THERAPY OF REPOLARIZATION ABNORMALITIES

在前一个资助周期中，我们对长QT综合征（LQTS）的研究从遗传学到临床研究中的离子通道生物物理学进展迅速。基廷实验室发现LQT 2基因缺陷后，很快导致桑吉内蒂实验室发现LQT是由l/Kr缺陷引起的。我们的第一个临床研究静脉钾与LQT 2患者发生在四个月内发现的异常基因。项目6继续我们的努力，发展基因特异性治疗继发于复极异常的心律失常。子项目3.1是一项钾预防l/Kr突变患者心律失常的多中心可行性试验。我们已经证明，急性血清钾增加改善这种形式的LQTS患者的复极。我们打算研究这一发现是否可以应用于临床。在这项试点研究中，我们将确定多中心识别和受影响家庭的基因分型，招募遗传性LQTS的儿童和成人，长期治疗的依从性，以及多中心数据收集和方案执行的有效性的可行性。在一项子研究中，我们将测试在LQT 2和LQT 3中被认为具有基因特异性的治疗的特异性。我们假设，非特异性治疗QT间期缩短的疗效低于基因特异性治疗，我们预计这将产生更大的改善ST段和T波（STT）异常比非特异性治疗。子项目3.2是在显示Brugada综合征表型的患者中进行的与抗心律失常药物促心律失常（pIVF）相关的特发性室颤（IVF）和VF的临床研究。这些患者中的许多人都有SCN 5A突变。我们将研究传导和跨室壁复极的差异，以了解假定的钠通道功能障碍如何干扰正常的跨室壁激活和恢复过程。我们还将评估药物治疗纠正异常的能力。一些治疗已经被设想，而其他的将在本项目的电生理观察概念化。我们随后将评估这种疾病的潜在治疗方法的长期疗效。

In the preceding grant cycle our work on the long QT syndrome (LQTS) progressed rapidly from genetics through ion channel biophysics in clinical studies. The discovery in Keating's laboratory of the gene defect in LQT2 led rapidly to the discovery in Sanguinetti's laboratory that LQT is due to l/Kr defects. Our first clinical study of intravenous potassium in a patient with LQT2 took place within four months of the discovery of the abnormal gene. Project 6 continues our effort to develop gene-specific therapy for arrhythmias secondary to repolarization abnormalities. Subproject 3.1 is a multicenter feasibility trial of potassium for prevention of arrhythmia in patients with l/Kr mutations. We have already shown that acutely increased serum potassium improves repolarization in patients with this form of LQTS. We intend to investigate whether this finding can be applied clinically. In this pilot study, we will determine the feasibility of multicenter identification and genotyping of affected families, recruitment of both children and adults with inherited LQTS, compliance with prolonged therapy, and effectiveness of multicenter data collection and protocol enforcement. In a sub-study, we will test the specificity of therapies that have been considered gene-specific in LQT2 and LQT3. We hypothesize that QT reduction by non-specific therapy has less therapeutic efficacy than gene-specific therapy, which we expect to effect a much greater improvement in ST segment and T wave (STT) abnormalities than non-specific therapy. Subproject 3.2 is a clinical investigation of idiopathic ventricular fibrillation (IVF) and VF associated with anti-arrhythmic drug pro- arrhythmia (pIVF) in patients displaying the Brugada syndrome phenotype. Many of these patients have SCN5A mutations. We will investigate conduction and transmural repolarization differences in order to understand how presumed sodium channel dysfunction disturbs the normal transmural activation and recovery processes. We will also evaluate the ability of pharmacologic therapy to correct the abnormalities. Some therapies have already been envisioned, while others will be conceptualized on the electrophysiological observations in this Project. We will subsequently evaluate long term efficacy of potential treatments for this disease.