Ionic Basis of the Brugada Syndrome

描述（由申请人提供）：Brugada综合征是一种恶性室性心律失常，与每年约10%的高死亡率相关。据信，它至少占所有猝死的4%。虽然我们对Brugada综合征的认识取得了重要进展，但仍存在重大差距。关于该综合征的病理生理机制的主要理论大多是基于一些使用灌注心室楔的研究。在这些研究中产生Brugada样ECG的方式值得怀疑，并且所提出的离子机制尚未得到有力的测试。我们的目标是通过描绘Ito和晚期INa在Brugada综合征的细胞电异常以及收缩功能障碍中的作用来弥合这些差距。我们研究的第二个目标是探索治疗该疾病的潜在新治疗策略。 我们的具体目标是1）确定Ito在Brugada表型中产生AP异常的作用。我们将研究是否伊藤，再加上减少Na+电流，是足以产生异常的心外膜AP复极特性在Brugada综合征，以及是否封锁伊藤恢复正常AP形态。2)探讨Brugada综合征收缩功能异常的离子基础。室壁运动异常已被描述在Brugada患者，这种异常的基础是直接相关的，我们的理解的致瘤性基板的疾病。我们将研究Brugada细胞电设置下的肌细胞收缩和Ca2+瞬时异常。（3）探讨晚发性INa在Brugada综合征AP异常中的作用。我们将研究是否需要减少晚INa除了快速Na+电流产生异常AP形态的Brugada综合征，并测试治疗潜力的恢复晚INa作为一种治疗的综合征。我们采用的关键方法是一种新的技术，动态钳位。这将使我们能够选择性地和定量地操纵感兴趣的单个心肌细胞的电导，并深入了解Brugada综合征的细胞机制。我们提出的研究非常符合R21计划公告的目的，因为它是创新和探索性的，并且与资助计划的目标一致。

DESCRIPTION (provided by applicant): The Brugada syndrome is a malignant form of ventricular arrhythmia that is associated with a high mortality rate of approximately 10% per year. It is believed to be responsible for at least 4% of all sudden deaths. Although important progress has been made in our understanding of the Brugada syndrome, significant gaps remain. Much of the dominating the theory on the pathophysiological mechanism of the syndrome is based on a few studies using perfused ventricular wedges. The way by which the Brugada-like ECG is generated in these studies is questionable, and the proposed ionic mechanisms have not been vigorously tested. Our goal is to bridge these gaps by delineating the role of Ito and late INa in the cellular electrical abnormalities as well as contractile dysfunction of the Brugada syndrome. A second goal of our study is to explore potential new therapeutic strategies for the treatment of the disease. Our specific aims are 1) to determine the role of Ito in generating the AP abnormalities in the Brugada phenotype. We will examine whether Ito, when coupled with a reduced Na+ current, is sufficient to produce the abnormal epicardial AP repolarization properties in Brugada syndrome, and whether blockade of Ito restores the normal AP morphology. 2) To determine the ionic basis of the contractile abnormality in Brugada syndrome. Wall-motion abnormality has been described in Brugada patients, and the basis of such abnormality is directly relevant to our understanding of the arrhythmogenic substrate of the disease. We will examine myocyte contractile and Ca2+ transient abnormalities under Brugada cellular electrical settings. And 3) to determine the role of late INa in the AP abnormalities in the Brugada syndrome. We will examine whether reduction of the late INa in addition to the fast Na+ current is required to produce the abnormal AP morphology of the Brugada syndrome, and test the therapeutic potential of restoration of the late INa as a treatment of the syndrome. The key approach we employment is a novel technique, the dynamic clamp. It will allow us to selectively and quantitatively manipulate the conductance of interest in single myocytes, and gain in depth knowledge of the cellular mechanisms of the Brugada syndrome. Our proposed study closely fits the stated purpose of the R21 Program Announcement because it is innovative and exploratory, and it is consistent with the goal of the funding program.