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, 41(34), pp. 3239-3252. (doi: 10.1093/eurheartj/ehz915) (PMID:31972008) (PMCID:PMC7557475)

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: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Berry, Professor Colin and Robertson, Dr Keith and Shaukat, Dr Aadil and Padmanabhan, Professor Sandosh and Ford, Thomas and McEntegart, Dr Margaret and Aman, Ms Alisha and Eteiba, Professor 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 > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Life 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 41(34): 3239-3252
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
190814		BHF centre of excellence	Rhian Touyz	British Heart Foundation (BHF)	RE/13/5/30177	Institute of Cardiovascular & Medical Sciences