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(JWSS)由Brugada综合征(BRS)和早期复极综合征(ERS)组成 这是心脏病学界二十多年来面临的挑战。JWSS是遗传性心律失常和突发性心脏病 死亡综合征具有相同的心电特征、临床结果和危险因素，以及共同的心律失常平台 与心电图的J波放大有关。有两个主要假设被提出作为BRS的基础： 复极化和去极化。该方案的主要目的是开发BRS和ERS的全心模型，以 促进我们对这些综合征的病理生理学的理解。我们将在药理上模仿基因 已知的缺陷是JWSS的基础，并从右侧记录12导联的心电图、单极和双极跨室壁电 朗宁多夫灌流全心的室流出道(RVOT)、右室心尖部和左室下壁。一个 关键和独特的特征将是使用浮动玻璃微电极记录来自 完整心脏右室流出道的心外膜表面。这个目标将首次提供一个全心全意的模型 JWSS能够直接测试两个假设，并确定负责的底物和触发因素 室性心动过速和室颤(VT/VF)的发展。尽管植入了心律转复除颤器 (ICD)被普遍认为是治疗有症状的JWS患者的一线治疗方法，治疗的药理学方法是 建议在电暴的情况下，作为ICD的辅助手段，并作为无症状患者的预防性治疗 发生心律失常事件的风险。这项建议的第二个目标是确定安全有效的药物治疗方法 这些危及生命的综合症的治疗。我们将确定金合欢素的构效关系(SAR)并进行一项测试 一组结构相似的同系物，能够选择性地抑制Ito，从而起到防止或抑制的作用 致心律失常。我们将确定在HEK细胞中抑制Ito的效力和有效性。 野生型(WT)Kv4.3和KCNIP2以及使用多顺反子构建物的病理介导的Ito增强 包括与JWSS相关的WT和突变的SCN5A和KCND3基因。我们将确定 这些药物在犬和人心肌细胞中的选择性。然后，我们将推动最有前途的 复方(S)在犬冠状动脉灌注楔形制剂中的研究，最终在朗宁多夫犬中的研究 BRS和ERS的全心模型。这些具体目标的成功实现将极大地推动我们 了解JWSS发病的细胞机制并取得重大进展 以药理学的方法进行治疗。这些研究有可能提供第一个主要的 20多年来在JWS安全有效药剂(S)的鉴定上取得了突破。同样重要的是， 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，其治疗替代方案是 目前非常有限，将填补我们在治疗高危人群方面的一个非常重要的差距 因为心源性猝死。

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.