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dc.contributor.authorFord, Thomas Jen
dc.contributor.authorCorcoran, Daviden
dc.contributor.authorPadmanabhan, Sandoshen
dc.contributor.authorAman, Alishaen
dc.contributor.authorRocchiccioli, Paulen
dc.contributor.authorGood, Richarden
dc.contributor.authorMcEntegart, Margareten
dc.contributor.authorMaguire, Janeten
dc.contributor.authorWatkins, Stuarten
dc.contributor.authorEteiba, Hanyen
dc.contributor.authorShaukat, Aadilen
dc.contributor.authorLindsay, Mitchellen
dc.contributor.authorRobertson, Keithen
dc.contributor.authorHood, Stuarten
dc.contributor.authorMcGeoch, Rossen
dc.contributor.authorMcDade, Roberten
dc.contributor.authorYii, Ericen
dc.contributor.authorSattar, Naveeden
dc.contributor.authorHsu, Li-Yuehen
dc.contributor.authorArai, Andrew Een
dc.contributor.authorOldroyd, Keith Gen
dc.contributor.authorTouyz, Rhian Men
dc.contributor.authorDavenport, Anthonyen
dc.contributor.authorBerry, Colinen
dc.date.accessioned2020-02-21T00:30:15Z
dc.date.available2020-02-21T00:30:15Z
dc.date.issued2020-09en
dc.identifier.issn0195-668X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/302449
dc.description.abstractBackground: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (INOCA). Methods and Results: 391 angina patients were enrolled, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. 109 (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects (allele frequency 46% (129/280 alleles) v 39% (5551/14380); P=0.013). The G allele was associated with higher plasma serum ET-1 (LS mean 1.59pg/mL v 1.28pg/mL; 95% CI 0.10 to 0.53; P=0.005). Patients with rs9349379-G allele had over double the odds of CMD (OR 2.33; 95% CI 1.10 – 4.96; P=0.027). Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 Tesla (N=107; GG 56%, AG 43%, AA 31%, P=0.042) and exercise testing (N=87; -3.0 units in Duke Exercise Treadmill Score; -5.8 to -0.1; P=0.045). ET-1 related vascular mechanisms were assessed ex vivo using wire myography with ETA receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status. Conclusion: We identify a novel genetic risk locus for coronary microvascular dysfunction. More research is needed however these findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina.
dc.description.sponsorshipThe Wellcome Trust 107715/Z/15/Z.
dc.format.mediumPrinten
dc.languageengen
dc.publisherOxford University Press
dc.rightsAll rights reserved
dc.rights.uri
dc.titleGenetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction.en
dc.typeArticle
prism.endingPage3252
prism.issueIdentifier34en
prism.publicationDate2020en
prism.publicationNameEuropean heart journalen
prism.startingPage3239
prism.volume41en
dc.identifier.doi10.17863/CAM.49520
dcterms.dateAccepted2019-12-09en
rioxxterms.versionofrecord10.1093/eurheartj/ehz915en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2020-09en
dc.contributor.orcidFord, Thomas J [0000-0003-4009-6652]
dc.contributor.orcidCorcoran, David [0000-0001-5047-0885]
dc.contributor.orcidPadmanabhan, Sandosh [0000-0003-3869-5808]
dc.contributor.orcidAman, Alisha [0000-0003-4022-5880]
dc.contributor.orcidMaguire, Janet [0000-0002-9254-7040]
dc.contributor.orcidDavenport, Anthony [0000-0002-2096-3117]
dc.identifier.eissn1522-9645
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWELLCOME TRUST (107715/Z/15/Z)
cam.orpheus.successTue Mar 31 10:35:48 BST 2020 - Embargo updated*
rioxxterms.freetoread.startdate2021-01-23


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