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

Abstract

Background: 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 (INOCA). Methods and Results: 391 angina patients were enrolled, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. 109 (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) v 39% (5551/14380); P=0.013). The G allele was associated with higher plasma serum ET-1 (LS mean 1.59pg/mL v 1.28pg/mL; 95% CI 0.10 to 0.53; P=0.005). Patients with rs9349379-G allele had over double the odds of CMD (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 Tesla (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). ET-1 related vascular mechanisms were assessed ex vivo using wire myography with ETA 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 coronary microvascular dysfunction. More research is needed however 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.