Ionic Basis of the Brugada Syndrome

描述(申请人提供)：Brugada综合征是一种恶性的室性心律失常，与每年约10%的高死亡率有关。据信，在所有的突然死亡中，至少有4%是由它造成的。尽管在我们对Brugada综合征的理解方面取得了重要进展，但仍然存在重大差距。关于该综合征的病理生理机制的大部分理论都是基于对灌流的心室楔形的少数研究。在这些研究中，Brugada样心电信号的产生方式是有问题的，所提出的离子机制也没有得到有力的测试。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的治疗策略。 我们的具体目标是：1)确定Ito在Brugada表型AP异常发生中的作用。我们将研究Ito与降低的Na+电流结合是否足以在Brugada综合征中产生异常的心外膜AP复极特性，以及阻断Ito是否能恢复正常的AP形态。2)探讨Brugada综合征收缩功能异常的离子基础。在Brugada患者中已经描述了室壁运动异常，这种异常的基础直接关系到我们对这种疾病的致心律失常底物的理解。我们将在Brugada细胞电设置下检测心肌细胞收缩和钙瞬变异常。(3)探讨晚期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期INA和快速Na+电流，以产生Brugada综合征的异常AP形态，并测试恢复晚期INA作为治疗该综合征的治疗潜力。我们采用的关键方法是一种新技术，即动态夹具。这将使我们能够有选择地和定量地操纵单个心肌细胞中感兴趣的电导，并深入了解Brugada综合征的细胞机制。我们建议的研究非常符合R21计划声明的目的，因为它具有创新性和探索性，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.