1. Prof. C. Moro, Madrid Non antiarrhythmic drugs for AF

4. AF Treatment Substrate Modifyers Drugs Antiagregation Anticoagulation Rate Control ? Substrate Ablation AVN Ablation Rhythm Control ?

5. Therapy Objectives for AF Symptomatic Improvement Quality of life Improvement Thromboembolism Prevention Remodelling Prevention Heart Failure Prevention Mortality Reduction Symptomatic Improvement Quality of life Improvement Thromboembolism Prevention Remodelling Prevention Heart Failure Prevention Mortality Reduction

6. Therapy Options in AF –Type and Duration of AF –Type y Severity of Symptoms –Associated Cardiac Diseases –Age –Systemic Associated Diseases –Long or Short Term Follow up –Pharmacologic or Non Pharmacologic

7. Upstream Therapy in AF – Renin Angiotensin Inhibitors Drugs ACE`s ARB`s – Statins – Steroids – PUFA

8. Blockade of Ang II prevents electrical remodeling induced by rapid atrial pacing. Nakashima, 2000. ACE–dependent Ekr1/Ekr2 responsible of atrial fibrosis. Goette, 2000 Candesartan prevents development of structural remodeling in the atria. Kumagai, 2003 Experimental Data

9. Nakashima et al. 2000 Effect of Candesartan/ Captopril preventing electrical remodeling with rapid atrial pacing in the animal model

10. Genetic Determinants of AF Potasium and Sodium Channels

11. Candesartan Kumagai K et al. JACC 2003 Experimental AF. Electro/Anatomic Changes with Candesartan Control

12. ACEI´s and ARB´s Hemodynamic Effects Decrease Peripheral Vascular Resistance Improve Cardiac Distensibility Reduce Arterial Pressure in Hypertension In HF patients –Venous and Arterial Dilatation – Reduce Preload and Afterload – Reduce PWP and Pulmonary Congestion – Increase Cardiac Output

13. ACEI´s and ARB´s Neurohormonal Effects Decrease Angiotensin II. Decrease Aldosterone. Increase in Renin and Angiotensin I. Reduce Epinephrine and Norepinephrine. ACEI´s increase Bradikinin.

14. ACEI`s or ARB`s for IHD Prevention Plaque Stabilization Improvement of Endothelial Dysfunction Improvement of Fibrinolysis Modulation of Arterial Vasoconstriction Blood Pressure Reduction

15. ACEI´s and ARB´s Antiproliferative Effects Reduction of Vascular Hypertrophy. Reduction of Ventricular Hypertrophy. Reduce Extracellular Proliferation. –Reduction of Fibrosis.

16. Atrial Remodeling: Mechanisms of Efficacy for ARB´s Hemodynamic effect: –Decreased atrial stretch –Lowering end-diastolic left ventricular pressure Prevention of electrical remodeling: –Direct action on ionic currents at the atrial level –Modifying the sympathetic tone Preventing structural remodeling – Reduction of atrial fibrosis Reduction of atrial dilatation and apoptosis Madrid A, Moro C. Circulation 2002;106:331–6

17. Electrophysiological Effect of Irbesartan 1. Irbesartán does not modify IKr or IKs: Should not alter APD at VENTRICULAR level 2. Irbesartán blocks moderately IKur and Ito currents: it should prolong APD at ATRIAL level IKur: hKv1.5ITo: Kv4.3 Moreno et al., J Pharmacol Exp Ther 2003;304:862

18. Maintenance of Sinus Rhythm after Conversion from Persistent AF Amiodarone + Irbesartan Amiodarone 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Follow-up (days) 2-month lower recurrence rate of atrial fibrillation Longer time to first arrhythmia recurrence 2-month lower recurrence rate of atrial fibrillation Longer time to first arrhythmia recurrence Log Rank = 0.007 Madrid AH, Moro C et al. Circulation 2002;106:331-6. % Event-free patients

19. Madrid AH, Moro C. PACE 2004 Prevention of Atrial Fibrillation Metaanalysis with ACEI’s ARB’s

20. Irbesartan in Lone AF Dose Response : 150-300 mg Madrid AH, Moro C. JRAAS 2004; 5 :114-120

21. RAS Inhibitors in Lone AF

24. Ramipril in Lone AF Preventing histological remodeling such as Inflammation, myocarditis- like changes,Fibrosis and atrial dilatation. Preventing electrical remodeling induced by Angiotensin II. Reducing atrial stretch and intraatrial pressure. Reduction of sympathetic tone. Reduction of blood pressure. Belluzi et al JACC 2009;53:24

26. Randomized clinical trials of RAS I in AF Primary Prevention TrialPat NDrugResults CAPP210985Captopril/StNo Diff STOP-26628Enal-Lisi/StNo Diff LIFE8851Losart/Ateno3,5 vs 5,3% HOPE8335Ramip/PlacNo Diff VALUE13760Vals/Amlod3,7 vs 4,3%

27. Randomized clinical trials of RAS I in AF Secondary Prevention Author/year Pat NDrugResults Van den Bergh 18Lisinopril/PlacSig reduction Madrid154Irb+Amio/AmioSig Reduction Ueng145Ena+Amio/AmioSig Reduction Tveit137Cande/PlacSig reduction Fogari222Losar+Amio/Am lo+Amio Sig Reduction Yin177Losar+Amio/ Peri+Amio/Amio Sig Reduction

28. APD EEF SR AF SR AF ACTION POTENTIAL ANATOMICAL EEF Fybrosis Hypertrophy Inflammation Reduced AERP Loss of AERP adaptation to rate Inflammation and AF

30. Statins for AF

33. Review of randomized clinical trials of Statins to prevent Post Thoracic Surgery AF Author/yearDesignnFindings Auer/04Prospective253Sig reduction Amar/05Prospective131Sig Reduction Marin/06Prospective234Sig Reduction Patty/06Double blind200Sig Reduction Chello/06Doble blind40Sig reduction Ozaydin/07Prospective362Sig Reduction Virani/08Retrospective4044No Diff Letsburapa/08Prospective555Sig Reduction

34. Steroids for AF Prevention Double blind study with 104 patients Persistent AF. After Cardioversion. High PCR levels. Profafenone + 16mg-4 mg Methylprednisolone vs Placebo. Follow- up mean 23 months. Recurrent AF was reduced from 50-9,6% Permanent AF was reduced from 29-2%. Significant reduction also of PCR levels. Dernellis et al Eur H J 2004; 25:1100-07

35. Steroids for AF Prevention

36. Clinical Trials with PUFA Mozaffarian/044815 12 years++ Calo/05160days++ Frost/05479495,7 years -- Brouwer/0652846,4 years -- Author/Year PublicationPatientsFollow upResults

37. Conclusions ACE`s and ARB´s are equipotent tools to fight against AF in primary and secondary prevention. Lone AF may also be treated with them. (Not recognized yet in Guidelines). The RR for AF prevention with those drugs is higher in patients with high arryhthmogenic risk. Steroids should not be used in AF prevention due to its plural and potent adverse effects. Statins are useful to prevent post surgical AF. PUFA effects for AF prevention show controversial results.