Elsevier

Heart Rhythm

Volume 7, Issue 10, October 2010, Pages 1438-1445
Heart Rhythm

Focus issue: Sudden cardiac arrest
Experimental
Pirfenidone mitigates left ventricular fibrosis and dysfunction after myocardial infarction and reduces arrhythmias

https://doi.org/10.1016/j.hrthm.2010.04.030Get rights and content

Background

Post–myocardial infarction (MI) complications include ventricular tachycardia (VT). Excessive non-MI fibrosis, involving the infarct border zone (IBZ) and beyond, is an important substrate for VT vulnerability.

Objective

This study assessed whether the antifibrotic agent pirfenidone can mitigate fibrosis in remodeling and determined its effects on myocardial function and VT susceptibility in a rodent MI model.

Methods

We studied 2 groups of rats undergoing MI 1 week prior to treatment: a control group (n = 15) treated with placebo and a pirfenidone group (n = 15). We performed serial echocardiograms, and after 4 weeks of treatment, we conducted electrophysiological and optical mapping studies as well as histology.

Results

There was less decline in left ventricular (LV) ejection fraction for pirfenidone-treated rats, 8.6% versus 24.3% in controls (P <0.01). Pirfenidone rats also had lower rates of VT inducibility, 28.6% versus 73.3% in control rats (P <0.05). Furthermore, pirfenidone-treated rats had faster conduction velocities in their IBZs compared with controls, at all pacing cycle lengths (P <0.05). Rats treated with pirfenidone also had smaller infarct dense scar (8.9% of LV myocardium vs. 15.7% in controls, P <0.014), less total LV fibrosis (15% vs. 30% in controls, P <0.003), and less nonscar fibrosis (6.6% vs. 12.6% in controls, P <0.006).

Conclusion

Pirfenidone decreased total and nonscar fibrosis in a rat MI model, which correlated with decreased infarct scar, improved LV function, and decreased VT susceptibility. Directly targeting post-MI fibrotic substrates may have a role in limiting infarct-dense scar, improving LV function, and reducing VT vulnerability.

Introduction

Despite advances in treating acute coronary syndromes, significant morbidity and mortality remain after a myocardial infarction (MI), including ventricular arrhythmias. Abnormal conduction in the infarct border zone (IBZ) is important in the pathogenesis of post-MI arrhythmias.1 These abnormalities are due to remodeling in tissue architecture. An MI can be considered a healing wound, characterized by an initial inflammatory response, and followed by fibrosis development, thus minimizing infarct expansion and cardiac perforation.2 However, ongoing and excessive fibrosis contributes to adverse cardiac remodeling. Fibrosis causes nonuniform anisotropic conduction that may lead to re-entry circuits and wave breaks predisposing to arrhythmogenesis.3, 4

Fibrogenesis consists of redundant pathways and feedback loops, with transforming growth factor β1 (TGFβ1) signaling pathway being integral.5 Pirfenidone is an oral antifibrotic agent that significantly diminishes and possibly reverses collagen formation by affecting TGFβ1-mediated fibrosis.6 We therefore hypothesized that attenuation of post-MI fibrosis by pirfenidone will ameliorate arrhythmogenesis. To address this hypothesis, we studied ventricular tachycardia (VT) inducibility in an ischemia-reperfusion rat MI model after pirfenidone treatment. Furthermore, we assessed ventricular function, electrophysiological properties, and extent of fibrosis.

Section snippets

Animal model

This study was approved and monitored by the Laboratory Animal Resource Center at University of California at San Francisco, and conformed to Guide for the Care and Use of Laboratory Animals by the U.S. National Institutes of Health (Publication No. 85-23, revised 1996).

After baseline echocardiography, 30 male Sprague-Dawley rats, ages 6 to 10 weeks, underwent an ischemia-reperfusion MI, as previously described.7 After a left thoracotomy and pericardiotomy were performed, a 7-0 Ticron suture

Results

All animals in control and pirfenidone groups survived after randomization at 1 week post-MI. There were no electrocardiographic differences or significant differences in body weights noted between groups (pirfenidone 407 ± 34 g vs. controls 398 ± 50 g, P = 0.66).

Discussion

In this study, we assessed the role of fibrosis attenuation in the post-MI setting. In our rodent ischemia-reperfusion model, significant remodeling occurred over the course of 5 weeks post-MI. Pirfenidone decreased both total and nonscar fibrosis, which correlated with decreased infarct-dense scar as well as with improved LV function. Furthermore, these effects were associated with decreased VT susceptibility as well as with an improvement in electrophysiological parameters.

Conclusion

In this study, we showed that an antifibrotic agent had beneficial effects on post-MI LV function, infarct scar, total and non-MI fibrosis (including within the IBZ), electrophysiology of the IBZ, and VT inducibility. Further studies are needed to determine the optimal timing and duration of such therapy to maximize effect. In conclusion, pharmacologic therapy of post-MI fibrotic substrates may have a role in limiting infarct dense scar, improving LV function, and reducing post-MI arrhythmias.

Acknowledgments

The authors thank Karl Kossen for helpful comments.

References (31)

  • Y. Zhang et al.

    Validation of the wall motion score and myocardial performance indexes as novel techniques to assess cardiac function in mice after myocardial infarction

    Am J Physiol Heart Circ Physiol

    (2007)
  • G. Salama et al.

    Properties of new, long-wavelength, voltage-sensitive dyes in the heart

    J Membr Biol

    (2005)
  • W.R. Mills et al.

    Optical mapping of late myocardial infarction in rats

    Am J Physiol Heart Circ Physiol

    (2006)
  • B.R. Choi et al.

    Cytosolic Ca2+ triggers early afterdepolarizations and torsade de pointes in rabbit hearts with type 2 long QT syndrome

    J Physiol

    (2002)
  • G. Salama et al.

    Subthreshold stimulation of Purkinje fibers interrupts ventricular tachycardia in intact heartsExperimental study with voltage-sensitive dyes and imaging techniques

    Circ Res

    (1994)
  • Cited by (99)

    View all citing articles on Scopus

    Drs. Nguyen and Ding contributed equally to this work. Supported by National Institutes of HealthRO1-HL072854 (Dr. Olgin); National Institutes of HealthF32HL090260 (Dr. Nguyen); and the Stephen and Nancy Grand Fund (Dr. Olgin). Dr. Olgin has received research funds from InterMune for separate research not reported here.

    View full text