Focus issue: Sudden cardiac arrestExperimentalPirfenidone mitigates left ventricular fibrosis and dysfunction after myocardial infarction and reduces arrhythmias
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)
- et al.
Global remodeling of the ventricular interstitium in idiopathic myocardial fibrosis and sudden cardiac death
Heart Rhythm
(2004) - et al.
Pirfenidone inhibits TGF-beta expression in malignant glioma cells
Biochem Biophys Res Commun
(2007) - et al.
Fibrosis: a living tissue and the infarcted heart
J Am Coll Cardiol
(2008) - et al.
Programmed myocyte cell death affects the viable myocardium after infarction in rats
Exp Cell Res
(1996) - et al.
Three-dimensional anatomic structure as substrate for ventricular tachycardia/ventricular fibrillation
Heart Rhythm
(2005) - et al.
Ventricular tachycardia in the infarcted, Langendorff-perfused human heart: role of the arrangement of surviving cardiac fibers
J Am Coll Cardiol
(1990) - et al.
Post-infarct remodeling: contribution of wound healing and inflammation
Cardiovasc Res
(2009) - et al.
Continuous and discontinuous propagation in heart muscle
J Cardiovasc Electrophysiol
(2006) TGFbeta, cardiac fibroblasts, and the fibrotic response
Cardiovasc Res
(2007)- et al.
A rodent model of myocardial infarction for testing the efficacy of cells and polymers for myocardial reconstruction
Nat Protoc
(2006)
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
Properties of new, long-wavelength, voltage-sensitive dyes in the heart
J Membr Biol
Optical mapping of late myocardial infarction in rats
Am J Physiol Heart Circ Physiol
Cytosolic Ca2+ triggers early afterdepolarizations and torsade de pointes in rabbit hearts with type 2 long QT syndrome
J Physiol
Subthreshold stimulation of Purkinje fibers interrupts ventricular tachycardia in intact heartsExperimental study with voltage-sensitive dyes and imaging techniques
Circ Res
Cited by (0)
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.