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Atrial Fibrillation and Heart Failure Bologna, February 2009

Atrial Fibrillation and Heart Failure Bologna, February 2009. Upstream Therapy for AF. Prof. C. Moro, Madrid. AF Treatment. AF Atrial Structural Remodeling. Cell stretch and reduced conexins. Atrial enlargement. Myocarditis. Patchy Fibrosis. Apoptotic death.

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Atrial Fibrillation and Heart Failure Bologna, February 2009

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  1. Atrial Fibrillation and Heart FailureBologna, February 2009 Upstream Therapy for AF Prof. C. Moro, Madrid

  2. AF Treatment

  3. AF Atrial Structural Remodeling Cell stretch and reduced conexins. Atrial enlargement. Myocarditis. Patchy Fibrosis. Apoptotic death. Cellular Degeneration. Increased expression of MMP and Collagen turnover.

  4. Upstream Therapy in AF Angiotensin II Inhibitor Drugs ACEI`s ARB`s Statins PUFA Steroids. Anti-Inflammatory Agents Antioxidants

  5. Experimental Data • 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

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

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

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

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

  10. 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

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

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

  13. RAS Inhibitors in Lone AF

  14. RAS Inhibitors in Lone AF

  15. RAS Inhibitors in Lone AF

  16. 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

  17. Randomized clinical trials of RAS I in AF Primary Prevention

  18. Randomized clinical trials of RAS I in AF Secondary Prevention

  19. Statins to prevent Atrial Remodeling • Anti-inflammatory Effect. • Anti-oxidant Effect. • Anti-fibrotic Effect • Modulation of MMP. • Interaction with Peroxisome receptor. • Interaction with Endotelial Nitric Oxide Synthase . • Antiatherogenic properties.

  20. Statins for AF

  21. Statins for AF Gillis AM Eur Heart J 2008 ;29:1873

  22. Statins for Post Operative AF

  23. Statins for Post operative AF

  24. Statins for AF

  25. Statins for AF

  26. Review of randomized clinical trials of Statins to prevent Post Thoracic Surgery AF

  27. 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

  28. Steroids for AF Prevention

  29. Clinical Trials with PUFA Author/Year Publication Patients Follow up Results • Mozaffarian/04 4815 12 years ++ • Calo/05 160 days ++ • Frost/05 47949 5,7 years -- • Brouwer/06 5284 6,4 years --

  30. Non AA Drugs with Antiarrhythmic efficacy for AF Prevention

  31. Conclusions I ACEI`s and ARB´s are supplementary agents to fight against AF in primary and secondary prevention . Lone AF may also be treated with them. (Not recognized yet in Guidelines). The RR achieved with those drugs is higher in patients with high arrhythmogenic risk.

  32. Conclusions II Steroids should not be used in AF prevention due to its plural and potent adverse effects. Statins are useful for primary /secondary AF prevention. PUFA effects for AF prevention show controversial results.

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