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.

中文翻译：

---

endothelin-1 的遗传失调与冠状动脉微血管功能障碍有关

摘要目的内皮素-1（ET-1）是一种有效的血管收缩肽，通过一个常见的内含子基因增强子[（rs9349379-G等位基因），染色体6（PHACTR1/EDN1）]与血管疾病相关联。我们对有缺血症状和/或体征但没有阻塞性冠状动脉疾病 (CAD) 的患者的冠状动脉微血管功能障碍 (CMD) 发病机制中的 ET-1 和该基因变异体的作用进行了多模式调查。方法与结果共纳入心绞痛患者391例。其中，206 名 (53%) 患有阻塞性 CAD 的患者被排除在外，剩下 185 名 (47%) 符合条件。在接受侵入性测试的 151 名受试者中，有 109 名 (72%) 有 CMD 的客观证据（COVADIS 标准）。rs9349379-G 等位基因频率高于当代参考基因组库对照受试者[等位基因频率 46% (129/280 等位基因) vs. 39% (5551/14380)；P = 0.013]。G 等位基因与较高的血浆血清 ET-1 相关[最小二乘平均 1.59 pg/mL 对 1.28 pg/mL；95% 置信区间 (CI) 0.10–0.53；P = 0.005]。具有 rs9349379-G 等位基因的患者发生 CMD 的几率超过两倍 [优势比 (OR) 2.33, 95% CI 1.10–4.96; P = 0.027]。多模式非侵入性测试证实，G 等位基因与 1.5 T 负荷心脏磁共振成像（N = 107；GG 56%，AG 43%，AA 31%，P = 0.042）和运动测试中心肌灌注相关的损伤相关（N = 87；杜克运动跑步机得分为 -3.0 单位；-5.8 至 -0.1；P = 0.045）。使用内皮素 A 受体 (ETA) 拮抗剂（包括 zibotentan）在体外使用线肌造影评估内皮素 1 相关的血管机制。具有 rs9349379-G 等位基因的受试者保留了外周小血管对 ET-1 的反应性，具有高亲和力的 ETA 拮抗剂。Zibotentan 独立于 G 等位基因状态逆转 ET-1 诱导的血管收缩。结论 我们确定了一个新的 CMD 遗传风险位点。这些发现暗示 ET-1 失调，并支持使用遗传学靶向口服 ETA 拮抗剂治疗微血管心绞痛患者的精准医学的可能性。试验注册 ClinicalTrials.gov：NCT03193294。Zibotentan 独立于 G 等位基因状态逆转 ET-1 诱导的血管收缩。结论 我们确定了一个新的 CMD 遗传风险位点。这些发现暗示 ET-1 失调，并支持使用遗传学靶向口服 ETA 拮抗剂治疗微血管心绞痛患者的精准医学的可能性。试验注册 ClinicalTrials.gov：NCT03193294。Zibotentan 独立于 G 等位基因状态逆转 ET-1 诱导的血管收缩。结论 我们确定了一个新的 CMD 遗传风险位点。这些发现暗示 ET-1 失调，并支持使用遗传学靶向口服 ETA 拮抗剂治疗微血管心绞痛患者的精准医学的可能性。试验注册 ClinicalTrials.gov：NCT03193294。