Am J Cardiovasc Dis 2011;1(2):101-109
Review Article
Targeting cardiac fibrosis: a new frontier in antiarrhythmic therapy?
Hrayr S. Karagueuzian
Translational Arrhythmia Research Section, UCLA Cardiovascular Research Laboratory and the Division of Cardiology,
Departments of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Received May 12, 2011; accepted May 29, 2011; Epub June 12, 2011; published August 15, 2011
Abstract: Increased cardiac fibrosis is shown to be associated with cardiac conduction block and reentry in
isolated-perfused animal and diseased human cardiac tissues as well as in isolated Langendorff-perfused explanted
human hearts with dilated cardiac myopathy. While alterations of cardiac conduction and the resulting reentrant wavefront
of excitation are uniformly accepted arrhythmic consequences of increased cardiac fibrosis, recent experimental findings in
isolated whole heart studies, indicate that fibrosis may also importantly modulate the formation of cardiac afterpotentials
notably early afterdepolarizations (EADs) that lead to triggered activity causing atrial fibrillation (AF) and ventricular
fibrillation (VF). These findings extend previous cardiac monolayer studies that showed myofibroblast coupling to
cardiomyocytes through gap junction formation imparts enhanced automaticity to cardiomyocytes when coupled to a finite
(critical) number of myofibroblasts. Taken together these findings indicate that increased cardiac fibrosis promotes
arrhythmias not only by the mechanism of reentry but also by the mechanism of triggered activity and enhanced
automaticity potentially making cardiac fibrosis a highly effective antiarrhythmic target. In this brief review we delineate
step-by-step how the interaction of aged fibrotic ventricles with oxidative stress leads to the emergence of early
afterdepolarizations (EADs), triggered activity and VF. We emphasize the importance of fibrosis as non-fibrotic hearts when
stressed similarly or at even higher stress levels do no manifest any arrhythmic events. Specifically, we describe the
dynamic scenario starting from cellular EADs that evolves to rapid focal ventricular tachycardia (VT) caused by triggered
activity which then degenerates to VF. In the second part we point out briefly on recent experimental and the potential of
drug-induced prevention and/or reduction of ventricular fibrosis as an antiarrhythmic strategy in humans. (AJCD1105004).
Keywords: Atherosclerosis, vascular inflammation, S100 proteins, S100A12, Receptor for advanced glycation endproducts
(RAGE), mouse models of human disease
Full Text PDF
Address all correspondence to:
Hrayr S. Karagueuzian, PhD, FHRS, FACC
Professor of Medicine & Director
Translational Arrhythmia Research Section
Cardiovascular Research Laboratory
David Geffen School of Medicine at UCLA
675 Charles E. Young Dr. South
MRL 1630, Mail Code: 176022
Los Angeles, CA 90095, USA.
Tel: 310-825-9360
Fax: 310-206-5777
E-mail: hkaragueuzian@mednet.ucla.edu (email)
Review Article
Targeting cardiac fibrosis: a new frontier in antiarrhythmic therapy?
Hrayr S. Karagueuzian
Translational Arrhythmia Research Section, UCLA Cardiovascular Research Laboratory and the Division of Cardiology,
Departments of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Received May 12, 2011; accepted May 29, 2011; Epub June 12, 2011; published August 15, 2011
Abstract: Increased cardiac fibrosis is shown to be associated with cardiac conduction block and reentry in
isolated-perfused animal and diseased human cardiac tissues as well as in isolated Langendorff-perfused explanted
human hearts with dilated cardiac myopathy. While alterations of cardiac conduction and the resulting reentrant wavefront
of excitation are uniformly accepted arrhythmic consequences of increased cardiac fibrosis, recent experimental findings in
isolated whole heart studies, indicate that fibrosis may also importantly modulate the formation of cardiac afterpotentials
notably early afterdepolarizations (EADs) that lead to triggered activity causing atrial fibrillation (AF) and ventricular
fibrillation (VF). These findings extend previous cardiac monolayer studies that showed myofibroblast coupling to
cardiomyocytes through gap junction formation imparts enhanced automaticity to cardiomyocytes when coupled to a finite
(critical) number of myofibroblasts. Taken together these findings indicate that increased cardiac fibrosis promotes
arrhythmias not only by the mechanism of reentry but also by the mechanism of triggered activity and enhanced
automaticity potentially making cardiac fibrosis a highly effective antiarrhythmic target. In this brief review we delineate
step-by-step how the interaction of aged fibrotic ventricles with oxidative stress leads to the emergence of early
afterdepolarizations (EADs), triggered activity and VF. We emphasize the importance of fibrosis as non-fibrotic hearts when
stressed similarly or at even higher stress levels do no manifest any arrhythmic events. Specifically, we describe the
dynamic scenario starting from cellular EADs that evolves to rapid focal ventricular tachycardia (VT) caused by triggered
activity which then degenerates to VF. In the second part we point out briefly on recent experimental and the potential of
drug-induced prevention and/or reduction of ventricular fibrosis as an antiarrhythmic strategy in humans. (AJCD1105004).
Keywords: Atherosclerosis, vascular inflammation, S100 proteins, S100A12, Receptor for advanced glycation endproducts
(RAGE), mouse models of human disease
Full Text PDF
Address all correspondence to:
Hrayr S. Karagueuzian, PhD, FHRS, FACC
Professor of Medicine & Director
Translational Arrhythmia Research Section
Cardiovascular Research Laboratory
David Geffen School of Medicine at UCLA
675 Charles E. Young Dr. South
MRL 1630, Mail Code: 176022
Los Angeles, CA 90095, USA.
Tel: 310-825-9360
Fax: 310-206-5777
E-mail: hkaragueuzian@mednet.ucla.edu (email)
 |  |  |  |  |  |  |
| AJCD Copyright © 2011-present, All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711, USA |