I have financial relationships to disclose Consultant for: st Jude, Boston, Sorin, Biotronik, Medtronic, Sanofi, Merck, Menarin Research support

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1 I have financial relationships to disclose Consultant for: st Jude, Boston, Sorin, Biotronik, Medtronic, Sanofi, Merck, Menarin Research support from: st Jude, Boston, Sorin, Biotronik, Medtronic, Sanofi, Merck, Menarin

2 Atrial Fibrillation and Sports. Hospital Clinic. Universitat de Barcelona

3 1777 competitive athletes without heart disease Mean age 24± 6 years Mean age at most recent assessment 33±6 mean time of sports involvement 6 years 61 % continued with the training during FU Pellicia et al. JACC 2005

4 In the thirties < 0.5% Pellicia et al. JACC 2005

5 Pellicia et al. JACC 2005

6 Lone atrial fibrillation in Marathon runners Hospital Clinic. Thorax Institute. University of Barcelona, Hospital del Mar. Autonomous University of Barcelona Institut Municipal Investigacions Mèdiques IMIM. Barcelona. Molina et al. Europace 2008

7 Methods 270 healthy men that ran the marathon in Barcelona in Control group: 305 healthy sedentary men < 300 Kcal/day of physical activity, recruited at the REGICOR study

8 In the forties 9/183 (5%) Molina et al. Europace 08

9 Lone atrial fibrillation in Marathon runners Adjusted for age and systolic blood pressure

10 In the sixties 15-18% Grimsmo J. Eur J Cardiovasc Prev Rehabil 17:

11 Athletes or vigorous exercise? Is there a threshold?

12 16921 participants at the Physicians Health Study Healthy individuals 12 years follow up

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15 70 patients with lone AF younger than 65y. Regular sport practice 65% among patients with AF and 15% in the general male population of individuals younger than 65 in Catalonia (REGICOR study)

16 Hospital Clínic. University of Barcelona. Institut Municipal d Investigacions Mèdiques de Barcelona. Int J Cardiol 2005

17 Logistic Regression Analysis Vagal Atrial Fibrillation Cases/Controls OR (95% CI) P Sport Practice 17/ ( ) 0.09 Current Sport Practice 6/ ( ) Lifetime hours hours 3/ (0.25-7) NS hours 7/ ( ) Current practice > 1500 hours (3 hours/week, 10 years 6/ ( ) 0.016

18 Is sports related lone AF a familial disease?

19 Familial Atrial Fibrillation and sports: hypothesis Dose related risk of AF in sports goes against a familial disease Genetic forms have a high penetrance and does not need the trigger effect of sport Familial forms of AF are very uncommon and a family history is rarely seen. Athletes show deep structural changes, that may explain AF withouth the need of other etiologic factors.

20 Genetic Predisposition or Genetic Disease Atrial fibrillation as a monogenic disease Atrial firillation associated with other monogenic diseases Genetic predispostion to acquired atrial fibrillation

21 ATRIAL FIBRILLATION AS A MONOGENIC DISEASE Historical Perspective Wolff L. N Engl J Med Gould WL Arch Int Med 1957 Phair WB Canad Med Ass 1963 Derrida JP et al Nouv Pres Med 1976 Wen-tai Y Chin Med J 1983 Ardiaca A et al Rev Esp Card 1987

22 I:1 I:2 FAMILIAL ATRIAL FIBRILLATION REGION SHARED ON 10q2 AFFECTED NON AFFECTED DEAD Brugada R et al NEJM, 1997

23 FAMILIAL ATRIAL FIBRILLATION CLINICAL FEATURES Mean Age of Diagnosis 18 years Range in Age of Diagnosis in utero-35 years Echocardiogram Normal Patients with Chronic AF 51/52 Asymptomatic 36/52 Heart rate bpm Brugada R et al NEJM, 1997

24 Chen YH, et al. Science 2003

25 Gussak et al. Cardiology 2000 Hong et al. JCE, 2005

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27 Clinical Implications Each family appears to have its own gene No change in clinical approach Penetrance appears high

28 From: Association Between Familial Atrial Fibrillation and Risk of New-Onset Atrial Fibrillation JAMA. 2010;304(20): doi: /jama Date of download: 8/18/2012 Copyright 2012 American Medical Association. All rights reserved.

