The sGC stimulator (BAY41-8543) improves the survival of rats with DOXO-induced HFrEF with nephrotic syndrome

Doxorubicin (DOXO) and other anthracyclines are still frequently used effective anticancer drugs. However, this class of drugs can exhibit cardiotoxicity with acute but also delayed onset. Since established therapies for heart failure are less efficient in preventing cardiac damage, especially when it is accompanied by cardiorenal syndrome, we tested if sGC stimulators, a novel drug class for the treatment of heart failure, could lead to improved outcomes. We tested the effectiveness of the sGC stimulator (BAY41-8543) in a novel rat model, recently developed in our laboratory which mimics DOXO-induced heart failure with reduced ejection fraction (HFrEF) associated with nephrotic syndrome. DOXO was administered to Ren-2 transgenic rats (TGR) via five intravenous injections (cumulative dose 10 mg/kg of body weight). The long-term survival (20 weeks) was evaluated during treatment with sGCstim. in comparison to ACE inhibitor (ACEi). Cardiac function was evaluated by echocardiography. The treatment with the sGC stimulator BAY41-8543 significantly improved the survival of TGR+DOXO (p=0.029 versus TGR+DOXO+placebo) and in the end there was no difference between BAY41-8543 and ACEi. Cardiac output (CO) decreased in all DOXO groups, but four weeks of treatment with sGCstim. attenuated the decline in CO, in contrast to placebo and ACEi. The fractional area change of right ventricle was also preserved after sGCstim., whereas in placebo and ACEi there was a significant decrease after 4 weeks. The observed changes were rather moderate, but most parameters did not differ from ACEi, and in some cases there was a greater improvement after sGC stimulation with BAY41-8543.