Association of elevated cyclic GMP levels with hemodynamic changes in HFrEF patients treated with sacubitril/valsartan and vericiguat: a pilot study

Background: Patients with heart failure (HF) often present with a relative deficiency of cyclic guanosine monophosphate (cGMP) despite elevated B-type natriuretic peptide (BNP) levels. Sacubitril/valsartan and vericiguat target the cGMP pathway, but the relative contribution of cardiac versus systemic cGMP production remains uncertain. This study evaluated the association between cGMP changes and hemodynamic changes in patients with HF with reduced ejection fraction (HFrEF) receiving these agents. Methods: Fourteen symptomatic HFrEF patients (median age 65.0 [IQR: 56.0-72.3]years, EF 25.5 [24.0-33.3]%) and 20 control patients without HF (66.0 years, EF 66.5 %) were enrolled. Of the HFrEF patients, five received sacubitril/valsartan alone and nine received vericiguat (newly initiated or added to sacubitril/valsartan). All HFrEF patients underwent right heart catheterization before the treatment and two months after treatment. Blood samples were collected from the coronary sinus, arteries, and veins. Results: HFrEF patients showed higher coronary sinus cGMP levels compared with controls (15.8 ± 1.7 vs. 10.9 ± 1.2 nM, p < 0.05) but a markedly lower cGMP/BNP ratio (0.09 ± 0.02 vs. 1.71 ± 0.63, p < 0.05), suggesting a relative cGMP deficiency. After the therapy, the cGMP/BNP ratio significantly increased (0.278, p < 0.05). The change in coronary sinus cGMP correlated with improvement in cardiac index (r = 0.57, p = 0.039). cGMP levels rose consistently across all sampling sites, indicating a systemic augmentation of the cGMP pathway. Conclusion: Elevation of cGMP levels were associated with hemodynamic improvement in HFrEF patients treated with sacubitril/valsartan and vericiguat. These findings highlight the therapeutic relevance of cGMP pathway augmentation and provide mechanistic insights aligned with the known clinical effects of these agents in HFrEF.