Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure

Ken W. Lee, Thomas Everett, Dulkon Rahmutula, Jose M. Guerra, Emily Wilson, Chunhua Ding, Jeffrey E. Olgin

Research output: Contribution to journalArticle

149 Citations (Scopus)

Abstract

BACKGROUND - Atrial fibrosis is an important substrate in atrial fibrillation (AF), particularly in the setting of structural heart disease. In a canine model, congestive heart failure (CHF) produces significant atrial fibrosis and the substrate for sustained AF. This atrial remodeling is a potential therapeutic target. The objective of the present study is to evaluate the effects of the antifibrotic drug pirfenidone (PFD) on arrhythmogenic atrial remodeling in a canine CHF model. METHODS AND RESULTS - We studied 15 canines, divided equally into 3 groups: control, CHF canines not treated with PFD, and CHF canines treated with PFD. CHF was induced by ventricular tachypacing (220 bpm for 3 weeks), and oral PFD was administered for the 3-week pacing period. We performed electrophysiology and AF vulnerability studies, atrial fibrosis measurements, and atrial cytokine expression studies. Only canines in the untreated CHF group developed sustained AF (>30 minutes, 4 of 5 canines; P<0.05). Treatment of CHF canines with PFD resulted in an attenuation of arrhythmogenic left atrial remodeling, with a significant reduction in left atrial conduction heterogeneity index (median [25% to 75% interquartile range] 4.96 [3.53 to 5.64] versus 2.52 [2.11 to 2.82], P<0.01; pacing cycle length 300 ms), left atrial fibrosis (16.0% [13.0% to 17.5%] versus 8.7% [5.7% to 10.6%], P<0.01), and AF duration (1800 [1020 to 1800] seconds versus 6 [5 to 22] seconds, P<0.01). Immunoblotting studies demonstrated the drug's effects on multiple cytokines, including a reduction in transforming growth factor-β1 expression. CONCLUSIONS - Treatment of CHF canines with PFD results in significantly reduced arrhythmogenic atrial remodeling and AF vulnerability. Pharmacological therapy targeted at the fibrotic substrate itself may play an important role in the management of AF.

Original languageEnglish (US)
Pages (from-to)1703-1712
Number of pages10
JournalCirculation
Volume114
Issue number16
DOIs
StatePublished - Oct 2006
Externally publishedYes

Fingerprint

Atrial Fibrillation
Canidae
Heart Failure
Atrial Remodeling
Fibrosis
Cytokines
pirfenidone
Electrophysiology
Transforming Growth Factors
Immunoblotting
Pharmaceutical Preparations
Heart Diseases
Pharmacology
Control Groups
Therapeutics

Keywords

  • Atrial fibrillation
  • Drugs
  • Heart failure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure. / Lee, Ken W.; Everett, Thomas; Rahmutula, Dulkon; Guerra, Jose M.; Wilson, Emily; Ding, Chunhua; Olgin, Jeffrey E.

In: Circulation, Vol. 114, No. 16, 10.2006, p. 1703-1712.

Research output: Contribution to journalArticle

Lee, Ken W. ; Everett, Thomas ; Rahmutula, Dulkon ; Guerra, Jose M. ; Wilson, Emily ; Ding, Chunhua ; Olgin, Jeffrey E. / Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure. In: Circulation. 2006 ; Vol. 114, No. 16. pp. 1703-1712.
@article{c078da2507eb48f6b3db9debf7d74749,
title = "Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure",
abstract = "BACKGROUND - Atrial fibrosis is an important substrate in atrial fibrillation (AF), particularly in the setting of structural heart disease. In a canine model, congestive heart failure (CHF) produces significant atrial fibrosis and the substrate for sustained AF. This atrial remodeling is a potential therapeutic target. The objective of the present study is to evaluate the effects of the antifibrotic drug pirfenidone (PFD) on arrhythmogenic atrial remodeling in a canine CHF model. METHODS AND RESULTS - We studied 15 canines, divided equally into 3 groups: control, CHF canines not treated with PFD, and CHF canines treated with PFD. CHF was induced by ventricular tachypacing (220 bpm for 3 weeks), and oral PFD was administered for the 3-week pacing period. We performed electrophysiology and AF vulnerability studies, atrial fibrosis measurements, and atrial cytokine expression studies. Only canines in the untreated CHF group developed sustained AF (>30 minutes, 4 of 5 canines; P<0.05). Treatment of CHF canines with PFD resulted in an attenuation of arrhythmogenic left atrial remodeling, with a significant reduction in left atrial conduction heterogeneity index (median [25{\%} to 75{\%} interquartile range] 4.96 [3.53 to 5.64] versus 2.52 [2.11 to 2.82], P<0.01; pacing cycle length 300 ms), left atrial fibrosis (16.0{\%} [13.0{\%} to 17.5{\%}] versus 8.7{\%} [5.7{\%} to 10.6{\%}], P<0.01), and AF duration (1800 [1020 to 1800] seconds versus 6 [5 to 22] seconds, P<0.01). Immunoblotting studies demonstrated the drug's effects on multiple cytokines, including a reduction in transforming growth factor-β1 expression. CONCLUSIONS - Treatment of CHF canines with PFD results in significantly reduced arrhythmogenic atrial remodeling and AF vulnerability. Pharmacological therapy targeted at the fibrotic substrate itself may play an important role in the management of AF.",
keywords = "Atrial fibrillation, Drugs, Heart failure",
author = "Lee, {Ken W.} and Thomas Everett and Dulkon Rahmutula and Guerra, {Jose M.} and Emily Wilson and Chunhua Ding and Olgin, {Jeffrey E.}",
year = "2006",
month = "10",
doi = "10.1161/CIRCULATIONAHA.106.624320",
language = "English (US)",
volume = "114",
pages = "1703--1712",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "16",

}

TY - JOUR

T1 - Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure

AU - Lee, Ken W.

