Treatment with a selective androgen receptor modulator (RAD140) is linked to better cardiac function, with...

Low testosterone levels are associated with impaired cardiac function and elevated circulating inflammatory markers, which are mechanistically related. Selective androgen receptor (AR) modulators (SARMs) can stimulate ARs and mimic testosterone. Whether SARMs affect cardiac structure or function and if circulating inflammatory markers grade these changes is unclear. We investigated the effects of a SARM (RAD140) on cardiac function and structure in older male and female mice and explored how systemic inflammatory markers relate. Older (23-month-old) male and female mice were treated with RAD140 (5 mg/kg/day) for 6-weeks. Left ventricular (LV) structure and function were measured with echocardiography. Serum cytokine levels were assessed with a multiplex assay, and LV gene expression was tested. RAD140 treated males and females had higher ejection fraction (+ 10.4%), stroke volume (+ 9.6 µL) and cardiac output (+ 4.5 mL/min), versus controls. However, RAD140 treated males had better markers of cardiac function, including myocardial strain (-5.8%) and isovolumic relaxation times (-4.7 ms) compared to controls, with lesser or opposite effects in females. Higher levels of interleukin-6 correlated with worse global circumferential strain in males, but not females. qPCR analysis for genes coding proteins related to cardiac function and structure revealed no differences, although AR mRNA was lower with RAD140 treatment in both sexes. No structural differences were observed. RAD140 treatment may enhance cardiac function in older male mice, but less so in older female mice. Increased circumferential strain in males related to lower interleukin-6 levels, supporting the AR's connecting role between cardiac function and inflammatory markers.