surveillance of hospitalized HF and hospitalized and outpatient HF identified in administrative claims databases. We estimated sensitivity, specificity, positive predicted value, kappa, prevalence and bias-adjusted kappa (PABAK), and prevalence. Compared with physician-diagnosed HF, sensitivity of self-report was low (28%-38%) and specificity was high (96%-97%). Agreement was poor (kappa 0.32-0.39) and increased when adjusted for prevalence and bias (PABAK 0.73-0.83). Prevalence of HF measured by self-report (9.0%), ARIC-classified hospitalizations (11.2%), and administrative hospitalization claims (12.7%) were similar. When outpatient HF claims were included, prevalence of HF increased to 18.6%. CONCLUSIONS: For accurate estimates HF burden, self-reports of HF are best confirmed by means of appropriate diagnostic tests or medical records. Our results highlight the need for improved awareness and understanding of HF by patients, because accurate patient awareness of the diagnosis may enhance management of this common condition.

Repeatability of ectopic beats from 48-hr ambulatory electrocardiography: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: The purpose of this study was to characterize the repeatability of ectopic beats, defined by premature atrial contractions (PACs) and premature ventricular contractions (PVCs), on ambulatory electrocardiogram (aECG) monitoring and evaluate the effect of length of aECG monitoring on the repeatability estimates. METHODS: This analysis includes 95 randomly selected participants from the Atherosclerosis Risk in Communities Study (ARIC; 2011-2013). The participants wore a Holter monitor for two, 48-hr periods separated by a mean of 38 days following an identical, standardized protocol. We divided each 48-hr recording into 3-, 6-, 12-, and 24-hr recording periods and calculated intraclass correlation coefficients (ICCs) for PACs and PVCs and also as a percentage of the corresponding total of recorded beats per hour among these periods. RESULTS: All participants had ≥1 PAC during the 48-hr recordings, and only two participants had no PVCs. ICCs were >0.83 for all indices and recording lengths ≥12 hrs. ICCs were intermediate for 6-hr recordings (range 0.80-0.83) and lower for 3-hr recordings (range 0.74-0.80). The ratio of the between- to within-participant variation increased with recording length. CONCLUSION: Repeatability of PACs and PVCs was excellent for recording lengths of 6-24 hr and fair for 3 hr. Repeatability varies over shorter duration recordings within the 48-hr recording period, and thus the present results have implications for detection algorithms for ectopic beats and can facilitate epidemiologic and clinical applications in which knowledge of measurement variability and misclassification are needed.