THERAPY OF REPOLARIZATION ABNORMALITIES

复极异常的治疗

• 批准号: 6420546
• 负责人: Jay W. Mason
• 金额: $ 20.67万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6420546
• 关键词: antiarrhythmic agent; arrhythmia; bioimaging /biomedical imaging; clinical research; electrocardiography; family genetics; heart pharmacology; human subject; human therapy evaluation; long QT syndrome; membrane potentials; potassium channel; potassium ion; sodium channel; ventricular fibrillation

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.

在前面的赠款周期中，我们对长QT综合征（LQT）的工作在临床研究中从遗传学通过离子通道生物物理学迅速发展。基廷对LQT2基因缺陷实验室的发现迅速导致Sanguinetti实验室发现LQT是由于L/KR缺陷引起的。我们对LQT2患者静脉注射钾的首次临床研究发生在发现异常基因的四个月内。项目6继续努力开发用于继发于复极异常的心律不齐的基因疗法。 Subproject 3.1是钾在L/KR突变患者中预防心律不齐的钾的多中心可行试验。我们已经表明，急性增加的血清钾可以改善这种LQT形式的患者的复极化。我们打算研究是否可以在临床上应用这一发现。在这项试点研究中，我们将确定受影响家庭的多中心鉴定和基因分型的可行性，招募具有遗传LQT的儿童和成人，遵守延长治疗以及多中心数据收集和协议执法的有效性。在子研究中，我们将测试在LQT2和LQT3中被认为是基因特异性的疗法的特异性。我们假设与基因特异性治疗相比，非特异性治疗的QT降低具有较低的治疗疗效，我们期望这会比非特异性治疗相比，这会在ST段和T段和T波（STT）异常方面的改善更大。 subproject 3.2是对表现出Brugada综合征表型的患者的特发性心室纤颤（IVF）和与抗心律失常药物心律不齐（PIVF）相关的临床研究。这些患者中有许多患有SCN5A突变。我们将研究传导和透壁复极化差异，以了解假定的钠通道功能障碍如何干扰正常的透壁激活和恢复过程。我们还将评估药理疗法纠正异常的能力。已经设想了一些疗法，而其他疗法将在该项目的电生理观察结果上进行概念化。随后，我们将评估该疾病潜在治疗的长期疗效。