Background
Electrophysiological (EP) properties have been studied mainly in the monocrotaline (MCT) model of pulmonary arterial hypertension (PAH). Findings from these studies however are confounded by major extra-pulmonary toxicities, including liver failure and direct myocardial damage. This has precluded the ability to draw definitive conclusions regarding the role of PAH per se in EP remodeling.
Objective
To investigate the EP substrate in a new model of PAH that avoids extra-cardiopulmonary toxicities.
Methods
Sprague Dawley rats underwent surgical left pneumonectomy (Pn) followed by injection of the VEGF inhibitor Sugen 5416 (Su/Pn). 5 wks later, hemodynamic measurements and cardiac MRI were performed in vivo, optical action potential (AP) mapping ex vivo and molecular analyses in vitro. The control (CTRL) group consisted of age matched rats.
Results
Su/Pn rats exhibited substantial RV hypertrophy and were prone to pacing induced VT. Underlying this differential susceptibility was disproportionate RV sided prolongation of AP duration in Su/Pn hearts. This, in turn, promoted the formation of right-sided AP alternans at physiological rates in Su/Pn but not CTRL. Correspondingly, key K channel transcripts were downregulated in the RV of Su/Pn rats. While propagation was impaired at all rates in Su/Pn, the extent of conduction slowing was most severe immediately prior to the emergence of inter-ventricular lines of conduction block and onset of sustained VT. Measurement of the cardiac wavelength at elevated rates revealed a decrease in Su/Pn relative to CTRL. Nav1.5 and total Cx43 expression were not altered while Cx43 phosphorylation was markedly decreased in PAH. Col1a1 and Col3a1 transcripts were upregulated coinciding with myocardial fibrosis. Once generated, VT was sustained by multiple reentrant circuits likely facilitated by the short wavelengths with lower frequency of activation in RV corresponding to wave break formation in that chamber.
Conclusion
In this pure model of PAH, we document RV-predominant EP remodeling that facilitates the initiation of multi-wavelet 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 extra-pulmonary toxicity.
Article info
Identification
Copyright
© 2021 Published by Elsevier Inc.
