Validation of Swine Model for Testing a Novel Therapy for Postoperative Atrial Fibrillation using Nanoformulated Calcium Chloride to Suppress Cardiac Ganglionated Plexi

使用纳米氯化钙抑制心脏神经节丛来测试术后心房颤动新疗法的猪模型的验证

• 批准号: 10293549
• 负责人: Alex Y Tan
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10293549
• 关键词: Acute; Adverse effects; Affect; Anatomy; Animal Model; Arrhythmia; Atrial Fibrillation; Autonomic nervous system; Calcium; Calcium Chloride; Canis familiaris; Cardiac; Cardiac Surgery procedures; Characteristics; Chronic; Complication; Coronary Artery Bypass; Data; Development; Electrophysiology (science); Family suidae; Glutamates; Glycolic-Lactic Acid Polyester; Goals; Health Expenditures; Heart; Heart Atrium; Heart failure; Human; Incidence; Inflammation; Injury; Institution; Length of Stay; Mediating; Methods; Microinjections; Miniature Swine; Modeling; Operative Surgical Procedures; Patients; Pericardial body location; Pericarditis; Pericardotomy; Postoperative Period; Predisposition; Prevention therapy; Publishing; Recurrence; Reporting; Risk; Safety; Site; Testing; Thoracotomy; Validation; autonomic nerve; canine model; clinical translation; cost; cost effective; high risk population; in vivo; in vivo Model; injury and repair; military veteran; myocardial damage; nanoparticle; neuron apoptosis; neuroregulation; novel; novel therapeutics; porcine model; prevent; relating to nervous system; response; safety testing

The goal of this proposal is to validate the feasibility of the swine model to test our novel therapy for the prevention of postoperative atrial fibrillation (POAF). POAF is the most common complication from cardiac surgery affecting 30%-50% of patients after coronary artery bypass grafting and/or valve surgeries. POAF leads to increased heart failure and hospital stays, costing an excess of US$2 billion per annum. POAF is an independent predictor of the development of AF long term. POAF is a highly prevalent issue in the veteran population. We recently reported a 40% incidence of POAF at our institution, with a 30% 5-year risk of recurrence of AF compared to 3% without POAF. Overactivity of the cardiac autonomic nervous system (CANS), is an important substrate for both POAF and AF. We hypothesize that neuromodulation of CANS can suppress POAF. We recently published in a canine model of POAF, that microinjection of nanoformulated CaCl2 into cardiac ganglionated plexi (GP), a critical component of the CANS, during open heart surgery, suppresses/prevents POAF. The mechanism of action is by inducing neuronal apoptosis in GP thus protecting the heart from sympathetic surge and inducing reverse remodeling of the heart, with potentially long term suppression of AF.7 The goals of this proposal are to (a) validate our successful canine model of POAF in Yucatan miniature swine species (b) test the safety and efficacy of nCaCl2 for neuromodulation and suppression POAF vulnerability in swine. Validating the swine model facilitates clinical translation of our novel therapy with the significance of targeted, effective and safe therapy for POAF and potentially long term suppression of AF vulnerability in a high-risk population.

本提案的目的是验证猪模型的可行性，以测试我们的新疗法， 预防术后房颤（POAF）。POAF是心脏手术最常见的并发症， 冠状动脉旁路移植术和/或瓣膜手术后影响30%-50%患者的手术。POAF 导致心力衰竭和住院时间增加，每年花费超过20亿美元。POAF是一个 AF长期发展的独立预测因素。POAF是退伍军人中非常普遍的问题， 人口我们最近报道了在我们机构POAF的发生率为40%，5年风险为30%。 AF复发率为3%，而无POAF时为3%。心脏自主神经系统过度活跃 CANS是POAF和AF的重要底物。我们假设CANS的神经调节可以 抑制POAF。我们最近在POAF的犬模型中发表了， 在心脏直视手术期间，CaCl 2进入心脏神经节丛（GP），这是CANS的关键组成部分， 抑制/预防POAF。其作用机制是通过诱导GP中的神经元凋亡，从而保护 心脏的交感神经冲动和诱导心脏的逆向重塑，具有潜在的长期 抑制AF。7本提案的目标是（a）验证我们成功的POAF犬模型， 尤卡坦小型猪物种（B）测试nCaCl 2用于神经调节的安全性和功效， 抑制猪POAF易感性。验证猪模型有助于我们的小说的临床翻译 具有靶向、有效、安全治疗POAF的意义， 抑制高风险人群的房颤易感性。