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Targeting oxidized sGC in calcific aortic valve stenosis: a narrative review of ataciguat | ||
| Cardiovascular Biomedicine | ||
| Volume 5, Issue 2, December 2025, Pages 13-32 PDF (672.59 K) | ||
| Document Type: review article | ||
| DOI: 10.18502/cbj.v5i2.21133 | ||
| Authors | ||
| Farid Taghavi1; Shirin Alord2; Somayyeh Mehanfar1; Kamran Mohammadi* 1 | ||
| 1Cardiovascular Research Center, Department of Cardiology, Tabriz University of Medical Sciences, Tabriz, Iran | ||
| 2Cardiovascular 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 | ||
| Calcific aortic valve stenosis; soluble guanylate cyclase; oxidized sGC; heme-free sGC; ataciguat (HMR-1766); cyclic GMP | ||
| References | ||
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