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，其死亡率约为每年10%。据信，至少4%的突然死亡是由它造成的。尽管我们对Brugada综合征的认识取得了重要进展，但仍存在重大差距。关于该综合征病理生理机制的主流理论大多是基于灌注脑室楔的一些研究。Brugada-like ECG在这些研究中产生的方式是有问题的，并且所提出的离子机制还没有得到有力的测试。我们的目标是通过描述Ito和晚期INa在Brugada综合征的细胞电异常和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这种疾病的潜在新治疗策略。

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.