29 From: Association Between Familial Atrial Fibrillation and Risk of New-Onset Atrial Fibrillation JAMA. 2010;304(20): doi: /jama Date of download: 8/18/2012 Copyright 2012 American Medical Association. All rights reserved.

30 Physical activity, height and left atrial size are independent risk factors for lone atrial fibrillation in middle aged healthy individuals - Thorax Institute. Hospital Clinic, University of Barcelona - IMIM. Institut Municipal de Investigació Mèdica. Barcelona Mont L, Tamborero D, Elosua R, Molina I, Collvinent B, Sitges M, Vidal B, Scalise A, Tejeira A, Berruezo and Brugada J on behalf of the GIRAFA (Grup Integrat de Recerca en FA) investigators Mont et al. Europace 2008

31 Methods Design: Prospective, case-control study Population: 107 consecutive patients younger 18 to 65 Recent onset Lone AF, seen at the emergency room (> 48 hours). Controls: 1:1 age and sex matched controls

32 Demographic characteristics Patients N=107 Controls N= 107 Age (years) 48.0± ±10.2 Male sex (%) 74 (69%) 74 (69%) Smoking (%) 53 (50%) 53 (50%) Paroxysmal/Persistent AF (%) 61 (57%) / 46 (43%) -- Vagal AF (%) 75 (70%) -- First AF episode/ recurrent AF 46 (43%) / 61(57%) -- Number of AF episodes 4.5± AF duration (hours) 15.4±

33 Adjusted Odds ratios and 95% IC of lone AF form heavy physical activity, height and LA AP diameter Odds ratio (95% confidence interval) Cumulated intense physical activity P value 0 hours hours 1.77 ( ) > hours 7.31 ( ) Height ( ) ( ) Left atrial anteroposterior ( ) diameter (mm)

34 Sustained Endurance Training Creates a Substrate for Atrial Fibrillation in Rats Hospital Clínic. University of Barcelona Montreal Heart Institute Begoña Benito Gemma Gay Eduard Guasch Valeria Sirenko David Tamborero Anna Serrano Lluis Mont Benito et al. Circulation 2011 Sophie Cardin Yanfen Shi Patrick Lawler Ange Maguy Jean-Claude Tardif Nathalie L Heureux Chantal St-Cyr Audrey Bonard Stanley Nattel

35 Training Protocol 4 weeks 8 weeks 16 weeks Rest for 3 days Sacrifice

36 Echocardiographic data after 16 weeks of training sedentary exercise IVS thickness (cm) LV diameter (cm) 3.0 ± ± 0.1 *** 14.3 ± ± 0.3 *** LV mass (g) 18.1 ± ± 0.7 *** LA diam (SYST) LA diam (DIAST) 9.2 ± ± 0.3 *** 6.4 ± ± 0.2 * Adjusted for BSA

37 ECG parameters 16 weeks CTL (n=18) Ex (n=17) HR (bpm) 346 ± ± 11 ** PR interval (ms) 56.4 ± ± 1.8 QRS duration (ms) 23.1 ± ± 0.4 QTc interval (ms) (Bazett s) 224 ± ± 4

38 EPS parameters CTL (n=15) Ex (n=14) EP parameters Sinus cycle length (ms) ± ± 5.8 ** SN recovery time (ms) ± ± 7.1 Anterograde Wenck (ms) Atrial refractory period (ms) ± ± 4.5 ** 42.9 ± ± 1.0

39 Inducible arrhythmias Mean duration: 8.7 ± 2.0 min *

40 Protein expression of fibrotic markers in atria: Mean ± SEM;* p<0.05 (n CTL=6, n Ex=8)

41 Atrial fibrosis RA LA Ex CTL Mean ± SEM. * p<0.05; ** p<0.01; *** p<0.001

42 Summary of mechanisms Chronic high-level exercise Hemodynamic effects: Increased vagal tone Atrial overload Atrial enlargement Atrial fibrosis ATRIAL FIBRILLATION

43 Summary AF related to sports seems to be the consequence of atrial remodelling and increased vagal tone. Monogenic AF seems to be a high penetrance and not particularly linked to sport practice A genetic predisposition may be present in certain individuals.