Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia: from a stem cell derived cardiomyocyte-based model to clinical biomarkers of disease outcome.
OBJECTIVE
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is characterized by fibrofatty infiltration of the myocardium and ventricular arrhythmias that may lead to sudden cardiac death. It has been observed that male patients develop the disease earlier and present with more severe phenotypes as compared to females. Thus, we hypothesized that serum levels of sex hormones may contribute to major arrhythmic cardiovascular events (MACE) in patients with ARVC/D.


RESULTS
The serum levels of five sex hormones, sex hormone-binding globulin, high sensitivity troponin T, pro-brain natriuretic peptide, cholesterol, triglycerides, insulin, and glucose were measured in 54 ARVC/D patients (72% male). Twenty-six patients (48%) experienced MACE. Total and free testosterone levels were significantly increased in males with MACE as compared to males with a favourable outcome, whereas estradiol was significantly lower in females with MACE as compared to females with a favourable outcome. Increased testosterone levels remained independently associated with MACE in males after adjusting for age, body mass index, Task Force criteria, ventricular function, and desmosomal mutation status. Furthermore, an induced pluripotent stem cell-derived ARVC/D cardiomyocyte model was used to investigate the effects of sex hormones. In this model, testosterone worsened and estradiol improved ARVC/D-related pathologies such as cardiomyocyte apoptosis and lipogenesis, strongly supporting our clinical findings.


CONCLUSIONS
Elevated serum testosterone levels in males and decreased estradiol levels in females are independently associated with MACE in ARVC/D, and directly influence disease pathology. Therefore, determining the levels of sex hormones may be useful for risk stratification and may open a new window for preventive interventions.
Department of Cardiology, University Heart Center Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.
Deniz
D
Akdis
Department of Cardiology, University Heart Center Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.
Ardan M
AM
Saguner
Development, Aging and Regeneration Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA.
Khooshbu
K
Shah
Development, Aging and Regeneration Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA.
Chuanyu
C
Wei
Department of Cardiology, Inselspital Bern, Freiburgstrasse 10, 3010 Bern, Switzerland.
Argelia
A
Medeiros-Domingo
Department of Clinical Chemistry, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.|Center for Integrative Human Physiology, University of Zurich, Winterthurerstr 190, 8057 Zurich, Switzerland.
Arnold
A
von Eckardstein
Department of Cardiology, University Heart Center Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.|Center for Integrative Human Physiology, University of Zurich, Winterthurerstr 190, 8057 Zurich, Switzerland.
Thomas F
TF
Lüscher
Department of Cardiology, University Heart Center Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.
Corinna
C
Brunckhorst
Development, Aging and Regeneration Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA.
H S Vincent
HSV
Chen
Department of Cardiology, University Heart Center Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.|Center for Integrative Human Physiology, University of Zurich, Winterthurerstr 190, 8057 Zurich, Switzerland.
Firat
F
Duru
D000328:Adult; D000704:Analysis of Variance; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000097:blood / Q000209:etiology*; D015415:Biomarkers / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000209:etiology; D003896:Desmosomes / Q000235:genetics; D004958:Estradiol / Q000378:metabolism; D015444:Exercise / Q000502:physiology; D005260:Female; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000502:physiology; D011379:Prognosis; D012727:Sex Characteristics; D013739:Testosterone / Q000378:metabolism
D015415:Biomarkers; D012739:Gonadal Steroid Hormones; D013739:Testosterone; D004958:Estradiol
Arrhythmic outcome ; Dysplasia ; Right ventricular cardiomyopathy ; Risk stratification; Sex hormones 