Development of a whole heart model of the J wave syndromes and novel approaches to pharmacologic management of associated life-threatening arrhythmias

J波综合征的全心脏模型的开发以及相关危及生命的心律失常的药物治疗新方法

• 批准号: 10379445
• 负责人: Charles Antzelevitch
• 金额: $ 62.95万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379445
• 关键词: Action Potentials; Arrhythmia; Atrial Fibrillation; Brugada syndrome; Canis familiaris; Cardiac Myocytes; Cardiology; Cells; Clinical; Communities; Coronary; Damiana; Data; Defibrillators; Development; Dose; Effectiveness; Event; Experimental Models; Flavones; Functional disorder; Genes; Glass; Heart; Human; Individual; Inferior; Inherited; Ion Channel; Isoproterenol; Lead; Left; Life; Mediating; Medication Management; Microelectrodes; Modality; Modeling; Mutation; Outcome; Pathogenesis; Pathologic; Pathology; Patients; Pharmacology; Plants; Preparation; Preventive therapy; Quinidine; Research; Risk; Risk Factors; Structure-Activity Relationship; Sudden Death; Sudden infant death syndrome; Surface; Syndrome; Testing; Therapeutic; Time; Torsades de Pointes; Turnera; Ventricular; Ventricular Fibrillation; Ventricular Tachycardia; alternative treatment; antagonist; clinically relevant; design; gastrointestinal; implantation; inhibitor; mutant; novel; novel strategies; novel therapeutics; phosphoric diester hydrolase; prevent; response; side effect; sudden cardiac death; young adult

The J-wave syndromes (JWSs), consisting of the Brugada (BrS) and Early Repolarization Syndromes (ERS), have presented a challenge to the cardiology community for over two decades. JWSs are inherited cardiac arrhythmia and sudden cardiac death syndromes that share ECG features, clinical outcomes, and risk factors, as well as a common arrhythmic platform related to amplification of the J wave of the ECG. Two principle hypotheses have been proposed to underlie BrS: repolarization and depolarization. The principal aim of this proposal is to develop a whole heart model of BrS and ERS to advance our understanding of the pathophysiology of these syndromes. We will pharmacologically mimic the genetic defects known to underlie the JWSs and record a 12 lead ECG, unipolar and bipolar transmural electrograms from the right ventricular outflow tract (RVOT), RV apex and Left Ventricular inferior wall of Langendorff-perfused whole-hearts. A critical and unique feature will be the use of floating glass microelectrodes to record transmembrane action potentials from the epicardial surface of the RVOT of the intact heart. This aim will, for the first time, provide a whole heart model of the JWSs capable of a direct test of the two hypotheses and definitive identification of the substrate and triggers responsible for the development of ventricular tachycardia and fibrillation (VT/VF). Although implantation of a cardioverter defibrillator (ICD) is generally accepted as first-line therapy for symptomatic JWS patients, a pharmacological approach to therapy is recommended in cases of electrical storm, as an adjunct to ICD, and as preventative therapy for asymptomatic patients at risk for arrhythmic events. A secondary aim of this proposal is to identify safe an effective pharmacologic approaches to therapy of these life-threatening syndromes. We will determine structure-activity relationships (SAR) for acacetin and a test set of structurally similar congeners capable of selectively inhibiting Ito, thus acting to prevent or suppress arrhythmogenicity. We will determine the potency and efficacy of the congeners for inhibition of Ito in HEK cells expressing wild type (WT) Kv4.3 and KCNIP2 as well as pathology-mediated augmentation of Ito using polycistronic constructs that include WT and mutant SCN5A and KCND3 genes that have been associated with the JWSs. We will determine the selectivity of these agents in canine and human ventricular cardiomyocytes. We will then promote the most promising compound(s) to studies in canine coronary-perfused wedge preparations and, ultimately in Langendorff-perfused canine whole-heart models of BrS and ERS. Successful completion of these specific aims should importantly advance our understanding of the cellular mechanisms involved in the pathogenesis of the JWSs and provide a major advance in the pharmacological approach to therapy. These studies have the potential to provide the first major breakthrough in over 20 years for identification of safe and effective agent(s) for JWS. Equally important, the data generated will provide a unique platform for further development of novel therapies via the identification of efficacious lead compounds. Successful management of these syndromes, for which treatment alternatives are currently very limited, will close a very significant gap in our therapeutic armamentarium for individuals at risk for sudden cardiac death.

J波综合征（JWS），包括Brugada（BrS）和早期复极综合征（ERS）， 这是心脏病学界二十多年来的一个挑战。JWS是遗传性心律失常和突发性心脏病 共享ECG特征、临床结局和风险因素以及共同的病理平台的死亡综合征 与心电图J波的放大有关。已经提出了两个基本假设作为BrS的基础： 复极化和去极化。该提案的主要目的是开发BrS和ERS的整体心脏模型， 推进我们对这些综合征的病理生理学的理解。我们将模仿基因 已知JWS的基础缺陷，并记录12导联ECG、单极和双极右侧透壁电描记图 心室流出道（RVOT）、RV心尖和Langendorff灌注全心的左室下壁。一 关键和独特的特点将是使用浮动玻璃微电极记录跨膜动作电位， 完整心脏RVOT的心外膜表面。这一目标将首次提供一个完整的心脏模型， JWS能够直接测试两种假设，并明确识别负责的底物和触发因素 室性心动过速和室颤（VT/VF）的发展。虽然植入心律转复除颤器 (ICD)被普遍接受为有症状JWS患者的一线治疗，治疗的药理学方法是 建议在电风暴的情况下，作为ICD的辅助治疗，并作为无症状患者的预防性治疗， 发生中毒事件的风险。该建议的第二个目的是确定安全有效的药理学方法， 治疗这些危及生命的综合征。我们将确定刺槐素的构效关系（SAR），并进行测试 一组结构相似的同系物，能够选择性抑制伊藤，从而起到预防或抑制的作用 致炎性。我们将确定同源物在表达Ito的HEK细胞中抑制Ito的效力和功效。 野生型（WT）Kv4.3和KCNIP 2以及使用多顺反子构建体的病理介导的Ito增强，所述多顺反子构建体 包括与JWS相关的WT和突变的SCN 5A和KCND 3基因。康贝特人将以 这些药物在犬和人心室心肌细胞中的选择性。然后我们将促进最有前途的 将化合物用于犬冠状动脉灌注楔形制剂的研究，并最终用于Langendorff灌注犬的研究 BrS和ERS的全心脏模型。这些具体目标的成功实现将极大地推动我们的 了解参与JWS发病机制的细胞机制，并提供了一个重大进展 在药理学治疗方法中的应用。这些研究有可能提供第一个主要的 20多年来在识别JWS安全有效药剂方面取得了突破。同样重要的是 所产生的数据将为进一步开发新疗法提供一个独特的平台， 有效的先导化合物。这些综合征的成功管理，对于这些综合征， 目前非常有限，将关闭一个非常显着的差距，在我们的治疗设备的个人在风险 心脏性猝死