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/文摘