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

• Published in: European heart journal Vol. 41; no. 34; pp. 3239 - 3252
• Main Authors: Ford, Thomas J, Corcoran, David, Padmanabhan, Sandosh, Aman, Alisha, Rocchiccioli, Paul, Good, Richard, McEntegart, Margaret, Maguire, Janet J, Watkins, Stuart, Eteiba, Hany, Shaukat, Aadil, Lindsay, Mitchell, Robertson, Keith, Hood, Stuart, McGeoch, Ross, McDade, Robert, Yii, Eric, Sattar, Naveed, Hsu, Li-Yueh, Arai, Andrew E, Oldroyd, Keith G, Touyz, Rhian M, Davenport, Anthony P, Berry, Colin
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 07.09.2020
• Subjects: Clinical Research; Coronary Artery Disease - genetics; Editor's Choice; Endothelin-1 - genetics; Humans; Microvascular Angina - genetics; Myocardial Ischemia; Vasoconstriction; Stable angina pectoris; Microvascular angina; Single-nucleotide polymorphism; Precision medicine; Coronary microvascular dysfunction; Endothelin-1
• ISSN: 0195-668X; 1522-9645; 1522-9645
• DOI: 10.1093/eurheartj/ehz915

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). 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. 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. ClinicalTrials.gov: NCT03193294.