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Title: Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction
Authors: Ford, Tom ;Corcoran, D.;Padmanabhan, S.;Aman, A.;Rocchiccioli, P.;Good, R.;McEntegart, M.;Maguire, J.J.;Watkins, S.;Eteiba, H.;Shaukat, A.;Lindsay, M.;Robertson, K.;Hood, S.;McGeoch, R.;McDade, R.;Yii, E.;Sattar, N.;Hsu, L.Y.;Arai, A.E.;Oldroyd, K.G.;Touyz, R.M.;Davenport, A.P.;Berry, C.
Affliation: Central Coast Local Health District
Gosford Hospital
The University of Newcastle
Issue Date: Jan-2020
Source: 41(34):3239-3252
Journal title: European Heart Journal
Department: Cardiology
Abstract: AIMS: 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 (CAD). METHODS AND RESULTS: Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (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) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10-0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (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 T (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). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A 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 CMD. 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. TRIAL REGISTRATION: NCT03193294.
DOI: 10.1093/eurheartj/ehz915
ISSN: 0195-668x
Publicaton type: Journal Article
Keywords: Cardiovascular Disease
Heart Disease
Appears in Collections:Cardiology

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