Benjamin Strauss1, Malik Bisserier2, Emerson Obus2, Michael G Katz2, Anthony Fargnoli2, Marine Cacheux3, Joseph G Akar3, James P Hummel3, Lahouaria Hadri2, Yassine Sassi4, Fadi G Akar5. 1. Electro-Biology and Arrhythmia Therapeutics Laboratory, Cardiovascular Research Center, Yale University, New Haven, Connecticut; Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York. 2. Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York. 3. Electro-Biology and Arrhythmia Therapeutics Laboratory, Cardiovascular Research Center, Yale University, New Haven, Connecticut. 4. Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York; Center for Vascular and Heart Research, Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, Virginia; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia. 5. Electro-Biology and Arrhythmia Therapeutics Laboratory, Cardiovascular Research Center, Yale University, New Haven, Connecticut. Electronic address: fadi.akar@yale.edu.
Abstract
BACKGROUND: Electrophysiological (EP) properties have been studied mainly in the monocrotaline model of pulmonary arterial hypertension (PAH). Findings are confounded by major extrapulmonary toxicities, which preclude the ability to draw definitive conclusions regarding the role of PAH per se in EP remodeling. OBJECTIVE: The purpose of this study was to investigate the EP substrate and arrhythmic vulnerability of a new model of PAH that avoids extracardiopulmonary toxicities. METHODS: Sprague-Dawley rats underwent left pneumonectomy (Pn) followed by injection of the vascular endothelial growth factor inhibitor Sugen-5416 (Su/Pn). Five weeks later, cardiac magnetic resonance imaging was performed in vivo, optical action potential (AP) mapping ex vivo, and molecular analyses in vitro. RESULTS: Su/Pn rats exhibited right ventricular (RV) hypertrophy and were highly prone to pacing-induced ventricular tachycardia/fibrillation (VT/VF). Underlying this susceptibility was disproportionate RV-sided prolongation of AP duration, which promoted formation of right-sided AP alternans at physiological rates. While propagation was impaired at all rates in Su/Pn rats, the extent of conduction slowing was most severe immediately before the emergence of interventricular lines of block and onset of VT/VF. Measurement of the cardiac wavelength revealed a decrease in Su/Pn relative to control. Nav1.5 and total connexin 43 expression was not altered, while connexin 43 phosphorylation was decreased in PAH. Col1a1 and Col3a1 transcripts were upregulated coinciding with myocardial fibrosis. Once generated, VT/VF was sustained by multiple reentrant circuits with a lower frequency of RV activation due to wavebreak formation. CONCLUSION: In this pure model of PAH, we document RV-predominant remodeling that promotes multiwavelet reentry underlying VT. The Su/Pn model represents a severe form of PAH that allows the study of EP properties without the confounding influence of extrapulmonary toxicity.
BACKGROUND: Electrophysiological (EP) properties have been studied mainly in the monocrotaline model of pulmonary arterial hypertension (PAH). Findings are confounded by major extrapulmonary toxicities, which preclude the ability to draw definitive conclusions regarding the role of PAH per se in EP remodeling. OBJECTIVE: The purpose of this study was to investigate the EP substrate and arrhythmic vulnerability of a new model of PAH that avoids extracardiopulmonary toxicities. METHODS: Sprague-Dawley rats underwent left pneumonectomy (Pn) followed by injection of the vascular endothelial growth factor inhibitor Sugen-5416 (Su/Pn). Five weeks later, cardiac magnetic resonance imaging was performed in vivo, optical action potential (AP) mapping ex vivo, and molecular analyses in vitro. RESULTS: Su/Pn rats exhibited right ventricular (RV) hypertrophy and were highly prone to pacing-induced ventricular tachycardia/fibrillation (VT/VF). Underlying this susceptibility was disproportionate RV-sided prolongation of AP duration, which promoted formation of right-sided AP alternans at physiological rates. While propagation was impaired at all rates in Su/Pn rats, the extent of conduction slowing was most severe immediately before the emergence of interventricular lines of block and onset of VT/VF. Measurement of the cardiac wavelength revealed a decrease in Su/Pn relative to control. Nav1.5 and total connexin 43 expression was not altered, while connexin 43 phosphorylation was decreased in PAH. Col1a1 and Col3a1 transcripts were upregulated coinciding with myocardial fibrosis. Once generated, VT/VF was sustained by multiple reentrant circuits with a lower frequency of RV activation due to wavebreak formation. CONCLUSION: In this pure model of PAH, we document RV-predominant remodeling that promotes multiwavelet reentry underlying VT. The Su/Pn model represents a severe form of PAH that allows the study of EP properties without the confounding influence of extrapulmonary toxicity.
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