There has been sustained focus on the secondary prevention of coronary heart disease and heart failure; yet, apart from stroke prevention, the evidence base for the secondary prevention of atrial fibrillation (AF) recurrence, AF progression, and AF-related complications is modest. Although there are multiple observational studies, there are few large, robust, randomized trials providing definitive effective approaches for the secondary prevention of AF. Given the increasing incidence and prevalence of AF nationally and internationally, the AF field needs transformative research and a commitment to evidenced-based secondary prevention strategies. We report on a National Heart, Lung, and Blood Institute virtual workshop directed at identifying knowledge gaps and research opportunities in the secondary prevention of AF. Once AF has been detected, lifestyle changes and novel models of care delivery may contribute to the prevention of AF recurrence, AF progression, and AF-related complications. Although benefits seen in small subgroups, cohort studies, and selected randomized trials are impressive, the widespread effectiveness of AF secondary prevention strategies remains unknown, calling for development of scalable interventions suitable for diverse populations and for identification of subpopulations who may particularly benefit from intensive management. We identified critical research questions for 6 topics relevant to the secondary prevention of AF: (1) weight loss; (2) alcohol intake, smoking cessation, and diet; (3) cardiac rehabilitation; (4) approaches to sleep disorders; (5) integrated, team-based care; and (6) nonanticoagulant pharmacotherapy. Our goal is to stimulate innovative research that will accelerate the generation of the evidence to effectively pursue the secondary prevention of AF.

Background: The burden imposed by multimorbidity on outcomes and on the effectiveness of atrial fibrillation therapies in elderly adults with atrial fibrillation is unknown. Methods: Patients with nonvalvular atrial fibrillation ages ≥75 years in the MarketScan Medicare Supplemental database from 2007-2015. Prevalence of 14 chronic conditions at the time of atrial fibrillation diagnosis were obtained and classified as cardiometabolic or noncardiometabolic. Cox regression estimated the associations of the number and type of conditions with stroke, severe bleeding, and heart failure hospitalizations. Tests for interaction were assessed between atrial fibrillation treatments and multimorbidity. Results: Among 275,617 patients with atrial fibrillation (mean age 83 years, 51% women), the mean (SD) number of conditions per participant was 3.0 (2.1). Over a mean follow-up of 23 months, 7814 strokes, 13,622 severe bleeds, and 19,252 heart failure events occurred. After adjustment, an increase in the number of cardiometabolic conditions was associated with greater risk of stroke (hazard ratio [HR] 1.07; 95% confidence interval [CI], 1.05-1.10), severe bleeding (HR 1.09; 95% CI, 1.07-1.11), and heart failure (HR 1.19, 95% CI, 1.18-1.20). In contrast, number of noncardiometabolic conditions had weak or null associations with risk of cardiovascular endpoints. Overall, the effectiveness of atrial fibrillation treatment on stroke and heart failure were similar across multimorbidity status, but bleeding risk associated with atrial fibrillation treatments was higher in patients with overall and subgroup multimorbidity. Conclusion: Cardiometabolic multimorbidity was associated with worse outcomes and modified bleeding risk in atrial fibrillation patients. These findings underscore the impact of cardiometabolic conditions on atrial fibrillation outcomes and highlights the need to incorporate multimorbidity management in atrial fibrillation treatment guidelines.

Background: Atrial fibrillation (AF) is linked to increased risk of dementia and cognitive decline, but whether AF and its ascertainment methods affect cognition in patients with hypertension has received less attention. Methods: We studied 8469 participants with elevated systolic blood pressure who were free of stroke and diabetes at baseline enrolled in the Systolic Blood Pressure Intervention Trial. AF was ascertained using three approaches: self-report of AF, AF from a safety event, and study electrocardiogram-determined (ECG) AF. Mild cognitive impairment (MCI) and probable dementia (PD) were ascertained from in-person assessments or telephone interviews from the participant or an informant. We used Cox proportional hazard models to estimate hazard ratios for the association of AF (all three sources) with outcomes of MCI, PD, and a composite MCI/PD outcome. Results: During a mean follow-up of 4.6 years, 974 (12%) participants had AF (prevalent or incident), 634 were diagnosed with MCI, and 316 with PD. When comparing those with AF (from any source) to those without, no differences were detected in the risk of MCI or PD. Comparison between AF sources found ECG-AF to be associated with an elevated risk of MCI/PD (hazard ratio (HR) 1.59, 95% confidence interval (95%CI) 1.06, 2.38). Neither AF ascertained through safety events nor self-reported AF were associated with MCI or PD. Conclusion: The association of AF with incidence of MCI/PD differed by method of AF ascertainment. Case definition of AF and quantification of AF burden are important factors in studies evaluating the link between AF and cognitive dysfunction.

