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

Farid  Taghavi; Shirin  Alord; Somayyeh  Mehanfar; Kamran  Mohammadi

doi:10.18502/cbj.v5i2.21133

Farid Taghavi Cardiovascular Research Center, Department of Cardiology, Tabriz University of Medical Sciences, Tabriz, Iran
Shirin Alord Cardiovascular Research Center, Health Policy and Promotion Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
Somayyeh Mehanfar Cardiovascular Research Center, Department of Cardiology, Tabriz University of Medical Sciences, Tabriz, Iran
Kamran Mohammadi Cardiovascular Research Center, Department of Cardiology, Tabriz University of Medical Sciences, Tabriz, Iran

DOI: https://doi.org/10.18502/cbj.v5i2.21133

Keywords: Calcific aortic valve stenosis; soluble guanylate cyclase; oxidized sGC; heme-free sGC; ataciguat (HMR-1766); cyclic GMP

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.