Carolin Zwadlo1, Elisa Schmidtmann1, Malgorzata Szaroszyk1, Badder Kattih1, Natali Froese1, Hebke Hinz1, Jan Dieter Schmitto1, Julian Widder1, Sandor Batkai1, Heike Bähre1, Volkhard Kaever1, Thomas Thum1, Johann Bauersachs1, Joerg Heineke2. 1. From Medizinische Hochschule Hannover, Klinik für Kardiologie und Angiologie, Hanover, Germany (C.Z., E.S., M.S., B.K., N.F., H.H., J.W., J.B., J.H.); Klinik für Herz-, Thorax-, Transplantations- und Gefäßchirurgie, Hanover, Germany (J.D.S.); Institut für Molekulare und Translationale Therapiestrategien (IMTTS), Hannover, Germany (S.B., T.T.); National Heart and Lung Institute, Imperial College, London, United Kingdom (T.T.); and Medizinische Hochschule Hannover, Zentrale Forschungseinrichtung Metabolomics, Institut für Pharmakologie, Hannover, Germany (H.B., V.K.). 2. From Medizinische Hochschule Hannover, Klinik für Kardiologie und Angiologie, Hanover, Germany (C.Z., E.S., M.S., B.K., N.F., H.H., J.W., J.B., J.H.); Klinik für Herz-, Thorax-, Transplantations- und Gefäßchirurgie, Hanover, Germany (J.D.S.); Institut für Molekulare und Translationale Therapiestrategien (IMTTS), Hannover, Germany (S.B., T.T.); National Heart and Lung Institute, Imperial College, London, United Kingdom (T.T.); and Medizinische Hochschule Hannover, Zentrale Forschungseinrichtung Metabolomics, Institut für Pharmakologie, Hannover, Germany (H.B., V.K.). Heineke.Joerg@Mh-Hannover.de.
Abstract
BACKGROUND: In comparison with men, women have a better prognosis when experiencing aortic valve stenosis, hypertrophic cardiomyopathy, or heart failure. Recent data suggest that androgens like testosterone or the more potent dihydrotestosterone contribute to the development of cardiac hypertrophy and failure. Therefore, we analyzed whether antiandrogenic therapy with finasteride, which inhibits the generation of dihydrotestosterone by the enzyme 5-α-reductase, improves pathological ventricular remodeling and heart failure. METHODS AND RESULTS: We found a strongly induced expression of all 3 isoforms of the 5-α-reductase (Srd5a1 to Srd5a3) in human and mouse hearts with pathological hypertrophy, which was associated with increased myocardial accumulation of dihydrotestosterone. Starting 1 week after the induction of pressure overload by transaortic constriction, mice were treated with finasteride for 2 weeks. Cardiac function, hypertrophy, dilation, and fibrosis were markedly improved in response to finasteride treatment in not only male, but also in female mice. In addition, finasteride also very effectively improved cardiac function and mortality after long-term pressure overload and prevented disease progression in cardiomyopathic mice with myocardial Gαq overexpression. Mechanistically, finasteride, by decreasing dihydrotestosterone, potently inhibited hypertrophy and Akt-dependent prohypertrophic signaling in isolated cardiac myocytes, whereas the introduction of constitutively active Akt blunted these effects of finasteride. CONCLUSIONS: Finasteride, which is currently used in patients to treat prostate disease, potently reverses pathological cardiac hypertrophy and dysfunction in mice and might be a therapeutic option for heart failure.
BACKGROUND: In comparison with men, women have a better prognosis when experiencing aortic valve stenosis, hypertrophic cardiomyopathy, or heart failure. Recent data suggest that androgens like testosterone or the more potent dihydrotestosterone contribute to the development of cardiac hypertrophy and failure. Therefore, we analyzed whether antiandrogenic therapy with finasteride, which inhibits the generation of dihydrotestosterone by the enzyme 5-α-reductase, improves pathological ventricular remodeling and heart failure. METHODS AND RESULTS: We found a strongly induced expression of all 3 isoforms of the 5-α-reductase (Srd5a1 to Srd5a3) in human and mouse hearts with pathological hypertrophy, which was associated with increased myocardial accumulation of dihydrotestosterone. Starting 1 week after the induction of pressure overload by transaortic constriction, mice were treated with finasteride for 2 weeks. Cardiac function, hypertrophy, dilation, and fibrosis were markedly improved in response to finasteride treatment in not only male, but also in female mice. In addition, finasteride also very effectively improved cardiac function and mortality after long-term pressure overload and prevented disease progression in cardiomyopathicmice with myocardial Gαq overexpression. Mechanistically, finasteride, by decreasing dihydrotestosterone, potently inhibited hypertrophy and Akt-dependent prohypertrophic signaling in isolated cardiac myocytes, whereas the introduction of constitutively active Akt blunted these effects of finasteride. CONCLUSIONS:Finasteride, which is currently used in patients to treat prostate disease, potently reverses pathological cardiac hypertrophy and dysfunction in mice and might be a therapeutic option for heart failure.
Authors: Anish N Bhuva; Thomas A Treibel; Antonio De Marvao; Carlo Biffi; Timothy J W Dawes; Georgia Doumou; Wenjia Bai; Kush Patel; Redha Boubertakh; Daniel Rueckert; Declan P O'Regan; Alun D Hughes; James C Moon; Charlotte H Manisty Journal: Eur Heart J Cardiovasc Imaging Date: 2020-04-01 Impact factor: 6.875