BACKGROUND: Timely hospitalization of patients who are diagnosed with an acute coronary syndrome (ACS) at the emergency department (ED) is a crucial step to lower the risk of ACS mortality. We examined whether there are racial and ethnic differences in the risk of being discharged home among patients who received a diagnostic code of ACS at the ED and whether having health insurance plays a role. METHODS AND RESULTS: We examined 51022910 discharge records of ED visits in Florida, New York, and Utah in the years 2008, 2011, 2014, and 2016/2017 using state-specific data from the Healthcare Cost and Utilization Project. We identified ED admissions for acute myocardial infarction or unstable angina using the International Classification of Diseases, Ninth Revision (ICD-9)/International Statistical Classification of Diseases, Tenth Revision (ICD-10) diagnostic codes. We used generalized estimating equation models to compare the risk of being discharged home across racial and ethnic groups. We used Poisson marginal structural models to estimate the mediating role of health insurance status. The proportion discharged home with a diagnostic code of ACS was 12% among Black patients, 6% among White patients, 9% among Hispanic patients, and 9% among Asian/Pacific Islander patients. The incidence risk ratio for being discharged home was 1.26 (95% CI, 1.18–1.34) in Black patients, 1.23 (95% CI, 1.15–1.32) in Hispanic patients, and 1.11 (95% CI, 0.93–1.31) in Asian/Pacific Islander patients compared with White patients. Race and ethnicity were marginally associated with discharge home via pathways not mediated by health insurance. CONCLUSIONS: Racial and ethnic disparities exist in the hospitalization of patients who received a diagnostic code of ACS in the ED. Possible causes need to be investigated.

Background: The metabolic syndrome (MetS) is associated with increased cardiovascular morbidity and mortality. Characterization of cardiac structural and functional abnormalities due to the MetS can help recognize individuals who would benefit the most from preventive interventions. Transthoracic echocardiography (TTE) provides an opportunity to identify those abnormalities in a reproducible and cost-efficient manner. In research settings, implementation of protocols for the acquisition and analysis of TTE images are key to ensure validity and reproducibility, thus facilitating answering relevant questions about the association of the MetS with cardiac alterations. Methods and Results: The Palma Echo Platform (PEP) is a coordinated network that is built up to evaluate the underlying structural and functional cardiac substrate of participants with MetS. Repeated TTE will be used to evaluate 5-year changes in the cardiac structure and function in a group of 565 individuals participating in a randomized trial of a lifestyle intervention for the primary prevention of cardiovascular disease. The echocardiographic studies will be performed at three study sites, and will be centrally evaluated at the PEP core laboratory. Planned analyses will involve evaluating the effect of the lifestyle intervention on cardiac structure and function, and the association of the MetS and its components with changes in cardiac structure and function. Particular emphasis will be placed on evaluating parameters of left atrial structure and function, which have received more limited attention in past investigations. This PEP will be available for future studies addressing comparable questions. Conclusion: In this article we describe the protocol of a central echocardiography laboratory for the study of functional and structural alterations of the MetS.

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 (QTFram) 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 QTFram 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 QTFram 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.

