Reactivation of Oxidized Soluble Guanylate Cyclase as a Novel Treatment Strategy to Slow Progression of Calcific Aortic Valve Stenosis: Preclinical and Randomized Clinical Trials to Assess Safety and Efficacy.

• Tác giả: Philip Araoz, Anna Bartoo, Grace Casaclang-Verzosa, Kevin Y Cunningham, Brandon Dunagan, Maurice Enriquez-Sarano, Michael A Hagler, Jon Hawkinson, Runqing Huang, Michael J Joyner, Walter K Kremers, Hector I Michelena, Jordan D Miller, Vuyisile Nkomo, Sorin Pislaru, Sushant Ranadive, Carolyn M Roos, Hartzell V Schaff, Gurpreet Singh, Jaeyun Sung, Michael A Walters, Ze Yi, Bin Zhang, Heyu Zhang
• Ngôn ngữ: eng
• Ký hiệu phân loại: 809.008 History and description with respect to kinds of persons
• Thông tin xuất bản: United States : Circulation , 2025
• Bộ sưu tập: NCBI
• ID: 662922

Tóm tắt

 BACKGROUND: Pharmacological treatments for fibrocalcific aortic valve stenosis (FCAVS) have been elusive for >
 50 years. Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), the primary receptor for nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression of FCAVS. METHODS: We used quantitative real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry to characterize sGC signaling and the biological effects of ataciguat on signaling cascades related to nitric oxide, calcification, and fibrosis in excised human aortic valve tissue, aortic valve interstitial cells, and mouse aortic valves. We then conducted randomized, placebo-controlled phase I (14-day safety/tolerance) and phase II (6-month efficacy) trials in patients with moderate aortic valve stenosis. RESULTS: In excised human tissue, we found robust losses in sGC signaling despite upregulation of sGC subunits. In vitro, ataciguat increased sGC signaling and reduced BMP2 (bone morphogenetic protein 2) signaling in aortic valve interstitial cells. In mice with established FCAVS, treatment with ataciguat attenuated BMP signaling and slowed progression of valve calcification and dysfunction. In a phase I, randomized, placebo-controlled trial, treatment with ataciguat for 2 weeks was safe and well tolerated in patients with moderate FCAVS (https://www.clinicaltrials.gov
  Unique identifier: NCT02049203). In a separate phase II, randomized, placebo-controlled trial, treatment with ataciguat for 6 months slowed the progression of aortic valve calcification and tended to slow the progression of valvular and ventricular dysfunction in patients with moderate FCAVS (https://www.clinicaltrials.gov
  Unique identifier: NCT02481258). CONCLUSIONS: Collectively, this study highlights the therapeutic potential of the targeted restoration of the diseased/inactive form of sGC for treatment of FCAVS. REGISTRATION: URL: https://www.clinicaltrials.gov
  Unique identifier: NCT02049203. URL: https://www.clinicaltrials.gov
  Unique identifier: NCT02481258.