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Atrial fibrillation and Inflammation Targeting the Substrate Matthew McKillop, M.D. Florida Chapter of the ACC Annual Meeting August 27 th, 2011.

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Presentation on theme: "Atrial fibrillation and Inflammation Targeting the Substrate Matthew McKillop, M.D. Florida Chapter of the ACC Annual Meeting August 27 th, 2011."— Presentation transcript:

1 Atrial fibrillation and Inflammation Targeting the Substrate Matthew McKillop, M.D. Florida Chapter of the ACC Annual Meeting August 27 th, 2011

2 No disclosures

3 Paroxysms of atrial fibrillation (AF) with increasing duration and frequency are associated with the eventual development of sustained AF.Paroxysms of atrial fibrillation (AF) with increasing duration and frequency are associated with the eventual development of sustained AF. “AF begets AF”“AF begets AF” Introduction Substrate Remodeling Electrical Remodeling Structural Remodeling Allessie MA et al. Circulation

4 Alterations in intracellular calcium causing shorter action potentials and shorter refractory periods.Alterations in intracellular calcium causing shorter action potentials and shorter refractory periods. Alterations in intercellular communication (connexins) creating a heterogeneity of atrial pulse propagation.Alterations in intercellular communication (connexins) creating a heterogeneity of atrial pulse propagation. Both facilitate micro-reentryBoth facilitate micro-reentry Electrical Remodeling I ca Nattel S Nature, 2002 Firouzi M Cir Res Atrial fibrillation leads to:

5 In rapid atrial pacing animal models periods of sinus rhythm led to a reversal in electrical remodeling.In rapid atrial pacing animal models periods of sinus rhythm led to a reversal in electrical remodeling. The susceptibility to and stability of AF remained leading to the concept of a second component.The susceptibility to and stability of AF remained leading to the concept of a second component. Todd DM et al. Circulation A Second Component

6 Sustained atrial tachyarrhythmia increases formation of atrial interstitial fibrosis.Sustained atrial tachyarrhythmia increases formation of atrial interstitial fibrosis. Formation of interstitial fibrosis creates areas of conduction delay further facilitating micro- reentry.Formation of interstitial fibrosis creates areas of conduction delay further facilitating micro- reentry. Todd DM et al. Circulation Structural Remodeling

7 If “AF begets AF,” then what gets the ball rolling? The Catch Inflammation

8 Substrate Predisposition Pro-Inflammatory states Hypertension Hypertension Myocardial Ischemia Myocardial Ischemia Atrial stretch – HOCM, MS Atrial stretch – HOCM, MS Triggers (PV) Atrial Interstitial Fibrosis Atrial Fibrillation Inflammatory cell infiltration with cytokine release

9 Substrate Predisposition Increases in inflammatory markers such as CRP, interleukins, and WBC correlate with AF recurrence post-ablation.Increases in inflammatory markers such as CRP, interleukins, and WBC correlate with AF recurrence post-ablation. Inflammation and pulmonary vein isolation Letsas KP et al. Europace McCabe JM et al. Pacing Clin Electrophysiol

10 Treatment – Modifying the Substrate Corticosteroids post-CABG reduce the incidence of post-operative AF.Corticosteroids post-CABG reduce the incidence of post-operative AF. Corticosteroids reduce the rate of recurrence after atrial fibrillation ablation.Corticosteroids reduce the rate of recurrence after atrial fibrillation ablation. Marik PE J Crit Care Dernellis J Eur Heart J Koyama T JACC Anti-inflammatory agents and AF

11 A Pilot Study Hypothesis: 1)AF recurrence post ablation is related to inflammation. 2)Anti-inflammatory proteins, Serp-1 and M-T7, have therapeutic potential for the prevention of excess inflammatory cell activation after AF ablation. 3) Targeted decrease in inflammatory cell activation after AF ablation will help prevent arrhythmia recurrence.

12 A Pilot Study Methods: We measured the systemic inflammatory response in 14 patients before and after AF ablation using high sensitivity CRP, total WBC, and fibrinogen levels. We measured the systemic inflammatory response in 14 patients before and after AF ablation using high sensitivity CRP, total WBC, and fibrinogen levels. Circulating peripheral blood mononuclear cells (PBMCs) from these patients were assayed 12 to 24 hours after ablation for adhesion to fibronectin coated plates with and without Serp-1 and M-T7 treatment. Circulating peripheral blood mononuclear cells (PBMCs) from these patients were assayed 12 to 24 hours after ablation for adhesion to fibronectin coated plates with and without Serp-1 and M-T7 treatment. PBMCs (1 million cells/ml) were labeled with a fluorescent calcein probe followed by activation with 160 nM PMA (phorbol myristate) with and without addition of Serp-1 (500ng/ml) or M-T7 (50ng/ml) and normalized to treatment with saline. PBMCs (1 million cells/ml) were labeled with a fluorescent calcein probe followed by activation with 160 nM PMA (phorbol myristate) with and without addition of Serp-1 (500ng/ml) or M-T7 (50ng/ml) and normalized to treatment with saline.