Background: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. Methods: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). Results: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals. Conclusions: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

Introduction: Low serum magnesium (Mg) is associated with an increased incidence of atrial and ventricular arrhythmias. A richer phenotyping of arrhythmia indices, such as burden or frequency, may provide etiologic insights. Objectives: To evaluate cross-sectional associations of serum Mg with burden of atrial arrhythmias [atrial fibrillation (AF), premature atrial contractions (PAC), supraventricular tachycardia (SVT)], and ventricular arrhythmias [premature ventricular contractions (PVC), non-sustained ventricular tachycardia (NSVT)] over 2-weeks of ECG monitoring. Methods: We included 2513 ARIC Study visit 6 (2016–2017) participants who wore the Zio XT Patch—a leadless, ambulatory ECG-monitor—for up to 2-weeks. Serum Mg was modeled categorically and continuously. AF burden was categorized as intermittent or continuous based on the percent of analyzable time spent in AF. Other arrhythmia burdens were defined by the average number of abnormal beats per day. Linear regression was used for continuous outcomes; logistic and multinomial regression were used for categorical outcomes. Results: Participants were mean ± SD age 79 ± 5 years, 58% were women and 25% black. Mean serum Mg was 0.82 ± 0.08 mmol/L and 19% had hypomagnesemia (<0.75 mmol/L). Serum Mg was inversely associated with PVC burden and continuous AF. The AF association was no longer statistically significant with further adjustment for traditional lifestyle risk factors, only the association with PVC burden remained significant. There were no associations between serum Mg and other arrhythmias examined. Conclusions: In this community-based cohort of older adults, we found little evidence of independent cross-sectional associations between serum Mg and arrhythmia burden.

Aims: The association of hyperglycemia and duration of diabetes with intracranial atherosclerotic stenosis (ICAS) in the general population is not well documented. We examined whether elevated glucose and longer diabetes duration is independently associated with ICAS in a community-based sample. Methods: We cross-sectionally analyzed 1644 participants (age 67–90 years) of the Atherosclerosis Risk in Communities Study who underwent cerebrovascular magnetic resonance angiography in 2011–13. We applied multivariable ordinal logistic regression to evaluate the association of ICAS category (“no stenosis”, “stenosis <50%”, or “stenosis ≥50%”) with glucose or diabetes duration (<10, 10 to 20, and ≥20 years). We also obtained the corresponding odds ratios applying inverse-probability weighting to account for potential selection bias due to attrition. Results: Compared to non-diabetic participants in the lowest glucose quartile, the weighted odds ratios (95% confidence interval) of higher ICAS category were 1.88 (1.18, 3.00) and 2.01 (1.08, 3.72) for non-diabetic and diabetic participants in the corresponding highest glucose quartile, respectively. We observed significant positive trends of ICAS across diabetes duration categories in unweighted, but not in weighted, analyses. Conclusions: Hyperglycemia and longer duration of diabetes were independently associated with ICAS, suggesting the importance of maintaining glycemic control to prevent stroke.

Purpose: Excessive daytime sleepiness is a common sleep complaint among older adults. Assessment of excessive daytime sleepiness is used to screen for obstructive sleep apnea, which may be linked to atrial fibrillation (AF) and other sustained arrhythmias. Using data from the Atherosclerosis Risk in Communities (ARIC) Study cohort, we examined the association of excessive daytime sleepiness with measures of arrhythmia burden derived from a continuous ECG recording device in a community-based sample of older adults. Methods: Participating older adults (N = 2306, mean age: 78.9 ± 4.5 years, 57.8% female) wore a Zio® XT Patch for 14 days. Excessive daytime sleepiness was assessed with the Epworth Sleepiness Scale. Measures of AF and supraventricular arrhythmia burden were derived from the Zio® XT Patch. Multiple adjusted logistic, multinomial, and linear regression models were used to assess associations of excessive daytime sleepiness with AF, AF burden, and supraventricular arrhythmia burden. Results: Approximately 18% of the sample had excessive daytime sleepiness, and 8.5% had AF. After adjustment, excessive daytime sleepiness was not significantly associated with AF (odds ratio (OR), 1.20; Confidence Interval (CI), 0.81–1.75), continuous AF burden (OR, 1.36; CI, 0.85–2.16), or measures of supraventricular arrhythmia burden (SVE burden: β 0.01; 95% CI, −0.09−0.11; SVT burden: β 0.02; 95% CI, −0.04−0.08). Conclusion: In this community-based sample of older adults, excessive daytime sleepiness was not associated with measures of arrhythmia burden. Future studies with objective measures of sleep are needed to further examine the role of sleep in the development and progression of arrhythmia burden.