{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:01:05Z","timestamp":1790870465210,"version":"4.1.0"},"reference-count":58,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","license":[{"start":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T00:00:00Z","timestamp":1731974400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UKRI | Medical Research Council","award":["MR\/S018905\/1"],"award-info":[{"award-number":["MR\/S018905\/1"]}]}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2024,11,19]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism\n              <jats:italic toggle=\"yes\">RS9349379<\/jats:italic>\n              enhances expression of the endothelin-1 gene (\n              <jats:italic toggle=\"yes\">EDN1<\/jats:italic>\n              ) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral\n              <jats:italic toggle=\"yes\">ET-A<\/jats:italic>\n              receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the\n              <jats:italic toggle=\"yes\">RS9349379<\/jats:italic>\n              single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              A total of 118 participants (mean\u00b1SD; years of age 63.5 [9.2]; 71 [60.2%] females; 25 [21.2%] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, \u22124.26 seconds [95% CI, \u221219.60 to 11.06]\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;0.001).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>REGISTRATION:<\/jats:title>\n            <jats:p>\n              URL:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n              ; Unique identifier: NCT04097314.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.124.069901","type":"journal-article","created":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T09:30:25Z","timestamp":1725183025000},"page":"1671-1683","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":38,"title":["Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial"],"prefix":"10.1161","volume":"150","clinical-trial-number":[{"clinical-trial-number":"nct04097314","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4067-8249","authenticated-orcid":true,"given":"Andrew","family":"Morrow","sequence":"first","affiliation":[{"name":"British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, University of Glasgow, United Kingdom (A.M., N.S., P.W.M., P.W., C.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Young","sequence":"additional","affiliation":[{"name":"Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, United Kingdom (R.Y., A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1442-4835","authenticated-orcid":true,"given":"George R.","family":"Abraham","sequence":"additional","affiliation":[{"name":"Royal Papworth 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