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.

项目总结/摘要 急性肾损伤和脑损伤表现为谵妄，各影响50万患者中的25 每年都要接受心脏手术，这些器官损伤与更长的住院时间有关， 死亡率增加，机械通气时间延长，但其潜在机制尚不清楚。 血管反应性是血管功能的组成部分，其能够通过平滑的血管反应性来控制组织灌注。 肌肉张力血管反应性是通过内皮型一氧化氮合酶信号传导引起的， 被炎症手术和氧化应激破坏内皮细胞是血管内皮细胞的主要调节器， 反应性、凝血和免疫细胞活化以及内皮功能障碍可能导致器官损伤。 手术后功能障碍我们最近发现，受损的血管反应性与 与手术后肾损伤有关。在正常情况下，一氧化氮从 血管内皮细胞与血管平滑肌的结合，并与可溶性鸟苷酸环化酶上的血红素部分结合， 这是一种构象变化，允许酶催化环状鸟苷一磷酸的形成。 然而，血红素部分中的铁氧化成三价铁状态会损害一氧化氮结合和血管生成。 反应性继发于可溶性鸟苷酸环化酶激活受损的血管反应性受损可能是一种 围手术期器官损伤的重要机制在临床护理中没有常规解决。 最近，已经开发了药理学可溶性鸟苷酸环化酶刺激剂以增强 可溶性鸟苷酸环化酶活化受损，并被批准用于心力衰竭患者， 肺动脉高压这些药物稳定可溶性鸟苷酸环化酶上的血红素部分， 结合酶在一个单独的网站，他们直接刺激可溶性鸟苷酸环化酶，以产生环 鸟苷一磷酸这个项目建立在我们先前的发现上， 作为围手术期器官损伤的潜在机制，并进一步研究了可溶性鸟苷酸的作用， 环化酶刺激剂vericiguat增强接受心脏手术和有风险患者的血管反应性 器官损伤。我们假设在手术前给予可溶性鸟苷酸环化酶刺激剂， 增强围手术期血管反应性，降低肾小管和神经元损伤的细胞标志物。 我们将使用金标准技术直接评估患者体内和体外的血管反应性 随机接受vericiguat与安慰剂，并将比较可溶性 鸟苷酸环化酶刺激、内皮活化、内皮屏障降解、肾小管损伤，以及 神经元损伤