Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction

Ford, T. J. et al. (2020) Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction. European Heart Journal, (doi: 10.1093/eurheartj/ehz915) (PMID:31972008) (Early Online Publication)

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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: ClinicalTrials.gov: NCT03193294.

Item Type:Articles
Keywords:Coronary microvascular dysfunction, endothelin-1, microvascular angina, precision medicine, single-nucleotide polymorphism, stable angina pectoris.
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:Berry, Professor Colin and Robertson, Dr Keith and Shaukat, Dr Aadil and Padmanabhan, Professor Sandosh and Ford, Tom and McEntegart, Dr Margaret and Aman, Alisha and Eteiba, Dr Hany and Oldroyd, Dr Keith and Corcoran, Dr David and Sattar, Professor Naveed and Touyz, Professor Rhian and Hood, Dr Stuart
Authors: Ford, T. J., 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., and Berry, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:European Heart Journal
Publisher:Oxford University Press
ISSN:0195-668X
ISSN (Online):1522-9645
Published Online:23 January 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in European Heart Journal 2020
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190814BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177Institute of Cardiovascular & Medical Sciences