Atrial fibrillation and Atrial fibrillation and InflammationInflammation

Targeting the SubstrateTargeting the Substrate

Matthew McKillop, M.D.Matthew McKillop, M.D.

Florida Chapter of the ACC Annual Meeting Florida Chapter of the ACC Annual Meeting

August 27August 27thth, 2011, 2011

No disclosuresNo disclosures

• Paroxysms of atrial fibrillation (AF) with Paroxysms of atrial fibrillation (AF) with increasing duration and frequency are associated increasing duration and frequency are associated with the eventual development of sustained AF.with the eventual development of sustained AF.

• ““AF begets AF”AF begets AF”

Introduction Introduction

Substrate RemodelingSubstrate Remodeling

Electrical RemodelingElectrical Remodeling Structural RemodelingStructural Remodeling

Allessie MA et al. Circulation. 2001.

• Alterations in intracellular calcium causing shorter Alterations in intracellular calcium causing shorter action potentials and shorter refractory periods.action potentials and shorter refractory periods.

• Alterations in intercellular communication (connexins) Alterations in intercellular communication (connexins) creating a heterogeneity of atrial pulse propagation.creating a heterogeneity of atrial pulse propagation.

• Both facilitate micro-reentryBoth facilitate micro-reentry

Electrical RemodelingElectrical Remodeling

Ica

Nattel S Nature, 2002Firouzi M Cir Res. 2004

Atrial fibrillation leads to:Atrial fibrillation leads to:

• In rapid atrial pacing animal models periods of In rapid atrial pacing animal models periods of sinus rhythm led to a reversal in electrical sinus rhythm led to a reversal in electrical remodeling.remodeling.

• The susceptibility to and stability of AF The susceptibility to and stability of AF remained leading to the concept of a second remained leading to the concept of a second component. component.

Todd DM et al. Circulation. 2004.

A Second ComponentA Second Component

• Sustained atrial tachyarrhythmia increases Sustained atrial tachyarrhythmia increases formation of atrial interstitial fibrosis. formation of atrial interstitial fibrosis.

• Formation of interstitial fibrosis creates areas of Formation of interstitial fibrosis creates areas of conduction delay further facilitating micro-conduction delay further facilitating micro-reentry.reentry.

Todd DM et al. Circulation. 2004.

Structural RemodelingStructural Remodeling

If “AF begets AF,” then what gets the ball rolling?If “AF begets AF,” then what gets the ball rolling?

The CatchThe Catch

InflammationInflammation

Substrate PredispositionSubstrate Predisposition

Pro-Inflammatory statesPro-Inflammatory states

• HypertensionHypertension

• Myocardial IschemiaMyocardial Ischemia

• Atrial stretch – HOCM, MSAtrial stretch – HOCM, MS

Triggers (PV)Triggers (PV)

Atrial Interstitial Atrial Interstitial FibrosisFibrosis

Atrial FibrillationAtrial Fibrillation

Inflammatory cell Inflammatory cell infiltration with infiltration with cytokine releasecytokine release

Substrate PredispositionSubstrate Predisposition

• Increases in inflammatory markers such as CRP, Increases in inflammatory markers such as CRP, interleukins, and WBC correlate with AF recurrence interleukins, and WBC correlate with AF recurrence post-ablation.post-ablation.

Inflammation and pulmonary vein isolationInflammation and pulmonary vein isolation

Letsas KP et al. Europace. 2009.McCabe JM et al. Pacing Clin Electrophysiol. 2008.

Treatment – Modifying the SubstrateTreatment – Modifying the Substrate

• Corticosteroids post-CABG reduce the incidence of Corticosteroids post-CABG reduce the incidence of post-operative AF.post-operative AF.

• Corticosteroids reduce the rate of recurrence after atrial Corticosteroids reduce the rate of recurrence after atrial fibrillation ablation.fibrillation ablation.

Marik PE J Crit Care. 2009.Dernellis J Eur Heart J. 2004.

