Cunningham, Kevin Y.

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.

Abstract Summary We recently introduced the Gut Microbiome Wellness Index (GMWI), a stool metagenome-based indicator for assessing health by determining the likelihood of disease given the state of one’s gut microbiome. The calculation of our wellness index depends on the relative abundances of health-prevalent and health-scarce species. Encouragingly, GMWI has already been utilized in various studies focusing on differences in the gut microbiome between cases and controls. Herein, we introduce the GMWI-webtool, a user-friendly browser application that computes GMWI, health-prevalent/-scarce species’ relative abundances, and α-diversities from stool shotgun metagenome taxonomic profiles. Users of our interactive online tool can visualize their results and compare them side-by-side with those from our pooled reference dataset of metagenomes, as well as export data in.csv format and high-resolution figures. Availability and implementation GMWI-webtool is freely available here: https://gmwi-webtool.github.io/. Supplementary information Supplementary data are available at Bioinformatics online.