Rheoerythrocrine dysfunction in stroke and remote ischemic conditioning (REDS)

尽管血管内血栓切除术(ET)有效，但50%的患者在3个月后仍有残疾。 溶栓和ET的辅助治疗需要提供“桥接神经保护”和改善 抵押品。远程缺血适应(RIC)，简单而安全的血液重复充气-放气 对四肢施加压力(BP)，改善急性中风时的侧支血流量。RIC现在正在进行大规模的测试 在丹麦对1500名受试者进行的第三阶段随机、假对照、院前急性卒中试验 审判。虽然一氧化氮合酶3(NOS3)被认为仅限于内皮细胞，但现在已知红色 血细胞(RBC)表达NOS3，这种红细胞NOS3(EryNOS3)可能在 缺血时微血管血流与器官保护。我们已经开发出两种推定的“Rheo- RBC变形性生物标志物：红细胞变形性通过细胞计数法检测，而ERNOS3通过流式细胞术检测。我们的假设 RBC变形性和ERNOS3是RIC的“药效学”生物标志物，并将与 改善了急性卒中的预后。为了验证这一假设，我们将利用RESTRACT的临床试验平台 生物标记物子研究的试验。我们的具体目标包括：目标1：确定RIC是否能改善红血球分泌 与Sham相比，生物标志物(RBC变形性，增加活化的erNOS3)和/或增加血浆亚硝酸盐 Ric.Aim 2：确定风湿性红细胞生成素生物标志物是否与改善的短期(24小时)或长期相关 (90天MRS)临床结果。我们预计RBC变形性和ERNOS3将成为 条件反应(药效学)和对中风患者临床结果改善的预测。

Despite the efficacy of endovascular thrombectomy (ET), 50% of the patients remain disabled at 3 months. Adjunctive therapies to thrombolysis and ET are needed that provide “bridging neuroprotection” and improve collaterals. Remote ischemic conditioning (RIC), the simple and safe repetitive inflation-deflation of a blood pressure (BP) cuff on the limbs, improves collateral blood flow in acute stroke. RIC is now being tested in a large phase III randomized, sham-controlled, prehospital acute stroke trial of 1500 subjects in Denmark, the RESIST trial. While nitric oxide synthase 3 (NOS3) was thought restricted to endothelial cells, it is now known that red blood cells (RBCs) express NOS3 and that this erythrocyte NOS3 (eryNOS3) may play a critical role in microvascular blood flow and organ protection during ischemia. We have developed two putative “rheo- erythocrine” biomarkers: RBC deformability by ektacytometry and eryNOS3 by flow cytometry. Our hypothesis is that RBC deformability and eryNOS3 are “pharmacodynamic” biomarkers of RIC and will be related to improved outcome in acute stroke. To test this hypothesis we will utilize the clinical trial platform of the RESIST trial for a biomarker substudy. Our specific aims include: Aim 1: Determine if RIC improves rheoerythrocrine biomarkers (RBC deformability, increases activated eryNOS3) and/or increases plasma nitrite compared to sham RIC .Aim 2: Determine if rheo-erythrocrine biomarkers are related to improved short term (24 hr) or long term (90 day mRS) clinical outcome. We expect that RBC deformability and eryNOS3 will be biomarkers of the conditioning response (pharmacodynamic) and predictive of improved clinical outcome in stroke patients.