Antiandrogenic Therapy With Finasteride Attenuates Cardiac Hypertrophy and Left Ventricular Dysfunction

Abstract

A pproximately 5 million Americans have chronic heart failure. 1 The most common causes for the development of chronic heart failure are chronic arterial hypertension, myocardial hypertrophy, and previous myocardial infarction. 1 The progression of heart failure is driven by pathological ventricular remodeling processes, which mainly involve cardiomyocyte hypertrophy, myocardial fibrosis, and profound changes in gene expression that together lead to left ventricular dilation and systolic, and diastolic dysfunction over time. [2][3][4] Despite recent therapeutic advances, the mortality of chronic heart failure remains high, and, a fact that is somewhat neglected, strikingly different between women and men. Women with heart failure have a lower mortality than men and also a better prognosis when experiencing hypertension, aortic valve stenosis, or hypertrophic cardiomyopathy.1,5 Sex hormones might account for these differences, and, indeed, the expression of androgen, and estrogen receptors was found in male and female hearts, implying that estrogen and androgens could directly act on the myocardium. 6,7 Although, in general, estrogen has been deemed cardioprotective, large randomized and controlled studies have failed to demonstrate the beneficial effects of estrogen therapy in postmenopausal women. 8,9 As a consequence, it is now proposed that the rise in cardiovascular mortality in women after the onset of menopause might be caused by an increased ovarian production of testosterone. 10 Clinical Perspective on p 1081Testosterone and its highly active metabolite dihydrotestosterone (DHT) operate by binding to the androgen receptor, 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 p...

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“…Support for this possibility is provided by previous studies in which antiandrogenic treatment attenuated cardiac hypertrophy. 110 , 111 …”

C1q-TNF-Related Protein-9 Promotes Cardiac Hypertrophy and Failure

“…Constriction of the transverse aortic arch (TAC) was performed in 8-to 10-week-old gene-deleted or WT mice around a 25-gauge needle, as previously described. 19,20 For the mice after adeno-associated virus serotype 9 (AAV9) injection, TAC was conducted using a 26-gauge needle. All procedures involving the use and care of animals were performed according to the Guide for the Care and Use of Laboratory Animals published by the National Research Council (NIH Publication No.…”

Injection of testosterone may be safer and more effective than transdermal administration for combating loss of muscle and bone in older men

“…In observational studies, Shores et al have shown that shown that high DHT is associated with increased cardiovascular events (66) and increased incident ischemic stroke (65). Interestingly, Zwadlo et al (96) have shown that cardiac expression of 5␣-reductase is markedly increased in humans with heart failure and in a mouse aortic constriction model of heart failure. In a mouse model, treatment with finasteride attenuated cardiac hypertrophy and improved left ventricular function.…”