Abstract 1503 Pro-arrhythmic alterations, larger action potentials, and increased fibrosis in right ventricular myocardium are associated with clinically severe acyanotic tetralogy of Fallot

Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w
Pro-arrhythmic alterations, larger action potentials, and increased fibrosis in right ventricular myocardium are associated with clinically severe acyanotic tetralogy of Fallot
H. E. Fürniss¹, E. M. Wülfers², P. Iaconianni³, U. Ravens³, J. Kroll⁴, B. Stiller¹, P. Kohl³, E. Rog-Zielinska³, R. Peyronnet³
¹Klinik für angeborene Herzfehler und Pädiatrische Kardiologie, Universitäts-Herzzentrum Freiburg - Bad Krozingen, Freiburg im Breisgau; ²Department of Physics and Astronomy, Ghent University, Ghent, BE; ³Institut für Experimentelle Kardiovaskuläre Medizin, Universitäts-Herzzentrum Freiburg - Bad Krozingen, Freiburg im Breisgau; ⁴Klinik für Herz- und Gefäßchirurgie, Universitäts-Herzzentrum Freiburg - Bad Krozingen, Freiburg im Breisgau;
Introduction: Recent data have demonstrated that in tetralogy of Fallot (TOF) patients arrhythmias may originate from right ventricular regions remote from surgical scars. In this study, we aimed to (i) investigate action potential remodelling and arrhythmia susceptibility in right ventricular myocardium of unrepaired and repaired TOF patients, (ii) identify links to clinical phenotype and structural myocardial alteration in the form of fibrosis, and (iii) compare the findings with those for patients with atrial septal defect (ASD), a less severe congenital heart defect. Methods: Intracellular action potentials were recorded ex vivo in right ventricular outflow tract samples from 22 TOF and three ASD patients. Arrhythmias were provoked by superfusion with solutions containing reduced potassium and barium chloride, or isoprenaline. Subsequently, myocardial fibrosis was quantified histologically based on picrosirius red staining, and correlations between action potential shape (resting membrane potential, maximum upstroke velocity, action potential amplitude, action potential duration [APD] at 20%, 50%, and 90% repolarisation, area under the curve [AUC] at 90% repolarisation), tissue arrhythmia propensities, fibrosis, and clinical phenotype were examined. Results: Electrophysiological pathologies (arrhythmias, APD alternans, impaired APD shortening with increased stimulation frequency) were observed in the majority of TOF samples, while being absent in ASD tissue but for the occurrence of one arrhythmia. These electrophysiological pathologies, as well as increased fibrosis and more severe clinical acyanotic disease were associated with longer APD and/or larger AUC, while pre-operative cyanosis was correlated with shorter APD and smaller amplitude. Repaired TOF status and tissue arrhythmias were associated with greater extent of fibrosis in itself. Conclusions: Arrhythmic myocardial activity at a very young age and differential action potential remodelling dependent on clinical disease presentation and myocardial fibrosis may point towards underlying mechanisms inherent to the disease and/or related to the inter-individually different haemodynamic overload situations. Further research into links between structural and electrical myocardial remodelling and with clinical data on TOF severity may help to identify predictive diagnostic indicators for patients at risk of arrhythmogenesis.
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