A soluble guanylate cyclase stimulator improves survival in a rat model of heart failure with reduced ejection fraction and chronic kidney disease induced by aorto-caval fistula and 5/6 nephrectomy

New therapeutic strategies for heart failure (HF) combined with chronic kidney disease (CKD) are needed, and the current knowledge, including our previous studies, suggests that targeting the NO/sGC/cGMP pathway could be a promising approach.

We hypothesised that chronic soluble guanylate cyclase (sGC) stimulation would attenuate the course of rodent HFrEF induced by volume overload achieved by the creation of the aorto-caval fistula (ACF) combined with CKD caused by ⅚ nephrectomy (⅚ Nx).

⅚ Nx was performed in Ren-2 transgenic rats (TGR), a model of angiotensin II-dependent hypertension, at the animal age of 8 weeks. One week later, ACF was created; another two weeks later, the animals were randomly divided into three groups, and the therapy was started: sGC stimulation with BAY-41-8543 (sGC stim.) (3 mg.kg-1.day-1 in food, n = 24), angiotensin-converting enzyme inhibitor (ACEi) (trandolapril, 2 mg.L-1 in drinking water, n = 24), or placebo (n = 22). Sham-operated TGR represented a control group (n = 8). The follow-up period was 20 weeks. GraphPad Prism 10 was used for statistical analysis with a log-rank (Mantel-Cox) test to analyse survival data.

All sham-operated rats survived till the end of the study. On the contrary, all untreated HF+CKD rats died by week 12. The treatment with the sGC stim. or with ACEi similarly improved the survival rate: 46 % in sGC stim. group (p < 0,0001 vs. placebo) and 58 % in the ACEi group (p < 0,0001 vs. placebo) (Figure 1).

Our results indicate that in the ACF-5/6Nx TGR animal model of combined HF and CKD, treatment with an sGC stimulator reduces mortality to a similar extent as ACEi monotherapy compared to placebo. Further preclinical research is needed to better understand the NO/sGC/cGMP pathway in HF with concurrent CKD.