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

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.

Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis

“…In considering the role(s) of PHACTR1 in endothelial cells, the consequences of lower PHACTR1 or higher endothelin-1 in these cells could be additive or synergistic with effects in macrophages, as these two cell types play complementary and interactive roles in atherosclerosis(2). Moreover, the endothelial hypothesis may also have relevance to non-atherosclerotic vascular diseases associated with rs9349379-G, including migraine headache, arterial dissection, fibromuscular dysplasia, hypertension, and coronary microvascular dysfunction(28,60,61). Except for coronary microvascular dysfunction, the risk of these non-atherosclerotic vascular diseases is lower in carriers of the rs9349379-G variant in contrast to the higher risk of CAD conferred by rs9349379-G, indicating that future work is needed to link the polymorphism to these diseases.In summary, we present new roles for PHACTR1, MLC, and PP1 in efferocytosisand show that the PHACTR1 intronic rs9349379 CAD risk allele lowers the fully functional form of PHACTR1 protein and impairs efferocytosis in human atherosclerotic lesional macrophages and HMDMs.…”

Oxidative Stress in Ischemic Heart Disease

“…Zibotentan tested at clinically relevant concentrations completely prevented the effect of endothelin-1. This study indicates that ETA receptor antagonism in this group of patients may have therapeutic benefits [ 168 , 169 ].…”

What Is the Role of Assessing Ischemia to Optimize Therapy and Outcomes for Patients with Stable Angina and Non-obstructed Coronary Arteries?

“…Genetic factors , female sex, smoking, inflammation, and illicit drug (cocaine, etc.) associations are also relevant [13][14][15][16][17].…”

“…For example, the Precision Medicine With Zibotentan in Microvascular Angina is a randomized, placebo-controlled, clinical trial of treatment for 12 weeks with the endothelin A receptor-selective antagonist, zibotentan [67]. The eligibility criteria require evidence of myocardial ischemia and/or microvascular dysfunction according to the COVADIS criteria and in addition, the population is enhanced with the G-risk allele rs9349379, which is a distal regulator of the endothelin gene [13]. The primary outcome is exercise duration on the Bruce treadmill exercise test protocol.…”