Reduced plakoglobin increases the risk of sodium current defects and atrial conduction abnormalities in response to androgenic anabolic steroid abuse

Sommerfeld, LC, Holmes, AP, Yu, TY, O'Shea, C, Kavanagh, DM, Pike, JM, Wright, T, Syeda, F, Aljehani, A, Kew, T, Cardoso, VR, Kabir, SN, Hepburn, C, Menon, PR, Broadway‐Stringer, S, O'Reilly, M, Witten, A, Fortmueller, L, Lutz, S, Kulle, A, Gkoutos, GV, Pavlovic, D, Arlt, W, Lavery, GG ORCID: https://orcid.org/0000-0001-5794-748X, Steeds, R, Gehmlich, K, Stoll, M, Kirchhof, P and Fabritz, L, 2024. Reduced plakoglobin increases the risk of sodium current defects and atrial conduction abnormalities in response to androgenic anabolic steroid abuse. The Journal of Physiology, 602 (18), pp. 4409-4436. ISSN 0022-3751

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Abstract

Androgenic anabolic steroids (AAS) are commonly abused by young men. Male sex and increased AAS levels are associated with earlier and more severe manifestation of common cardiac conditions, such as atrial fibrillation, and rare ones, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Clinical observations suggest a potential atrial involvement in ARVC. Arrhythmogenic right ventricular cardiomyopathy is caused by desmosomal gene defects, including reduced plakoglobin expression. Here, we analysed clinical records from 146 ARVC patients to identify that ARVC is more common in males than females. Patients with ARVC also had an increased incidence of atrial arrhythmias and P wave changes. To study desmosomal vulnerability and the effects of AAS on the atria, young adult male mice, heterozygously deficient for plakoglobin (Plako+/−), and wild type (WT) littermates were chronically exposed to 5α-dihydrotestosterone (DHT) or placebo. The DHT increased atrial expression of pro-hypertrophic, fibrotic and inflammatory transcripts. In mice with reduced plakoglobin, DHT exaggerated P wave abnormalities, atrial conduction slowing, sodium current depletion, action potential amplitude reduction and the fall in action potential depolarization rate. Super-resolution microscopy revealed a decrease in NaV1.5 membrane clustering in Plako+/− atrial cardiomyocytes after DHT exposure. In summary, AAS combined with plakoglobin deficiency cause pathological atrial electrical remodelling in young male hearts. Male sex is likely to increase the risk of atrial arrhythmia, particularly in those with desmosomal gene variants. This risk is likely to be exaggerated further by AAS use.

Item Type:	Journal article
Publication Title:	The Journal of Physiology
Creators:	Sommerfeld, L.C., Holmes, A.P., Yu, T.Y., O'Shea, C., Kavanagh, D.M., Pike, J.M., Wright, T., Syeda, F., Aljehani, A., Kew, T., Cardoso, V.R., Kabir, S.N., Hepburn, C., Menon, P.R., Broadway‐Stringer, S., O'Reilly, M., Witten, A., Fortmueller, L., Lutz, S., Kulle, A., Gkoutos, G.V., Pavlovic, D., Arlt, W., Lavery, G.G., Steeds, R., Gehmlich, K., Stoll, M., Kirchhof, P. and Fabritz, L.
Publisher:	Wiley
Date:	15 September 2024
Volume:	602
Number:	18
ISSN:	0022-3751
Identifiers:	Number Type 10.1113/jp284597 DOI 2554430 Other
Rights:	© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Borcherds
Date Added:	09 Jan 2026 11:26
Last Modified:	09 Jan 2026 11:26
URI:	https://irep.ntu.ac.uk/id/eprint/55003

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