Mechanistic study of the effect of Endothelin SNPs in microvascular angina – Protocol of the PRIZE Endothelin Sub-Study

Abraham, G. R., Morrow, A. J. , Oliveira, J., Weir-McCall, J. R., Davenport, E. E., Berry, C. , Davenport, A. P. and Hoole, S. P. (2022) Mechanistic study of the effect of Endothelin SNPs in microvascular angina – Protocol of the PRIZE Endothelin Sub-Study. International Journal of Cardiology: Heart and Vasculature, 39, 100980. (doi: 10.1016/j.ijcha.2022.100980) (PMID:35242999) (PMCID:PMC8885580)

Abstract

Introduction: Microvascular angina is a common cause of ischemia with non-obstructive coronary arteries (INOCA) and limited therapeutic options are available to those affected. Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the pathophysiology of microvascular angina. A large randomised, double blinded, placebo controlled crossover trial, the PRecIsion medicine with ZibotEntan in microvascular angina (PRIZE) trial is currently underway, investigating an endothelin receptor antagonist – Zibotentan, as a new drug treatment for microvascular angina. The trial uses a 'precision medicine' approach by preferential selection of those with higher ET-1 expression conferred by the PHACTR1 minor G allele single nucleotide polymorphism (SNP). The incidence of this SNP occurs in approximately one third of the population therefore a considerable number of screened patients will be ineligible for randomisation and the treatment phase of the trial. Methods: In the PRIZE Endothelin (ET) Sub-Study, patients screened out of the PRIZE trial will be genotyped for other genetic variants in the ET-1 pathway. These will be correlated with phenotypic characteristics including exercise tolerance, angina severity and quantitative measures of microvascular function on cardiovascular MRI as well as mechanistic data on endothelin pathway signalling. Conclusions: The study will provide a comprehensive genotype and phenotype bio-resource identifying novel ET-1 genotypes to inform the potential wider use of endothelin receptor antagonists for this indication.

• Item Type: Articles
• Additional Information: This research was funded in whole, or in part, by the British Heart Foundation [CB, RE/18/6134217], Medical Research Council [CB, MR/S018905/1], Wellcome Trust [EED, 206194; 108413/A/15/D; APD, WT107715/Z/15/Z].
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Berry, Professor Colin and Morrow, Dr Andrew
• Authors: Abraham, G. R., Morrow, A. J., Oliveira, J., Weir-McCall, J. R., Davenport, E. E., Berry, C., Davenport, A. P., and Hoole, S. P.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: International Journal of Cardiology: Heart and Vasculature
• Publisher: Elsevier
• ISSN: 2352-9067
• Published Online: 25 February 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
303684		A randomized, double-blind, placebo-controlled Phase 2A cross-over trial of oral zibotentan in patients with angina due to small vessel disease: a proof-of-concept, developmental trial for safety, efficacy and biomarkers development	Colin Berry	Medical Research Council (MRC)	MR/S018905/1	CAMS - Cardiovascular Science