AU - Everett, Thomas

AU - Rahmutula, Dulkon

AU - Guerra, Jose M.

AU - Wilson, Emily

AU - Ding, Chunhua

AU - Olgin, Jeffrey E.

PY - 2006/10

Y1 - 2006/10

N2 - BACKGROUND - Atrial fibrosis is an important substrate in atrial fibrillation (AF), particularly in the setting of structural heart disease. In a canine model, congestive heart failure (CHF) produces significant atrial fibrosis and the substrate for sustained AF. This atrial remodeling is a potential therapeutic target. The objective of the present study is to evaluate the effects of the antifibrotic drug pirfenidone (PFD) on arrhythmogenic atrial remodeling in a canine CHF model. METHODS AND RESULTS - We studied 15 canines, divided equally into 3 groups: control, CHF canines not treated with PFD, and CHF canines treated with PFD. CHF was induced by ventricular tachypacing (220 bpm for 3 weeks), and oral PFD was administered for the 3-week pacing period. We performed electrophysiology and AF vulnerability studies, atrial fibrosis measurements, and atrial cytokine expression studies. Only canines in the untreated CHF group developed sustained AF (>30 minutes, 4 of 5 canines; P<0.05). Treatment of CHF canines with PFD resulted in an attenuation of arrhythmogenic left atrial remodeling, with a significant reduction in left atrial conduction heterogeneity index (median [25% to 75% interquartile range] 4.96 [3.53 to 5.64] versus 2.52 [2.11 to 2.82], P<0.01; pacing cycle length 300 ms), left atrial fibrosis (16.0% [13.0% to 17.5%] versus 8.7% [5.7% to 10.6%], P<0.01), and AF duration (1800 [1020 to 1800] seconds versus 6 [5 to 22] seconds, P<0.01). Immunoblotting studies demonstrated the drug's effects on multiple cytokines, including a reduction in transforming growth factor-β1 expression. CONCLUSIONS - Treatment of CHF canines with PFD results in significantly reduced arrhythmogenic atrial remodeling and AF vulnerability. Pharmacological therapy targeted at the fibrotic substrate itself may play an important role in the management of AF.

AB - BACKGROUND - Atrial fibrosis is an important substrate in atrial fibrillation (AF), particularly in the setting of structural heart disease. In a canine model, congestive heart failure (CHF) produces significant atrial fibrosis and the substrate for sustained AF. This atrial remodeling is a potential therapeutic target. The objective of the present study is to evaluate the effects of the antifibrotic drug pirfenidone (PFD) on arrhythmogenic atrial remodeling in a canine CHF model. METHODS AND RESULTS - We studied 15 canines, divided equally into 3 groups: control, CHF canines not treated with PFD, and CHF canines treated with PFD. CHF was induced by ventricular tachypacing (220 bpm for 3 weeks), and oral PFD was administered for the 3-week pacing period. We performed electrophysiology and AF vulnerability studies, atrial fibrosis measurements, and atrial cytokine expression studies. Only canines in the untreated CHF group developed sustained AF (>30 minutes, 4 of 5 canines; P<0.05). Treatment of CHF canines with PFD resulted in an attenuation of arrhythmogenic left atrial remodeling, with a significant reduction in left atrial conduction heterogeneity index (median [25% to 75% interquartile range] 4.96 [3.53 to 5.64] versus 2.52 [2.11 to 2.82], P<0.01; pacing cycle length 300 ms), left atrial fibrosis (16.0% [13.0% to 17.5%] versus 8.7% [5.7% to 10.6%], P<0.01), and AF duration (1800 [1020 to 1800] seconds versus 6 [5 to 22] seconds, P<0.01). Immunoblotting studies demonstrated the drug's effects on multiple cytokines, including a reduction in transforming growth factor-β1 expression. CONCLUSIONS - Treatment of CHF canines with PFD results in significantly reduced arrhythmogenic atrial remodeling and AF vulnerability. Pharmacological therapy targeted at the fibrotic substrate itself may play an important role in the management of AF.

KW - Atrial fibrillation

KW - Drugs

KW - Heart failure

UR - http://www.scopus.com/inward/record.url?scp=33750223425&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33750223425&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.106.624320

DO - 10.1161/CIRCULATIONAHA.106.624320

M3 - Article

C2 - 17030685

AN - SCOPUS:33750223425

VL - 114

SP - 1703

EP - 1712

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 16

ER -