Koyama T JACC. 2010

Anti-inflammatory agents and AFAnti-inflammatory agents and AF

A Pilot StudyA Pilot Study

Hypothesis:Hypothesis:

1)1) AF recurrence post ablation is related to inflammation. AF recurrence post ablation is related to inflammation.

2)2) Anti-inflammatory proteins, Serp-1 and M-T7, have Anti-inflammatory proteins, Serp-1 and M-T7, have therapeutic potential for the prevention of excess therapeutic potential for the prevention of excess inflammatory cell activation after AF ablation. inflammatory cell activation after AF ablation.

3) Targeted decrease in inflammatory cell activation after AF 3) Targeted decrease in inflammatory cell activation after AF ablation will help prevent arrhythmia recurrence.ablation will help prevent arrhythmia recurrence.

A Pilot StudyA Pilot Study

Methods:Methods:

• We measured the systemic inflammatory response in 14 We measured the systemic inflammatory response in 14 patients before and after AF ablation using high sensitivity patients before and after AF ablation using high sensitivity CRP, total WBC, and fibrinogen levels. CRP, total WBC, and fibrinogen levels.

• Circulating peripheral blood mononuclear cells (PBMCs) from Circulating peripheral blood mononuclear cells (PBMCs) from these patients were assayed 12 to 24 hours after ablation for these patients were assayed 12 to 24 hours after ablation for adhesion to fibronectin coated plates with and without Serp-1 adhesion to fibronectin coated plates with and without Serp-1 and M-T7 treatment. and M-T7 treatment.

• PBMCs (1 million cells/ml) were labeled with a fluorescent PBMCs (1 million cells/ml) were labeled with a fluorescent calcein probe followed by activation with 160 nM PMA calcein probe followed by activation with 160 nM PMA (phorbol myristate) with and without addition of Serp-1 (phorbol myristate) with and without addition of Serp-1 (500ng/ml) or M-T7 (50ng/ml) and normalized to treatment (500ng/ml) or M-T7 (50ng/ml) and normalized to treatment with saline. with saline.

A Pilot StudyA Pilot Study

P.Gettins, Chem rev 2002

Serp-1Serp-1 is a secreted myxoma viral is a secreted myxoma viral serserine ine pprotease rotease ininhibitor (serpin). It potently hibitor (serpin). It potently inhibits human serine proteinases in the circulating blood and vascular tissues inhibits human serine proteinases in the circulating blood and vascular tissues including: plasmin, urokinase-type plasminogen activator (uPA) and tissue-type including: plasmin, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) as well as the thrombotic protease factor Xa. plasminogen activator (tPA) as well as the thrombotic protease factor Xa.

M-T7M-T7 is a secreted myxoma viral anti-inflammatory protein. It possess the is a secreted myxoma viral anti-inflammatory protein. It possess the dual function of inhibiting IFN-dual function of inhibiting IFN- and acting as a chemokine-binding protein. and acting as a chemokine-binding protein.

The Viral ProteinsThe Viral Proteins

A Pilot StudyA Pilot Study

Results – InjuryResults – Injury

P < 0.0001

A Pilot StudyA Pilot Study

Results – Systemic Inflammatory ResponseResults – Systemic Inflammatory Response

P = 0.0003

P = 0.0003

A Pilot StudyA Pilot StudyResults – Mononuclear Cell ActivationResults – Mononuclear Cell Activation

P < 0.0001 P = 0.0163 P < 0.0001

A Pilot StudyA Pilot Study

Conclusions:Conclusions:

• Patients post AF ablation have increased circulating markers of Patients post AF ablation have increased circulating markers of inflammation. inflammation.

• Two novel anti-inflammatory proteins, Serp-1 and M-T7, Two novel anti-inflammatory proteins, Serp-1 and M-T7, reduce mononuclear cell activation in circulating blood reduce mononuclear cell activation in circulating blood isolates from patients after AF ablation. isolates from patients after AF ablation.

• Reduction in mononuclear cell activation and subsequent Reduction in mononuclear cell activation and subsequent tissue inflammation provides a possible new therapeutic tissue inflammation provides a possible new therapeutic approach for the prevention of AF recurrence after ablation.approach for the prevention of AF recurrence after ablation.