13 A Pilot Study P.Gettins, Chem rev 2002 Serp-1 is a secreted myxoma viral serine protease inhibitor (serpin). It potently inhibits human serine proteinases in the circulating blood and vascular tissues including: plasmin, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) as well as the thrombotic protease factor Xa. M-T7 is a secreted myxoma viral anti-inflammatory protein. It possess the dual function of inhibiting IFN-  and acting as a chemokine-binding protein. The Viral Proteins

14 A Pilot Study Results – Injury P <

15 A Pilot Study Results – Systemic Inflammatory Response P =

16 A Pilot Study Results – Mononuclear Cell Activation P < P = P <

17 A Pilot Study Conclusions: Patients post AF ablation have increased circulating markers of inflammation. Patients post AF ablation have increased circulating markers of inflammation. Two novel anti-inflammatory proteins, Serp-1 and M-T7, reduce mononuclear cell activation in circulating blood isolates from patients after AF ablation. Two novel anti-inflammatory proteins, Serp-1 and M-T7, reduce mononuclear cell activation in circulating blood isolates from patients after AF ablation. Reduction in mononuclear cell activation and subsequent tissue inflammation provides a possible new therapeutic approach for the prevention of AF recurrence after ablation. Reduction in mononuclear cell activation and subsequent tissue inflammation provides a possible new therapeutic approach for the prevention of AF recurrence after ablation.

18 Future Study A prospective study following AF ablation patients with measures of inflammation (including response to Serp-1 and MT-7) pre and post ablation as well as at 3 and 6 month intervals compared to controls (SVT). A prospective study following AF ablation patients with measures of inflammation (including response to Serp-1 and MT-7) pre and post ablation as well as at 3 and 6 month intervals compared to controls (SVT). Evaluate the inflammatory response to cryoablation using this same model. Evaluate the inflammatory response to cryoablation using this same model.

19 Inflammation leads to substrate remodeling and pre- disposition to AF.Inflammation leads to substrate remodeling and pre- disposition to AF. Ectopic foci from the pulmonary veins trigger micro re- entry mechanisms within these substrate changes.Ectopic foci from the pulmonary veins trigger micro re- entry mechanisms within these substrate changes. Once started, atrial fibrillation leads to additional electrical and structural remodeling that further alters the substrate in favor of AF.Once started, atrial fibrillation leads to additional electrical and structural remodeling that further alters the substrate in favor of AF. In Summary

20 Atrial fibrillation ablation through pulmonary vein isolation can eliminate the ectopic triggers.Atrial fibrillation ablation through pulmonary vein isolation can eliminate the ectopic triggers. Treatment with anti-inflammatory agents may then reduce the inflammatory response post-ablation thereby limiting the re-formation of predisposed substrate and perhaps improve the long term success rate of ablation.Treatment with anti-inflammatory agents may then reduce the inflammatory response post-ablation thereby limiting the re-formation of predisposed substrate and perhaps improve the long term success rate of ablation. In Summary

21 Questions?

22 William Miles Alexandra Lucas Jamie Conti Chris Hudson Mark Panna Liying Liu Erbin Dai Joe Belgrade Debbie Olisky Special thanks to:

23 References and Citations Allessie MA, Boyden PA, Camm AJ, et al. Pathophysiology and prevention of atrial fibrillation. Circulation 2001;103: Moukabary. Understanding atrial fibrillation: a historical perspective. Cardiology Journal. 2008, Vol. 15, No. 4, pp. 396–397 Haïssaguerre et al.Haïssaguerre et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. NEJM Nattel S. New ideas about atrial fibrillation 50 years on. Nature : 219. Wijffels et al. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation Van der Velden et al. Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat. Cardiovas Res Todd DM et al. Repetitive 4-week periods of atrial electrical remodeling promote stability of atrial fibrillation: time course of a second factor involved in the self-perpetuation of atrial fibrillation. Circulation. 2004; 109:1434. Firouzi M et al. Association of human connexin 40 gene polymorphisms with atrial vulnerability as a risk factor for idiopathic atrial fibrillation. Cir Res Morillo CA et al. Circulation 1995 Xu J et al. Atrial extracellular matrix remodeling proteins and the maintenance of atrial fibrillation. Circulation. 2004, 109:363. Mariscalco G et al. Relationship between atrial histopathology and atrial fibrillation after coronary bypass surgery. J Thorac Cardiovasc Surg Frustaci et al. Histologic substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation. 1997, 96: Kourliouros et al. Current concepts in the pathogenesis of atrial fibrillation. American Heart Journal. Vol 157, Feb 2009, 243. Chung MK et al. C-reactive protein elevation in patients with atrial arrhythmias. Circulation. 2001, 104: Marik PE. The efficacy and dosage effect of corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a systematic review. J Crit Care : 458. Letsas KP et al. Pre-ablative predictors of atrial fibrillation recurrence following pulmonary vein isolation: the potential role of inflammation. Europace. 2009, 11:158. McCabe JM et al. Protracted CRP elevation after atrial fibrillation ablation. Pacing Clin Electrophysiol Sep;31(9): Yamashita T et al. Recruitment of Immune Cells Across Atrial Endocardium in Human Atrial Fibrillation. Circulation Journal : Dernellis J, Panaretous M. Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation. European Heart Journal. 2004, 25: Koyama T et al. Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency ablation. JACC. 2010, 56: 1463.

24 Substrate Predisposition Increases in CRP and other pro-inflammatory cytokines result in activation of the complement system, recruitment of inflammatory cells, and subsequent apoptosis/phagocytosis of atrial myocytes.Increases in CRP and other pro-inflammatory cytokines result in activation of the complement system, recruitment of inflammatory cells, and subsequent apoptosis/phagocytosis of atrial myocytes. This process leads to loss of atrial muscle mass and deposition of interstitial fibrosis initiating the remodeling process.This process leads to loss of atrial muscle mass and deposition of interstitial fibrosis initiating the remodeling process. Kourliouros et al. American Heart Journal Inflammation and substrate change

25 The Concept of Reentry Slow conduction 1.Two pathways with the ability to conduct in an antegrade and retrograde direction 2.Block in one direction 3.Slowed conduction in the other direction


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