Abstract
Androgenic anabolic steroids (AAS) are commonly abused by young men. Male sex associates with earlier manifestation of common and rare cardiac conditions including atrial fibrillation and arrhythmogenic right ventricular cardiomyopathy (ARVC). Clinical data suggest an atrial involvement in ARVC. The disease is caused by desmosomal gene defects such as reduced plakoglobin expression. Analysis of clinical records from 146 ARVC patients identified male preponderance and increased prevalence of atrial arrhythmias in patients with definite ARVC. Definite patients displayed ECG changes suggesting atrial remodelling. To study mechanisms of atrial remodelling due to desmosomal vulnerability and AAS, young adult male mice, heterozygously deficient for plakoglobin (Plako+/-) and wildtype (WT) littermates, were chronically exposed to 5α-dihydrotestosterone (DHT) or placebo. DHT increased atrial expression of pro-hypertrophic, fibrotic and inflammatory transcripts. DHT caused atrial conduction slowing, decreased peak sodium current density, reduced action potential amplitude and lowered the peak depolarisation rate in Plako+/- but not WT atria. Super-resolution microscopy revealed a reduction in Nav1.5 clustering in Plako+/- atrial cardiomyocytes following DHT exposure. These data reveal that AAS combined with plakoglobin deficiency cause pathological atrial electrical remodelling in young male hearts. AAS abuse may increase the risk of atrial myopathy in males with desmosomal gene variants.
Competing Interest Statement
The authors have declared no direct conflict of interest in regards to the manuscript. L.F. has received institutional research grants from governmental and charity funding agencies and several biomedical companies. P.K. has received research support from several drug and device companies active in atrial fibrillation and has received honoraria from several such companies in the past. L.F. and P.K. are listed as inventors on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 015140571, Markers for Atrial Fibrillation WO 2016012783).
Footnotes
Conflicts of interest, The authors have declared no direct conflict of interest in regards to the manuscript.
L.F. has received institutional research grants from governmental and charity funding agencies and several biomedical companies.
P.K. has received research support from several drug and device companies active in atrial fibrillation and has received honoraria from several such companies in the past.
L.F. and P.K. are listed as inventors on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 015140571, Markers for Atrial Fibrillation WO 2016012783).