Cardiovasc Drugs Ther. 2025 Dec 10. doi: 10.1007/s10557-025-07821-y. Online ahead of print.
ABSTRACT
PURPOSE: Natriuretic peptides (NPs) ANP, BNP, and CNP extend beyond biomarkers of wall stress to regulators of cardiovascular, renal, metabolic, and immune pathways via cGMP-PKG signaling. We synthesize mechanistic and translational evidence, highlight NP "resistance," and appraise therapeutic strategies that augment NP signaling.
METHODS: Narrative review integrating human physiology, preclinical studies, and key trials (e.g., PARADIGM-HF, PARAGON-HF, EMPEROR-Preserved), plus emerging agents (ARNIs, designer peptides, NPR-C modulation, receptor sensitizers).
RESULTS: NPs exert natriuretic, vasodilatory, antifibrotic, and immunomodulatory effects. Resistance via neprilysin degradation, NPR-C-mediated clearance, and receptor desensitization blunts efficacy in advanced disease. ARNIs improve outcomes in HFrEF; benefits in HFpEF are subgroup-dependent. NP biology intersects with metabolic and inflammatory circuits, suggesting potential synergy with SGLT2 inhibitors and other modulators.
CONCLUSIONS: NPs are promising therapeutic targets across cardio-renal-metabolic spectra, but for many strategies, the evidence remains preclinical or early-phase. We propose a translational roadmap emphasizing mechanistic validation, responder phenotyping, and rigorously powered trials to test NP augmentation (and combinations) in HFrEF, obesity-related HFpEF, pulmonary vascular disease, and immune-cardiometabolic syndromes.
PMID:41369834 | DOI:10.1007/s10557-025-07821-y