1. Overview management of Atrial Fibrillation-the cardiologist aspect 腦及行為科學整合課程 (Min-Forum -Summary) 跨領域教師 : 心臟血管科 林維祥

2. Outlines Historical review and mechanism, risk factors of atrial fibrillation Historical review and mechanism, risk factors of atrial fibrillation Impact of AF progression and benefits of early rhythm control Impact of AF progression and benefits of early rhythm control Overview of current management of atrial fibrillation Overview of current management of atrial fibrillation Take home messages Take home messages

3. Historical review of Atrial fibrillation A. « But I … have noticed, that after the heart proper, and even the right auricle were ceasing to beat and appeared on the point of death, an obscure movement, undulation / palpitation had clearly continued in the right auricular blood itself for as long as the blood was perceptly imbued with warthm and spitit » William Harvey – Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (1628) A. « But I … have noticed, that after the heart proper, and even the right auricle were ceasing to beat and appeared on the point of death, an obscure movement, undulation / palpitation had clearly continued in the right auricular blood itself for as long as the blood was perceptly imbued with warthm and spitit » William Harvey – Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (1628)  William Harvey (1578-1657), English physician and physiologist, was probably the first to describe « fibrillation of the auricles » in animals AF was described for the first time in 1628

4. AF is characterized by the presence of multiple abnormal electrical circuits

5. Role of Pulmonary Vein Electrical activity in the initiation of Atrial fibrillation by Professor Cheung DW Electrical activity of the pulmonary vein and its interaction with the right atrium in the guinea-pig. J Phsyiol 1981;314:445 Electrical activity of the pulmonary vein and its interaction with the right atrium in the guinea-pig. J Phsyiol 1981;314:445 Pulmonary vein as an ectopic focus in digitalis-induced arrhythmia. Nature 1981;294(5841):582 Pulmonary vein as an ectopic focus in digitalis-induced arrhythmia. Nature 1981;294(5841):582

6. Mechanisms of Atrial Fibrillation Ganglionic plexiMultiple reentrant wavelets PV and non-PV triggers Composite of the anatomic and arrhythmic mechanism

7. Multiple interacting risk factors drive AF development and progression Adapted from: Camm AJ et al. Am Heart J. 2012;164(3):292-302.e1. Kirchhof P et al. Europace. 2012;14(1):8-27. Structural remodelling Autonomic remodelling Electrical remodelling AF Reentry Triggered activity Heart diseases Pericarditis Hypertensive Valvular Ischemic Heart failure Aging Diabetic Extrinsic factors Thyroid dysfunction Endurance exercise Tobacco - Illicit drugs Sleep apnea Alcohol Obesity Genetics Mutations Polymorphisms

8. Outlines Historical review and mechanism, risk factors of atrial fibrillation Historical review and mechanism, risk factors of atrial fibrillation Impact of AF progression and benefits of early rhythm control Impact of AF progression and benefits of early rhythm control Overview of current management of atrial fibrillation Overview of current management of atrial fibrillation Take home messages Take home messages

9. ESC guidelines classify AF based on the presentation and duration of the arrhythmia Permanent (accepted) First diagnosed episode of atrial fibrillation Paroxysmal (usually ≤48 h) Persistent (>7 days or requires CV) Long-standing Persistent (>1 year) CV = cardioversion Adapted from: Camm AJ et al. Europace. 2010;12:1360-420.

10. ACCF/AHA/HRS guidelines classify AF based on duration and self-termination Adapted from: Fuster V et al. J Am Coll Cardiol. 2011 15;57(11):e101-98. "Recurrent AF" Patient has 2 or more episodes First detected Paroxysmal (self-terminating) Persistent (Not self-terminating)  Sustained beyond 7 days  Also includes cases of long- standing AF (e.g., greater than 1 year) Permanent  Cardioversion has failed or has not been attempted

11. AF progression Adapted from: Camm AJ et al. Europace. 2010;12:1360-420.  Self-terminating >> non-self-terminating AF Change from first detected AF or paroxysmal AF to persistent / permanent AF  Atrial dilatation, fibrosis  Tachycardiomyopathy, stroke, death  Atrial dilatation, fibrosis  Tachycardiomyopathy, stroke, death Progressive atrial and ventricular remodelling and cardiovascular events

12. Permanent Cannot be converted to sinus rhythm Persistent No spontaneous termination Paroxysmal Spontaneous termination AF usually progresses towards more sustained forms as time goes by Adapted from: Camm AJ et al. Europace. 2010;12:1360-420. Sinus rhythmAF episode Diagnosis  Only a small proportion of patients will remain in paroxysmal AF over several decades (2-3% of AF patients)

13. 13 Sanofi. Strictly confidential. Do not distribute. This information is provided for medical and scientific purpose only. GLB.DRO.12.10.02 – 11/12 Prevalence of comorbidities increases with degree of AF progression Adapted from: Chiang CE et al. Circ Arrhythm Electrophysiol. 2012 1;5(4):632-9. *Defined as patients aged <60 y with no coronary artery disease/heart failure/valvular heart disease/chronic pulmonary disease/venous thromboembolism/arterial hypertension. ParoxysmalPersistentPermanentp value At least 1 comorbidity, %69.375.784.8<0.0001 Heart failure, %32.944.355.6<0.0001 Heart failure in class, %<0.0001 No HF or NYHA I72.762.050.3 NYHA II20.024.329.5 NYHA III-IV7.313.720.2 Left ventricular ejection fraction within past 12 mo in %, n mean (SD) 1,975 58.5 (10.7) 1,892 54.3 (12.1) 3,481 53.3 (12.2) <0.0001 Left ventricular hypertrophy (ECG), %12.312.714.60.0117 Coronary artery disease, %30.032.934.30.0009 Cerebrovascular disease, %11.710.817.6<0.0001 Valvular heart disease, %16.721.235.8<0.0001 Chronic pulmonary disease, %9.48.912.9<0.0001 Liver diseases, %4.53.94.90.16 Chronic advanced renal failure, %3.53.94.30.22 Lone AF*, %9.35.32.0<0.0001 RealiseAF

