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
British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 9DH, UK.
Department of Cardiology, Gosford Hospital, NSW, Australia.
Eur Heart J. 2020 Sep 7;41(34):3239-3252. 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.
内皮素 -1（ET-1）是一种强效血管收缩肽，通过一个常见的内含子基因增强子[（rs9349379 - G等位基因），6号染色体（PHACTR1/EDN1）]与血管疾病相关。我们对ET-1和该基因变异在有缺血症状和/或体征但无阻塞性冠状动脉疾病（CAD）的患者冠状动脉微血管功能障碍（CMD）发病机制中的作用进行了多模态研究。
纳入391例心绞痛患者。其中，排除206例（53%）有阻塞性CAD的患者，剩余185例（47%）符合条件。151例接受有创检查的受试者中，109例（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个等位基因）对39%（5551/14380）；P = 0.013]。G等位基因与较高的血浆血清ET-1相关[最小二乘均值1.59 pg/mL对1.28 pg/mL；95%置信区间（CI）0.10 - 0.53；P = 0.005]。携带rs9349379 - G等位基因的患者患CMD的几率增加一倍以上[优势比（OR）2.33，95% CI 1.10 - 4.96；P = 0.027]。多模态无创检查证实，G等位基因与1.5 T压力心脏磁共振成像时心肌灌注的相关损伤有关（N = 107；GG 56%，AG 43%，AA 31%，P = 0.042）以及运动试验（N = 87；杜克运动平板评分 - 3.0单位； - 5.8至 - 0.1；P = 0.045）。使用包括齐考诺肽在内的内皮素A受体（ETA）拮抗剂的线肌描记法在体外评估ET-1相关的血管机制。携带rs9349379 - G等位基因的受试者对ET-1的外周小血管反应性保留，ETA拮抗剂具有高亲和力。齐考诺肽可逆转ET-1诱导的血管收缩，与G等位基因状态无关。
我们确定了CMD的一个新的遗传风险位点。这些发现提示ET-1失调，并支持在微血管性心绞痛患者中使用遗传学进行精准医学以靶向口服ETA拮抗剂治疗的可能性。
ClinicalTrials.gov：NCT03193294。
