Chronic Treatment With An Androgen Receptor Antagonist Promotes Maladaptive Structural And Functional Cardiac Remodeling In Aging Male Mice

Testosterone levels decrease with age in men, while the risk for cardiovascular diseases (CVD) increases dramatically. Indeed, low circulating testosterone levels in men are associated with diseases such as heart failure. Testosterone exerts its effects via androgen receptors, which are even present in the heart. In addition, androgen receptor antagonists are used to treat prostate cancer in older men who may also have CVD. We investigated the effects of the androgen receptor antagonist flutamide on cardiac structure and function in aged mice. Twenty-month-old male C57BL/6 mice were treated with flutamide for 90 days (slow-release pellet implant; ~20mg/kg/day). In-vivo heart structure/function was assessed using echocardiography and then hearts were Langendorff-perfused to assess load-independent ventricular function ex-vivo . Androgen receptor blockade via flutamide caused maladaptive ventricular remodeling. In-vivo studies showed that flutamide-treated mouse hearts had smaller left ventricular inner diameters when compared to vehicle-treated mice ( e.g. , diastolic: 4.7 ± 0.1 vs. 4.4 ± 0.1 mm; p=0.01; n=8,7). Flutamide also caused left ventricular (LV) atrophy with thinner posterior walls (0.91 ± 0.07 vs. 0.74 ± 0.04 mm; p=0.05) and reduced LV mass when compared to vehicle controls (140 ± 12 vs. 105 ± 6 mg; p=0.03). Ex-vivo functional assessment showed a marked reduction in LV developed pressure in the flutamide-treated mice (111 ± 11 vs. 71 ± 3 mmHg; p<0.01). These mice also had significantly slower rates of LV pressure rise (+dP/dT=2219 ± 263 vs. 1406 ± 95 mmHg/s; p<0.01) as well as LV pressure decay (-dP/dT=-1975 ± 263 vs. -1327 ± 132 mmHg/s; p=0.04). This indicates that flutamide-treated mice had defects in both systolic and diastolic cardiac function. These results demonstrate that suppressing the effects of testosterone by blocking androgen receptors promotes maladaptive structural remodeling of the left ventricle and promotes systolic and diastolic dysfunction in hearts from aged male mice. This study suggests that chronic treatment with androgen receptor antagonists may induce cardiac dysfunction in older men, which has implications for individuals taking these medications for prostate cancer treatment.