Targeting oxidized sGC in calcific aortic valve stenosis: a narrative review of ataciguat

Document Type : review article

Authors

1 Cardiovascular Research Center, Department of Cardiology, Tabriz University of Medical Sciences, Tabriz, Iran

2 Cardiovascular Research Center, Health Policy and Promotion Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

Abstract

Objectives: No pharmacologic treatment has been shown to slow the course of calcific aortic valve stenosis (CAVS), an active fibrocalcific disease. A downstream signaling bottleneck in the NO–sGC–cyclic guanosine monophosphate (cGMP) pathway is created when oxidative stress transforms soluble guanylate cyclase (sGC) into nitric oxide (NO)–insensitive, oxidized/heme-free states. With an emphasis on the NO-independent sGC activator ataciguat (HMR-1766), this narrative review aims to highlight the molecular, translational, and clinical evidence supporting oxidized/heme-free sGC as a therapeutic target in CAVS.
 

Methods: We conducted a structured narrative literature search across PubMed/MEDLINE, Embase, Web of Science, Scopus, Cochrane Central, and trial registries (ClinicalTrials.gov/WHO ICTRP) through October 19, 2025. We prioritized original mechanistic/structural studies, preclinical pharmacology, valve-biology investigations, and human translational/clinical studies evaluating ataciguat, sGC redox biology, and disease-modification endpoints (e.g., CT-derived aortic valve calcium [CT-AVC] and ^18F-NaF PET).
 

Results: Across structural and biochemical studies, heme-mimetic sGC activators selectively bind oxidized/heme-free sGC and restore cGMP signaling by occupying the heme pocket, thereby bypassing NO insensitivity. Valve-biology studies indicate that NO–sGC–cGMP signaling and NO-dependent S-nitrosylation/NOTCH pathways function as complementary anti-calcific mechanisms linked to shear stress and endothelial integrity. Imaging biomarkers such as CT-AVC and ^18F-NaF PET provide sensitive readouts of calcification burden and activity. Early randomized clinical evidence in moderate CAVS suggests oral ataciguat is generally well tolerated and is associated with a directional slowing of CT-AVC progression over six months.
 

Conclusions: All currently available information suggests that oxidized/heme-free sGC is a biologically reasonable and treatable target in CAVS. Ataciguat exhibits early human signs of delayed calcific development and redox-selective restoration of NO–cGMP signaling. To verify long-term structural advantages and clinical impact, however, longer-term, well-powered clinical investigations are needed.

Keywords

Main Subjects

References

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Cardiovascular Biomedicine
Volume 5, Issue 2
December 2025
Pages 13-32

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History

  • Receive Date: 08 November 2025
  • Revise Date: 29 November 2025
  • Accept Date: 20 December 2025

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