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Right predominant electrical remodeling in a pure model of pulmonary hypertension promotes reentrant arrhythmias

Published:September 23, 2021DOI:https://doi.org/10.1016/j.hrthm.2021.09.021

      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.

      Keywords

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      References

        • Strauss B.
        • Sassi Y.
        • Bueno-Beti C.
        • et al.
        Intra-tracheal gene delivery of aerosolized SERCA2a to the lung suppresses ventricular arrhythmias in a model of pulmonary arterial hypertension.
        J Mol Cell Cardiol. 2019; 127: 20-30
        • Gomez-Arroyo J.G.
        • Farkas L.
        • Alhussaini A.A.
        • et al.
        The monocrotaline model of pulmonary hypertension in perspective.
        Am J Physiol Lung Cell Mol Physiol. 2012; 302: L363-L369
        • Kasahara Y.
        • Kiyatake K.
        • Tatsumi K.
        • et al.
        Bioactivation of monocrotaline by P-450 3A in rat liver.
        J Cardiovasc Pharmacol. 1997; 30: 124-129
        • Huxtable R.J.
        Activation and pulmonary toxicity of pyrrolizidine alkaloids.
        Pharmacol Ther. 1990; 47: 371-389
        • Happe C.M.
        • de Raaf M.A.
        • Rol N.
        • et al.
        Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats.
        Am J Physiol Lung Cell Mol Physiol. 2016; 310: L1088-L1097
        • Mendel D.B.
        • Schreck R.E.
        • West D.C.
        • et al.
        The angiogenesis inhibitor SU5416 has long-lasting effects on vascular endothelial growth factor receptor phosphorylation and function.
        Clin Cancer Res. 2000; 6: 4848-4858
        • Mezrich J.D.
        • Nguyen L.P.
        • Kennedy G.
        • et al.
        SU5416, a VEGF receptor inhibitor and ligand of the AHR, represents a new alternative for immunomodulation.
        PLoS One. 2012; 7e44547
        • Sakao S.
        • Tatsumi K.
        The effects of antiangiogenic compound SU5416 in a rat model of pulmonary arterial hypertension.
        Respiration. 2011; 81: 253-261
        • Van Hung T.
        • Emoto N.
        • Vignon-Zellweger N.
        • et al.
        Inhibition of vascular endothelial growth factor receptor under hypoxia causes severe, human-like pulmonary arterial hypertension in mice: potential roles of interleukin-6 and endothelin.
        Life Sci. 2014; 118: 313-328
        • Mizuno S.
        • Farkas L.
        • Al Husseini A.
        • et al.
        Severe pulmonary arterial hypertension induced by SU5416 and ovalbumin immunization.
        Am J Respir Cell Mol Biol. 2012; 47: 679-687
      1. Katz MG, Fargnoli AS, Gubara SM, et al. The left pneumonectomy combined with monocrotaline or Sugen as a model of pulmonary hypertension in rats. J Vis Exp 2019;(145):10.3791/59050.

        • Jin H.
        • Chemaly E.R.
        • Lee A.
        • et al.
        Mechanoelectrical remodeling and arrhythmias during progression of hypertrophy.
        FASEB J. 2010; 24: 451-463
        • Xie C.
        • Hu J.
        • Motloch L.J.
        • Karam B.S.
        • Akar F.G.
        The classically cardioprotective agent diazoxide elicits arrhythmias in type 2 diabetes mellitus.
        J Am Coll Cardiol. 2015; 66: 1144-1156
        • Akar F.G.
        • Spragg D.D.
        • Tunin R.S.
        • Kass D.A.
        • Tomaselli G.F.
        Mechanisms underlying conduction slowing and arrhythmogenesis in nonischemic dilated cardiomyopathy.
        Circ Res. 2004; 95: 717-725
        • Akar F.G.
        • Nass R.D.
        • Hahn S.
        • et al.
        Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure.
        Am J Physiol Heart Circ Physiol. 2007; 293: H1223-H1230
        • Cirulis M.M.
        • Ryan J.J.
        • Archer S.L.
        Pathophysiology, incidence, management, and consequences of cardiac arrhythmia in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.
        Pulm Circ. 2019; 9 (2045894019834890)
        • Rajdev A.
        • Garan H.
        • Biviano A.
        Arrhythmias in pulmonary arterial hypertension.
        Prog Cardiovasc Dis. 2012; 55: 180-186
        • Benoist D.
        • Stones R.
        • Drinkhill M.
        • Bernus O.
        • White E.
        Arrhythmogenic substrate in hearts of rats with monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy.
        Am J Physiol Heart Circ Physiol. 2011; 300: H2230-H2237
        • Benoist D.
        • Stones R.
        • Benson A.P.
        • et al.
        Systems approach to the study of stretch and arrhythmias in right ventricular failure induced in rats by monocrotaline.
        Prog Biophys Mol Biol. 2014; 115: 162-172
        • Benoist D.
        • Stones R.
        • Drinkhill M.J.
        • et al.
        Cardiac arrhythmia mechanisms in rats with heart failure induced by pulmonary hypertension.
        Am J Physiol Heart Circ Physiol. 2012; 302: H2381-H2395
        • Tanaka Y.
        • Takase B.
        • Yao T.
        • Ishihara M.
        Right ventricular electrical remodeling and arrhythmogenic substrate in rat pulmonary hypertension.
        Am J Respir Cell Mol Biol. 2013; 49: 426-436
        • Umar S.
        • Lee J.H.
        • de Lange E.
        • et al.
        Spontaneous ventricular fibrillation in right ventricular failure secondary to chronic pulmonary hypertension.
        Circ Arrhythm Electrophysiol. 2012; 5: 181-190
        • Akar F.G.
        • Rosenbaum D.S.
        Transmural electrophysiological heterogeneities underlying arrhythmogenesis in heart failure.
        Circ Res. 2003; 93: 638-645
        • Volders P.G.
        • Sipido K.R.
        • Vos M.A.
        • Kulcsar A.
        • Verduyn S.C.
        • Wellens H.J.
        Cellular basis of biventricular hypertrophy and arrhythmogenesis in dogs with chronic complete atrioventricular block and acquired torsade de pointes.
        Circulation. 1998; 98: 1136-1147
        • Lewicka E.
        • Danilowicz-Szymanowicz L.
        • Dabrowska-Kugacka A.
        • Zieba B.
        • Zagozdzon P.
        • Raczak G.
        Microvolt T-wave alternans profile in patients with pulmonary arterial hypertension.
        Int J Cardiol. 2014; 176: 1294-1296
        • Danilowicz-Szymanowicz L.
        • Lewicka E.
        • Dabrowska-Kugacka A.
        • et al.
        Microvolt T-wave alternans profiles in patients with pulmonary arterial hypertension compared to patients with left ventricular systolic dysfunction and a group of healthy volunteers.
        Anatol J Cardiol. 2016; 16: 825-830
        • Antigny F.
        • Mercier O.
        • Humbert M.
        • Sabourin J.
        Excitation-contraction coupling and relaxation alteration in right ventricular remodelling caused by pulmonary arterial hypertension.
        Arch Cardiovasc Dis. 2020; 113: 70-84