IMPORTANCEAlthough rare variants in cardiac ion channels, transcription factors, and myocardial structural proteins are associated with early-onset atrial fibrillation (AF) in White individuals of European descent, it remains unclear whether genetic variation also contributes to the cause of AF in those of minority ethnicity.OBJECTIVES To assess the prevalence of rare and novel pathogenic variants in candidate genes in ethnic minority probands with early-onset AF and determine genotype-phenotype associations. DESIGN, SETTING, AND PARTICIPANTSIn this cohort, family-based study, probands of African and Hispanic descent with early-onset AF (defined as AF occurring in individuals aged Յ66 years) prospectively enrolled in a clinical and genetic biorepository underwent sequencing of 60 candidate genes.

IMPORTANCEThe association between obesity, an established risk factor for atrial fibrillation (AF), and response to antiarrhythmic drugs (AADs) remains unclear.OBJECTIVE To test the hypothesis that obesity differentially mediates response to AADs in patients with symptomatic AF and in mice with diet-induced obesity (DIO) and pacing induced AF. DESIGN, SETTING, AND PARTICIPANTSAn observational cohort study was conducted including 311 patients enrolled in a clinical-genetic registry. Mice fed a high-fat diet for 10 weeks were also evaluated. The study was conducted from January 1, 2018, to June 2, 2019.MAIN OUTCOMES AND MEASURES Symptomatic response was defined as continuation of the same AAD for at least 3 months. Nonresponse was defined as discontinuation of the AAD within 3 months of initiation because of poor symptomatic control of AF necessitating alternative rhythm control therapy. Outcome measures in DIO mice were pacing-induced AF and suppression of AF after 2 weeks of treatment with flecainide acetate or sotalol hydrochloride.RESULTS A total of 311 patients (mean [SD] age, 65 [12] years; 120 women [38.6%]) met the entry criteria and were treated with a class I or III AAD for symptomatic AF. Nonresponse to class I AADs in patients with obesity was less than in those without obesity (30% [obese] vs 6% [nonobese]; difference, 0.24; 95% CI, 0.11-0.37; P = .001). Both groups had similar symptomatic response to a potassium channel blocker AAD. On multivariate analysis, obesity, AAD class (class I vs III AAD [obese] odds ratio [OR], 4.54; 95% Wald CI, 1.84-11.20; P = .001), female vs male sex (OR, 2.31; 95% Wald CI, 1.07-4.99; P = .03), and hyperthyroidism (OR, 4.95; 95% Wald CI, 1.23-20.00; P = .02) were significant indicators of the probability of failure to respond to AADs. Pacing induced AF in 100% of DIO mice vs 30% (P < .001) in controls. Furthermore, DIO mice showed a greater reduction in AF burden when treated with sotalol compared with flecainide (85% vs 25%; P < .01). CONCLUSIONS AND RELEVANCEResults suggest that obesity differentially mediates response to AADs in patients and in mice with AF, possibly reducing the therapeutic effectiveness of sodium channel blockers. These findings may have implications for the management of AF in patients with obesity.

BACKGROUND: Smoking is associated with increased risk of developing atrial fibrillation (AF) and stroke. Yet, it remains unclear if it also predicts response to rhythm control therapy across race-ethnicity. We sought to determine if response to rhythm control therapy for AF is modulated by smoking across race-ethnicity. Methods: 529 patients treated with a rhythm control strategy were prospectively enrolled in the Chicagoland area. Patients were classified into White, Black or Hispanic\Latino based on race\ethnicity and ancestry markers. Rhythm control included antiarrhythmic drugs (AADs) and/or catheter ablation. Successful response was defined as continuation of the same AAD for at least 6 months and/or successful catheter ablation without recurrence of AF for 12 months. Results: 235 (44%) were Black, 192 (36%) were White, and 102 (19%) were Hispanic. 299 (57%) were treated with AADs and 230 (44%) with catheter ablation. One-hundred sixty-eight (35%) patients had a history of smoking. Baseline co-morbidities were similar across responders and non-responders. In multivariate regression analysis (Table 1), patients with a smoking history were more likely to have a recurrence of AF when treated with a rhythm control strategy (odds ratio [OR] 1.51, 95% confidence interval [CI] 1.03-2.21, P =0.03). Stratified multivariate regression analysis showed that smokers were more likely to have a recurrence of AF after ablation therapy as compared to AADs (OR 1.49, 95% CI 1.03-2.17, P = 0.03). Multivariate logistic regression showed that patients that smoked for >20 years were twice as likely to have a recurrence of AF with a rhythm control therapy than those who smoked for <20 years (OR 1.88, 95% CI 1.20- 2.93, P = 0.01). Conclusions: A smoking history modulates response to rhythm control therapy for AF across race-ethnicity. Our study highlights the importance of smoking cessation before initiation of rhythm control agents in patients with AF.

Introduction: Atrial fibrillation (AF) guidelines are heavily predicated on assessing the severity of symptoms experienced by individual patients when selecting either rate or rhythm control strategy. While the severity of symptoms can be highly variable, it remains unclear if race-ethnicity influences AF symptoms and quality-of-life (QoL). We sought to determine whether race-ethnicity modulates severity of AF symptoms, QoL and response to therapy. Methods: A prospective cohort study of 415 patients diagnosed with new-onset AF enrolled over a 30-month period in a clinical-genetic registry. Baseline assessment of patients prior to treatment initiation included a detailed patient history and the validated 20-item Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) questionnaire. We divided the cohort into groups based on race-ethnicity (African American[AA], European American[EA], Hispanic/Latino[H/L]) and treatment strategy (rate or rhythm control). Results: Of 306 consecutive patients with AF, 113 (36.9%) were AA, 108 (35.3%) EA and 85 (27.8%) H/L. The mean age was 61.9±13.0 years, and 105 (34.3%) were female with 154 (50.3%) patients treated with rate control versus 152 (49.7%) with rhythm control therapy. Both AA (52.1%) and H/L (65.9%) patients were more likely to be initiated on rate control therapy as compared with EAs (36.1%; P=0.0002) despite lower baseline AFEQT scores (AA: 72.9.9±23.2; H/L: 75.1±20.7; and EA: 80.2±17.9; P=0.24) and greater impairment of QoL. The overall AFEQT scores and QoL improved significantly in AAs (Δscore: 10.4±28.2; P<0.0001) and EAs (Δscore: 11.9±20.1; P<0.0001) and was mostly associated with improvement in activities of daily living. Multivariate predictors of improvement in QoL in patients with AF included not only rhythm control therapy but also a history of both coronary artery disease and obesity. Conclusion: The severity and perception of AF symptoms is highly variable in individual patients. Our study showed that ethnic minorities with AF are more likely to receive rate control therapy when compared to patients of European descent despite poorer QoL. Our findings may have important clinical implications for the assessment of symptoms and management of AF in AAs and H/Ls.

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