PS-B03-2: SGC STIMULATOR, BAY41 8543, FOR THE TREATMENT OF HEART FAILURE WITH REDUCED EJECTION FRACTION AND CARDIORENAL SYNDROME

Abstract

Objective: Heart failure with reduced ejection fraction (HFrEF) imposes a significant health and socioeconomic burden. The life expectancy and prognosis are particularly dreadful for patients that develop simultaneous renal dysfunction, so called cardiorenal syndrome, hence new treatment strategies are still in a great demand. Recent therapies for HFrEF include targeting the nitric oxide (NO)/ soluble guanylyl cyclase (sGC)/ cyclic guanosine monophosphate (cGMP) pathway by sGC stimulators. These compounds bind to the heme moiety of the sGC and stimulate the sGC in the absence of NO (NO independent action), but also they sensitize sGC to low levels of endogenous NO by stabilizing NO/sGC binding. Design and method: We explored the efficiency of sGC stimulator (BAY41 8543, an analogue of vericiguat) in the animal model of HFrEF with kidney dysfunction. We used ren2 transgenic hypertensive rats (TGR) with aortocaval fistula (ACF), in which HFrEF is due to volume overload. Firstly, we investigated the long term activity of BAY41 given alone (3 mg/kg/day in the food) or combined with an ACE inhibitor (ACEi, Trandolapril, 0.25 mg/kg/day in drinking water) on the survival rate of ACF induced HFrEF in TGR (30 weeks). In separate series of experiments the impact of BAY41 on blood pressure was measured by telemetry. Blood, urine and in the end tissue samples were collected to evaluate the levels of cGMP, albuminuria and the production of nitric oxide during the two week treatment. Results: sGC stimulator significantly improved the survival rate of ACF TGR in comparison to untreated animals with ACF. However, BAY41 administered together with ACEi decreased its beneficial activity. The overall survival in BAY41+ACEi treated group was 50%, while in the group which received only ACEi it was still 90% in the end of the observation. Noteworthy, a temporary blood pressure decrease (10 mmHg) was recorded during first few days after sGC stimulator administration, but early on SBP started to rise and by the end it was on the same level as in untreated ACF TGR (127 ± 3 vs 131 ± 6 mmHg, respectively; NS). Conclusions: It seems that the NO independent stimulation of sGC is a promising strategy to treat HFrEF with cardiorenal syndrome, however, more caution and additional studies are necessary to enlighten the puzzling decrease in survival rate in the group that received combined treatment with sGC stimulator and ACEi. Perhaps selected dose regimen was not optimal for the combined treatment (e.g. due to hypotension).