14. 14 Sanofi. Strictly confidential. Do not distribute. This information is provided for medical and scientific purpose only. GLB.DRO.12.10.02 – 11/12 OR = odd’s ratio Adapted from: De Vos CB et al. Am Heart J. 2012;163:887.93. RecordAF: AF progression is associated with CV events  The propensity score-adjusted OR of AF progression in patients with rate rather than rhythm control was 3.3 (95% CI 2.4-4.6, p<0.0001) Progression at one year Progression (n=318) No progression (n=1,819) p value Age, years67 ± 1165 ± 120.0011 Gender, % female48470.9749 Family history of AF, %8110.0527 Cardiovascular disease, % Coronary artery disease24180.0213 Stroke or TIA1170.0283 Arterial hypertension78690.0015 Heart failure3218<0.0001 Valvular heart disease19160.1932 Diabetes17150.2926 Lone AF1122<0.0001 RecordAF

15. 15 Sanofi. Strictly confidential. Do not distribute. This information is provided for medical and scientific purpose only. GLB.DRO.12.10.02 – 11/12 Euro Heart Survey: AF progression is associated with CV events Adapted from: De Vos CB et al. J Am Coll Cardiol. 2010;55:725-31. CV outcomes at 1-year follow-up All patients n (%) AF progression n (%) No AF progression n (%) p value Number of patients1,219 (100)178 (15)1,041 (85) Symptoms366 (32)86 (52)280 (29)<0.001 Death22 (2)6 (3)16 (2)0.118 Major adverse cardiovascular events Coronary artery disease72 (6)15 (8)57 (6)0.168 Myocardial infarction17 (1)5 (3)12 (1)0.091 Unstable angina44 (4)10 (6)34 (3)0.130 Ischaemic stroke or TIA31 (3)11 (6)20 (2)0.003 Ischaemic stroke20 (2)8 (5)12 (1)0.005 TIA11 (1)3 (2)8 (1)0.212 Combined mortality/stroke40 (3)13 (7)27 (3)0.005 Euro Heart Survey

16. Adapted from: 1. De Vos CB et al. Am Heart J. 2012;163:887-93. 2. De Vos CB et al. J Am Coll Cardiol. 2010;55:725-31. AF progression is associated with CV hospitalisations CV hospitalisations p<0.0001 RecordAF 1 Euro Heart Survey 2 p<0.001

17. Adapted from: Camm AJ et al. Europace. 2010;12:1360-420. Several treatment strategies are available for AF  Long-lasting AF usually renders maintenance of sinus rhythm more difficult  It is likely that a window of opportunity to maintain sinus rhythm exists early in the course of management of a patient with AF 'Upstream' therapy of concomitant conditions Anticoagulation Rate control Antiarrhythmic drugs Ablation AF cardioversion permanentLong-standing persistent persistentparoxysmalsilent First documented

18. Overview of current management of AF Pharmacologic therapy Rate or Rhythm control Anticoagulant therapy Upstream therapy Nonpharmacologic therapy Catheter based ablation Electrical cardioversion

19. Actual treatment options in AF Prevention of thrombo-embolism Rhythm control Rate control Prevent / Reverse remodeling

20. Strategy of AF Treatment

21. The Vaughan-Williams classification of anti-arrhythmic drugs  Commonly grouped into four broad categories by Vaughan Williams classification, based on their dominant electrophysiological effect: ClassChannels blockedAgentsMain Usage INa + Flecainide, Propafenone Rhythm Control II ß-receptors BetablockersRate Control III K+K+ Sotalol Amiodarone Dofetilide Rhythm Control IV Ca 2+ Diltiazem Verapamil Rate Control

22. 22 AF Disease Hypertension, heart failure Direct effects (anti-fibrotic, antiarrhythmic?) Aldosterone antagonists Lipid-lowering effects Direct antiarrhythmic effects n-3 PUFA (fish oil) Reduction of BP, CHF MI, etc. Direct antiarrhythmic effects Beta blockers Anti-inflammatory effects Corticosteroids Coronary artery disease Systemic atherosclerosis Direct effects (anti- inflammatory, antioxidant) Statins Hypertension Heart failure Direct effects (anti-fibrotic, antiarrhythmic?) ACE inhibitors and ARBs Therapies Possible Target Substrate Atrial remodelling Savelieva I & Camm AJ. Clin Cardiol. In press “Upstream” therapies in AF

23. Electrical Cardioversion aims at immediate restoration of sinus rhythm

24. 24 Non-pharmacologic therapy: catheter ablation

25. 25 Sites of 69 foci triggering AF in 45 patients Haissaguerre M et al. N Engl J Med 1998;339:659-666.

27. Ablation of Atrial fibrillation can only be performed in 3% of Patients A. PV IsolationB. PVI, Roof line, CTI C. PVI, Roof, CTI, Carina, SVCID. DF and CFAE Make sure to complete isolation Complete line block Find the residual PVP or non-PV ectopy AF substrate mapping

29. www.escardio.org Choice between ablation and AADs for patients with and without structural heart disease

30. Take Home Messages AF is a common problem that is difficult to treat due to the complexity of underlying mechanisms and large variability in pathophysiology. New pharmacological approaches are in active development including AAD, upstream therapy and anti-inflammatory agents. Several therapeutic options (hybrid therapy) should be needed for individual patients.