THERAPY OF REPOLARIZATION ABNORMALITIES

复极异常的治疗

• 批准号: 6302302
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-04-15 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302302
• 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.

在之前的资助周期中，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。 Keating 实验室对 LQT2 基因缺陷的发现很快导致 Sanguinetti 实验室发现 LQT 是由 l/Kr 缺陷引起的。我们对 LQT2 患者进行静脉注射钾的首次临床研究是在发现异常基因后四个月内进行的。项目 6 继续努力开发针对复极异常继发性心律失常的基因特异性疗法。子项目 3.1 是一项钾用于预防 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，血清钾的急剧升高可以改善这种 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，我们将确定受影响家庭的多中心鉴定和基因分型的可行性、招募患有遗传性 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。在一项子研究中，我们将测试 LQT2 和 LQT3 中被认为具有基因特异性的疗法的特异性。我们假设非特异性治疗减少 QT 的疗效低于基因特异性治疗，我们预计基因特异性治疗比非特异性治疗对 ST 段和 T 波 (STT) 异常有更大的改善。子项目 3.2 是对表现出 Brugada 综合征表型的患者特发性心室颤动 (IVF) 和与抗心律失常药物促心律失常 (pIVF) 相关的心室颤动 (VF) 的临床研究。其中许多患者有 SCN5A 突变。我们将研究传导和跨壁复极化差异，以了解假定的钠通道功能障碍如何扰乱正常的跨壁激活和恢复过程。我们还将评估药物治疗纠正异常的能力。一些疗法已经被设想出来，而另一些疗法将根据本项目中的电生理学观察进行概念化。我们随后将评估这种疾病的潜在治疗方法的长期疗效。