Abstract 175 Chronic deprivation and substitution of androgens modulates arrhythmogenicity and NaV1.5 expression in a SCN5A loss-of-function mouse model

Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5
Chronic deprivation and substitution of androgens modulates arrhythmogenicity and NaV1.5 expression in a SCN5A loss-of-function mouse model
M. Kruska¹, T. Fink², P. Yampolsky³, L. Fabritz⁴, P. Kirchhof⁵, D. Thomas³, H. A. Katus³, N. Frey³, M. Koenen⁶, P. Schweizer³
¹I. Medizinische Klinik, Universitätsklinikum Mannheim, Mannheim; ²Elektrophysiologie/ Rhythmologie, Herz- und Diabeteszentrum NRW, Bad Oeynhausen; ³Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg; ⁴College of Medical and Dental Science, Institute of Cardiovascular Sciences, Birmingham, UK; ⁵Klinik für Kardiologie, Universitäres Herz- und Gefäßzentrum Hamburg GmbH, Hamburg; ⁶Max-Planck-Institut für Medizinische Forschung, Heidelberg;
Background: The ionic and molecular mechanisms underlying sex differences in Brugada syndrome are poorly understood. We analysed the effects of in vivo chronic androgen deprivation and substitution on the arrhythmic and molecular phenotypes of a SCN5A-G1408R knock-in mouse model mimicking key features of the human phenotype regarding male predominance and susceptibility to ventricular arrhythmias. Methods and Results:The sodium channel blocker flecainide (10 mg/kg body weight) was administered toanesthetized heterozygous male and female mutant (MT) and wildtype (WT) mice. By flecainide challenge, 81% (25/31 animals)of male G1408R/+ and only 14% (2/14 animals) of their female littermates developed polymorphic ventricular tachycardias (VT).Patch-clamp electrophysiology in isolated cardiomyocytes revealed significantly decreased peak current density of MT animals but maintained biophysical properties of sodium current; with respect to gender male mutants exhibited significantly more reduced peak sodium current than female mutants. There were no particular differences in peak transient outward K+ current between G1408R/+ and WT myocytes of both genders, respectively. Corresponding to a reduced sodium current density, we found decreased Na_V1.5 expression in G1408R/+ animals of both sexes, with the lowest Na_V1.5 protein levels in male MT hearts. After four weeks of chronic treatment with the androgen receptor blocker flutamide by subcutaneously implanted osmotic pumps, male G1408R/+ animals showed decreased susceptibility to VT (12%, 1/8 animals) and Na_V1.5 expression comparable with those of WT males. Vice versa, arrhythmogenicity in terms of VT vulnerability was markedly exaggerated in female mutants after treatment with 5a-dihydrotestosterone (DHT) by subcutaneous pelletengraftment over 10 weeks (100%, 11/11). Chronic DHT treatment of G1408R/+ female mice resulted in attenuated sodium channel expression and decreased sodium current densities in ventricular cardiomyocytes. Conclusions: We show that chronic androgen substitution/deprivation significantly determines arrhythmogenicity in a mouse model of Brugada syndrome. Furthermore our data indicate that Na_V1.5 surface expression is modulated by the hormonal situation, which may be an important mechanism underlying sex-dependent arrhythmogenic phenotype.
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