PRIZE trial sub-study investigating SNPs in microvascular angina
Research type
Research Study
Full title
Mechanistic study of the effect of ET-1 SNPs in Coronary Microvascular Disease
IRAS ID
283303
Contact name
Stephen Hoole
Contact email
Sponsor organisation
Royal Papworth Hospital
Eudract number
2020-003964-18
Clinicaltrials.gov Identifier
Clinicaltrials.gov Identifier
NCT, NCT04508998
Duration of Study in the UK
1 years, 11 months, 29 days
Research summary
Research Summary:
Microvascular angina is a common cause of chest pain, and falls within the umbrella term of diagnoses known as ischaemia with non-obstructive coronary arteries (INOCA). The term ‘microvascular angina’ describes the clinical syndrome caused by coronary microvascular dysfunction (CMD): abnormalities of the structure and function of the small blood vessels in the heart. CMD can be detected and defined invasively at the time of diagnostic coronary angiography by guidewire based measurements of coronary blood flow and pressure, as well as using non-invasive methods including quantitative stress perfusion magnetic resonance imaging (MRI). Limited treatment is available for those affected.
Endothelin-1 (ET-1) is a peptide molecule synthesised by the endothelial cells that line all blood vessels in the body, crucial for physiological control of blood flow in coronary arteries, and with multiple other biological actions relevant for CMD. The best characterised action of ET-1 is potent and sustained constriction of blood vessels, after binding to ETA receptors expressed in vascular smooth muscle. Increased concentrations and sensitivity to ET-1 are especially relevant for the biological process known as ‘endothelial dysfunction’: a catch-all term describing a constellation of pathological features, most often including impaired vascular reactivity, up-regulation of inflammatory mediators and pro-thrombotic signalling in the vascular wall.
Identifying heritable risk in coronary artery disease is key to delivering ‘precision medicine’. Thus far over 200 relevant genetic loci are described, however only a minority have proven biological effects. Examples include a single nucleotide polymorphism (SNP) linked to the endothelin (ET-1) vasoconstrictor pathway, rs9349379, which was used to selectively enrol microvascular angina patients to the PRecIsion medicine with ZibotEntan in microvascular angina (PRIZE) trial: a randomised, double blind crossover study of the highly ETA selective antagonist drug: Zibotentan. It is unknown if other genetic variants contribute to ET-1 pathway dysregulation. The identification of these genetic variants is the focus of the PRIZE ET Sub-study: an observational sub-study of the PRIZE trial.Purpose
We aimed to identify a genetic classification of microvascular angina likely to benefit from ET receptor antagonist drugs.Methods
93 participants with microvascular angina were recruited prospectively from 10 hospitals in the United Kingdom to an observational sub-study of the Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial (figure). Clinical variables including exercise test parameters, health status questionnaires, quantitative perfusion cardiac MRI, and plasma biomarkers, were measured.Main findings and conclusions
The PRIZE ET sub-study identified a novel association between a coronary artery disease risk single nucleotide polymorphism (rs6842241) in the region of the gene encoding the ETA receptor, with elevated circulating ET-1. Particular clinical characteristics of patients with microvascular angina and the risk allele rs6842241-A, have been identified which suggest there is a measurable clinical effect related to excessive ET-1. Patients possessing this SNP had significantly higher ET-1 levels, increased likelihood of reduced blood flow in the inner portions of the heart on cardiac MRI, and higher resting diastolic blood pressure. Irrespective of genotype, increased ET-1 was associated with coronary atherosclerosis and hypertension, which has been noted in clinical studies previously and is consistent with the known biological actions of the peptide. The results are especially relevant to the proposed strategy of targeting the endothelin pathway with ETA receptor antagonist drugs as a novel treatment for microvascular angina. Specifically, the rs6842241-A variant can be considered a new target for precision medicine.Microvascular angina (MVA) is caused by abnormalities of the small blood vessels in the heart. Endothelin-1 (ET-1) is a chemical messenger that circulates and accumulates in the blood vessel walls, causing them to narrow or go into spasm and thicken over a long period especially as levels of ET-1 increase. As a result, patients experience pain, psychological distress and limitation of their daily activities.
Cambridge is a participating recruitment site for a large randomised, double blinded, placebo controlled crossover trial (the PRIZE study: NCT04097314) investigating Zibotentan as a new drug treatment for patients with MVA using a ‘precision medicine’ approach. Zibotentan is a drug originally developed by Astra Zeneca for prostate cancer but prior research has shown that it acts to relax the small blood vessels of patients with MVA, highlighting its potential as a novel therapy for this patient group. The PRIZE study population will be enriched for ‘responders’ to the drug by screening patients with MVA for a gene mutation known to increase levels of circulating endothelin. The trial aims to initially invite approximately 356 participants for genetic testing but only 100 participants will go forward into the main study, with approximately 2/3rd being screen failures.
In our sub-study, we will invite patients with MVA who are screen failures at our site for further blood tests looking for other genetic variants in the ET-1 signalling pathway and examine how this correlates with the severity of microvascular angina quantified by cardiac MRI and clinical assessments. Data from this sub-study would provide a bio-resource for further analysis of the main PRIZE trial to identify other patients that would benefit from Zibotentan.REC name
East Midlands - Leicester South Research Ethics Committee
REC reference
20/EM/0279
Date of REC Opinion
7 Dec 2020
REC opinion
Further Information Favourable Opinion