Future StudyFuture Study

• A prospective study following AF ablation patients with A prospective study following AF ablation patients with measures of inflammation (including response to Serp-1 and measures of inflammation (including response to Serp-1 and MT-7) pre and post ablation as well as at 3 and 6 month MT-7) pre and post ablation as well as at 3 and 6 month intervals compared to controls (SVT).intervals compared to controls (SVT).

• Evaluate the inflammatory response to cryoablation using this Evaluate the inflammatory response to cryoablation using this same model.same model.

• Inflammation leads to substrate remodeling and pre-Inflammation leads to substrate remodeling and pre-disposition to AF.disposition to AF.

• Ectopic foci from the pulmonary veins trigger micro re-Ectopic foci from the pulmonary veins trigger micro re-entry mechanisms within these substrate changes.entry mechanisms within these substrate changes.

• Once started, atrial fibrillation leads to additional Once started, atrial fibrillation leads to additional electrical and structural remodeling that further alters the electrical and structural remodeling that further alters the substrate in favor of AF.substrate in favor of AF.

In SummaryIn Summary

• Atrial fibrillation ablation through pulmonary vein Atrial fibrillation ablation through pulmonary vein isolation can eliminate the ectopic triggers.isolation can eliminate the ectopic triggers.

• Treatment with anti-inflammatory agents may then reduce Treatment with anti-inflammatory agents may then reduce the inflammatory response post-ablation thereby limiting the inflammatory response post-ablation thereby limiting the re-formation of predisposed substrate and perhaps the re-formation of predisposed substrate and perhaps improve the long term success rate of ablation. improve the long term success rate of ablation.

In SummaryIn Summary

Questions?Questions?

• William Miles

• Alexandra Lucas

• Jamie Conti

• Chris Hudson

• Mark Panna

• Liying Liu

• Erbin Dai

• Joe Belgrade

• Debbie Olisky

Special thanks to:Special thanks to:

References and CitationsReferences and Citations• Allessie MA, Boyden PA, Camm AJ, et al. Pathophysiology and prevention of atrial fibrillation. Circulation 2001;103:769-77.

• 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. 1998.

• Nattel S. New ideas about atrial fibrillation 50 years on. Nature 2002. 415: 219.

• Wijffels et al. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995.

• Van der Velden et al. Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat. Cardiovas Res. 2005

• 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. 2004

• 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. 2006.

• Frustaci et al. Histologic substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation. 1997, 96: 1180.

• 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: 2886.

• Marik PE. The efficacy and dosage effect of corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a systematic review. J Crit Care. 2009 24: 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. 2008 Sep;31(9):1146-51

• Yamashita T et al. Recruitment of Immune Cells Across Atrial Endocardium in Human Atrial Fibrillation. Circulation Journal. 2010. 74: 262-270.

• Dernellis J, Panaretous M. Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation. European Heart Journal. 2004, 25: 1100-1107.

• Koyama T et al. Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency ablation. JACC. 2010, 56: 1463.

Substrate PredispositionSubstrate Predisposition

• Increases in CRP and other pro-inflammatory Increases in CRP and other pro-inflammatory cytokines result in activation of the complement cytokines result in activation of the complement system, recruitment of inflammatory cells, and system, recruitment of inflammatory cells, and subsequent apoptosis/phagocytosis of atrial myocytes.subsequent apoptosis/phagocytosis of atrial myocytes.

• This process leads to loss of atrial muscle mass and This process leads to loss of atrial muscle mass and deposition of interstitial fibrosis initiating the deposition of interstitial fibrosis initiating the remodeling process.remodeling process.

Kourliouros et al. American Heart Journal. 2009.

Inflammation and substrate changeInflammation and substrate change

The Concept of ReentryThe Concept of ReentryS

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1.1. Two pathways with the ability to conduct in an antegrade and Two pathways with the ability to conduct in an antegrade and retrograde directionretrograde direction

2.2. Block in one directionBlock in one direction3.3. Slowed conduction in the other directionSlowed conduction in the other direction