M Benjamin Shoemaker1, Daniela Husser2, Carolina Roselli3, Meelad Al Jazairi4, Jonathan Chrispin5, Michael Kühne6,7, Benjamin Neumann8, Stacey Knight9,10, Han Sun11, Sanghamitra Mohanty12,13, Christian Shaffer1, Sébastien Thériault14,15, Lauren Lee Rinke1, Joylene E Siland4, Diane M Crawford1, Laura Ueberham2, Omeed Zardkoohi16, Petra Büttner2, Bastiaan Geelhoed4, Steffen Blum6,7, Stefanie Aeschbacher6,7, Jonathan D Smith17, David R Van Wagoner18, Rebecca Freudling8,19, Martina Müller-Nurasyid19,20, Jay Montgomery1, Zachary Yoneda1, Quinn Wells1, Tariq Issa1, Peter Weeke1, Victoria Jacobs9, Isabelle C Van Gelder4, Gerhard Hindricks2, John Barnard11, Hugh Calkins5, Dawood Darbar21, Greg Michaud1, Stefan Kääb8,20, Patrick Ellinor3,22, Andrea Natale12,13,23,24,25, Mina Chung16, Saman Nazarian26, Michael J Cutler27, Moritz F Sinner8,20, David Conen6,7,14, Michiel Rienstra4, Andreas Bollmann2, Dan M Roden28, Steven Lubitz3,22. 1. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.B.S., C.S., L.L.R., D.M.C., J.M., Z.Y., Q.W., T.I., P.W., G.M.). 2. Heart Center Leipzig, Department of Electrophysiology, Leipzig Heart Institute, University of Leipzig, Germany (D.H., L.U., P.B., G.H., A.B.). 3. Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, MA (C.R., P.E., S.L.). 4. Department of Cardiology, University of Groningen, University Medical Center Groningen, the Netherlands (M.A.J., J.E.S., B.G., I.C.V.G., M.R.). 5. Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.C., H.C.). 6. University Hospital Basel, Switzerland (M.K., S.B., S.A., D.C.). 7. Cardiovascular Research Institute Basel, University Hospital Basel, Switzerland (M.K., S.B., S.A., D.C.). 8. Department of Medicine, University Hospital Munich, Ludwig Maximilians University of Munich, Germany (B.N., R.F., S. Kääb, M.F.S.). 9. Intermountain Heart Institute, Intermountain Medical Center, Murray (S. Knight, V.J.). 10. Department of Medicine, University of Utah, Salt Lake City (S. Knight). 11. Department of Quantitative Health Sciences (H.S., J.B.), Lerner Research Institute, Cleveland Clinic, OH. 12. Texas Cardiac Arrhythmia Institute, Austin, TX (S.M., A.N.). 13. Department of Internal Medicine, Dell Medical School, Austin, TX (S.M., A.N.). 14. Population Health Research Institute, McMaster University, Hamilton, ON, Canada (S.T., D.C.). 15. Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec City, Canada (S.T.). 16. Departments of Cardiovascular Medicine and Molecular Cardiology, Heart and Vascular Institute (O.Z., M.C.), Lerner Research Institute, Cleveland Clinic, OH. 17. Department of Cellular and Molecular Medicine (J.D.S.), Lerner Research Institute, Cleveland Clinic, OH. 18. Department of Molecular Cardiology (D.R.V.W.), Lerner Research Institute, Cleveland Clinic, OH. 19. Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg (R.F., M.M.-N.). 20. German Centre for Cardiovascular Research (DZHK), partner site: Munich Heart Alliance, Germany (M.M.-N., S. Kääb, M.F.S.). 21. Division of Cardiology, Department of Medicine, University of Illinois Health, Chicago (D.D.). 22. Massachusetts General Hospital, Cardiac Arrhythmia Service, Boston (P.E., S.L.). 23. Scripps Clinic, Interventional Electrophysiology, San Diego, CA (A.N.). 24. Division of Cardiology, Stanford University, Palo Alto, CA (A.N.). 25. Case Western University, Cleveland, OH (A.N.). 26. Division of Cardiology, University of Pennsylvania Perelman School of Medicine, Philadelphia (S.N.). 27. Intermountain Heart Institute, Intermountain Medical Center, Murray, UT (M.J.C.). 28. Animal, Dairy, and Veterinary Sciences, Utah State University, Logan (D.M.R.).
Abstract
BACKGROUND: Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF. METHODS: Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation. RESULTS: Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger (P<0.001) and had fewer clinical risk factors for AF (P=0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22-1.58]; P<0.001), left atrial size (per cm: HR, 1.32 [95% CI, 1.19-1.46]; P<0.001), and left ventricular ejection fraction (per 10%: HR, 0.88 [95% CI, 0.80-0.97]; P=0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99-1.18]; P=0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98-1.15]; P=0.13). CONCLUSIONS: Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.
BACKGROUND: Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF. METHODS: Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation. RESULTS: Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger (P<0.001) and had fewer clinical risk factors for AF (P=0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22-1.58]; P<0.001), left atrial size (per cm: HR, 1.32 [95% CI, 1.19-1.46]; P<0.001), and left ventricular ejection fraction (per 10%: HR, 0.88 [95% CI, 0.80-0.97]; P=0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99-1.18]; P=0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98-1.15]; P=0.13). CONCLUSIONS: Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.
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