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Systemic cGMP pathway activation drives hemodynamic improvement in HfrEF sufferers treated with sacubitril/valsartan and vericiguat.
A mechanistic study reveals systemic cyclic guanosine monophosphate (cGMP) pathway activation as a key driver of cardiac improvement in heart failure with reduced ejection fraction (HFrEF).
This study, led by Takumi Inoue et al., included 14 symptomatic HFrEF patients (median age 65 years; median ejection fraction 25.5%) and 20 non-heart failure controls (mean ejection fraction 66.5%). Among the HFrEF cohort, 5 patients received sacubitril/valsartan alone, while 9 were treated with vericiguat, either newly initiated or added to background therapy.
All HFrEF sufferers underwent right heart catheterization at baseline and following 2 months of treatment. For assessing cGMP dynamics, blood samples were collected from the coronary sinus, arterial, and venous sites. At baseline, HFrEF patients had markedly higher coronary sinus cGMP levels compared to controls (15.8 ± 1.7 vs. 10.9 ± 1.2 nM), yet demonstrated a markedly reduced cGMP/B-type natriuretic peptide (BNP) ratio (0.09 ± 0.02 vs. 1.71 ± 0.63), confirming a relative cGMP deficiency.
Following treatment, the cGMP/BNP ratio considerably increased to 0.278. Importantly, improvements in coronary sinus cGMP levels were positively correlated with enhanced cardiac index (r = 0.57), indicating a direct link between cGMP augmentation and better cardiac performance. Notably, cGMP levels rose consistently across coronary, arterial, and venous samples, suggesting that both sacubitril/valsartan and vericiguat exert systemic effects on the cGMP pathway rather than being confined to cardiac tissue alone.
These findings reinforce the therapeutic value of targeting the cGMP signaling pathway in HFrEF. Augmentation of cGMP not only corrects a key biochemical deficit but also translates into improved hemodynamics, supporting the clinical benefits witnessed with sacubitril/valsartan and vericiguat.
IJC Heart & Vasculature
Association of elevated cyclic GMP levels with hemodynamic changes in HFrEF patients treated with sacubitril/valsartan and vericiguat: a pilot study
Takumi Inoue et al.
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