The effects of soluble guanylyl cyclase stimulation on perioperative vascular reactivity and organ injury in cardiac surgery trial

心脏手术试验中可溶性鸟苷酸环化酶刺激对围手术期血管反应性和器官损伤的影响

• 批准号: 10503911
• 负责人: Marcos G Lopez
• 金额: $ 49.78万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503911
• 关键词: Acetylcholine; Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Animal Model; Binding; Biological Markers; Biology; Blood Vessels; Brain Injuries; Cardiac Surgery procedures; Cells; Chronic Kidney Failure; Clinical; Coagulation Process; Collection; Conduct Clinical Trials; Congestive Heart Failure; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Delirium; Development; Diffuse; Disodium Salt Nitroprusside; Endothelium; Enzymes; Fatty acid glycerol esters; Free Radicals; Functional disorder; Future; Gold; Heart failure; Heme; Hemoglobin; Herpes zoster disease; Hospitalization; Human; IGFBP2 gene; Impairment; Inflammation; Infrastructure; Injury; Injury to Kidney; Intercellular adhesion molecule 1; Kidney; LCN2 gene; Mammary Arteries; Measurement; Measures; Mechanical ventilation; Mediastinal; Mediating; Molecular Conformation; Muscle Tonus; Muscle relaxation phase; NOS3 gene; Neuronal Injury; Neurons; Nitric Oxide; Nitric Oxide Donors; Operative Surgical Procedures; Organ; Outcome; Oxidants; Oxidative Stress; Oxygen; Participant; Pathway interactions; Patients; Perfusion; Perioperative; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Placebos; Plasma; Plasminogen Activator Inhibitor 1; Population; Positioning Attribute; Randomized; Randomized Clinical Trials; Recovery; Renal tubule structure; Research Design; Risk; Role; Sampling; Second Messenger Systems; Secondary to; Signal Transduction; Site; Smooth Muscle; Soluble Guanylate Cyclase; TIMP2 gene; Techniques; Testing; Tissue Inhibitor of Metalloproteinases; Tissues; Tubular formation; Urine; Vascular Diseases; Vascular Endothelium; Vascular Smooth Muscle; Vasodilator Agents; arteriole; base; brachial artery; clinical care; endothelial dysfunction; experience; experimental study; glomerulosclerosis; immune activation; improved; in vivo; insight; insulin-like growth factor binding protein-related protein 1; iron oxidation; mortality; mortality risk; organ injury; oxidation; postoperative delirium; preclinical study; pulmonary arterial hypertension; recruit; response; treatment group; ubiquitin C-terminal hydrolase; urinary; vascular factor; vasodilator-stimulated phosphoprotein

Project Summary/Abstract Acute kidney injury and brain injury manifest as delirium each affect over 25% of the 500,000 patients undergoing cardiac surgery annually, and these organ injuries are associated with longer hospitalization, increased mortality, longer mechanical ventilation, but the underlying mechanisms are poorly understood. Vascular reactivity is a component of vascular function which enables control of tissue perfusion via smooth muscle tone. Vascular reactivity is elicited via endothelial nitric oxide synthase signaling which may be disrupted by inflammation, surgery, and oxidative stress. The endothelium is a major regulator of vascular reactivity, coagulation, and immune cell activation, and endothelial dysfunction may contribute to organ dysfunction after surgery. We have recently identified that impaired vascular reactivity is independently associated with kidney injury after surgery. Under normal circumstances, nitric oxide diffuses from the endothelium to vascular smooth muscle and binds to the heme-moiety on soluble guanylyl cyclase inducing a conformational change that allows the enzyme to catalyze the formation of cyclic guanosine monophosphate. Oxidation of the iron in this heme moiety to the ferric state, however, impairs nitric oxide binding and vascular reactivity. Impaired vascular reactivity secondary to impaired soluble guanylyl cyclase activation may be an important mechanism underlying perioperative organ injury that is not routinely addressed in clinical care. Recently, pharmacologic soluble guanylyl cyclase stimulators have been developed to enhance impaired soluble guanylyl cyclase activation and are approved for use in patients with heart failure and pulmonary arterial hypertension. These drugs stabilize the heme moiety on soluble guanylyl cyclase while binding to the enzyme at a separate site, and they directly stimulate soluble guanylyl cyclase to generate cyclic guanosine monophosphate. This project builds on our prior findings that identified impaired vascular reactivity as a potential mechanism for perioperative organ injury, and further examines the role of the soluble guanylyl cyclase stimulator vericiguat in enhancing vascular reactivity in patients undergoing cardiac surgery and at risk of organ injury. We hypothesize that administration of a soluble guanylyl cyclase stimulator prior to surgery will enhance perioperative vascular reactivity and decrease cellular markers of renal tubule and neuronal injury. We will directly assess vascular reactivity in vivo and ex vivo using gold standard techniques in patients randomized to receive vericiguat versus placebo and will compare plasma and urine biomarkers of soluble guanylyl cyclase stimulation, endothelial activation, endothelial barrier degradation, renal tubular injury, and neuronal injury.

项目摘要/摘要 急性肾脏损伤和脑损伤表现出来，因为ir妄影响了500,000例患者中25％以上 每年接受心脏手术，这些器官损伤与住院时间更长有关， 死亡率增加，机械通气较长，但基本机制知之甚少。 血管反应性是血管功能的组成部分，可以通过平滑控制组织灌注 肌肉音。血管反应性通过内皮一氧化氮合酶信号引起，可能是 受炎症，手术和氧化应激的破坏。内皮是血管的主要调节剂 反应性，凝结和免疫细胞活化以及内皮功能障碍可能有助于器官 手术后功能障碍。我们最近确定血管反应受损是独立的 手术后与肾脏损伤有关。在正常情况下，一氧化氮从 内皮到血管平滑肌，并与诱导a的可溶性鸟叶叶尼环酶上的血红素运动结合 构象变化使酶可以催化环状鸟苷单磷酸盐的形成。 然而 反应性。继发性可溶性鸟叶尼环酶激活的继发性血管反应性受损可能是 围手术器官损伤的重要机制在临床护理中未常规解决。 最近，已经开发了药理学可溶性鸟叶烷刺激剂来增强 可溶性鸟烯酰基环化酶激活受损，并被批准用于心力衰竭和 肺动脉高压。这些药物稳定了可溶性鸟类环酶的血红素部分，而 在单独位点与酶结合，它们直接刺激可溶性鸟叶循环酶产生环状 鸟苷单磷酸盐。该项目建立在我们先前的发现，该发现确定了血管反应受损的受损 作为围手术器官损伤的潜在机制，并进一步研究了可溶性鸟叶的作用 循环酶刺激剂序列化在增强接受心脏手术的患者的血管反应性和处于危险中 器官损伤。我们假设在手术前施用可溶性鸟叶基环化酶刺激剂 增强围手术期的血管反应性，并降低肾小管和神经元损伤的细胞标记。 我们将使用患者的黄金标准技术直接在体内和离体中直接评估血管反应性 随机接收vericiguat与安慰剂，并将比较可溶性的血浆和尿液生物标志物 Guanylyl环酶刺激，内皮激活，内皮屏障降解，肾小管损伤和 神经元损伤。