Autoimmune Associated Novel Form of Acquired Long QT Syndrome

描述(由申请人提供)： 与细胞内可溶性核糖核蛋白SSA/Ro反应的自身抗体相关的标志性心脏表现是完全性房室传导阻滞，影响抗Ro抗体阳性母亲的胎儿和/或新生儿。抗Ro抗体不被认为是成人心脏传导系统的致病因素，但新的临床证据表明，在各种自身免疫性疾病的患者中，校正的QT(QTC)和复杂性室性心律失常的发生率高得惊人。抗Ro抗体中、高水平(e50U/ml)的患者QT间期延长，抗体滴度低的患者QT间期正常。这种自身免疫相关性长QT综合征的发病机制以及抗Ro抗体阳性患者QTc值的变化尚不清楚，初步数据表明，抗Ro抗体是干扰心室复极而导致心律失常的结果。钾通道HERG传导快速激活的延迟钾电流Ikr，在心室复极过程中起主要作用 药物引起QT间期延长的靶点。我们推测，来自QTC延长患者的抗Ro抗体特异性地靶向并抑制HERG通道功能，以剂量依赖的方式延长动作电位时程，导致延迟复极，在体表心电图上被视为QT延长。这一假说将通过四个目标来验证：目的1：研究抗Ro抗体阳性的结缔组织病(CTD)成人患者QTc变异性延长的电生理学基础。目的#2：探讨部分抗Ro抗体阳性的成人CTD患者QT间期无延长的电生理学基础。目的#3：阐明HERG通道上病理性抗体可能的抗原靶向。目的#4：建立自身免疫性QT间期延长的动物模型。对退伍军人健康的意义：结缔组织病患者QT间期延长的发生率和危及生命的心律失常的发生率都很高。与抗Ro抗体相关的QTC延长本身增加了发生心律失常的风险，对于既有获得性或先天性长QTC的患者来说，这是一个额外的危险因素。这项研究的一个主要影响是潜在的建议，即中到高抗Ro抗体的患者应该从常规的心电检测中受益，那些被确认为与QTC延长相关的抗Ro抗体的患者应该接受咨询，包括关于可能使他们面临危及生命的心律失常风险的药物的教育。这与退伍军人的健康有关，因为在退伍军人中，抗精神病和抗抑郁药物的使用非常普遍，众所周知，这些药物可以延长男性和女性退伍军人的QTC间期。

DESCRIPTION (provided by applicant): The hallmark cardiac manifestation associated with autoantibodies reactive with the intracellular soluble ribonucleoprotein SSA/Ro, is complete atrioventricular block that affects fetuses and/or newborn of mothers with anti-Ro antibodies. Anti-Ro antibodies are not considered pathogenic for the adult heart conduction system but emerging new clinical evidence demonstrates that the prevalence of corrected QT (QTc) and the frequency of complex ventricular arrhythmias is alarmingly higher in patients with various autoimmune diseases. Patients with moderate to high levels (e50 U/ml) of anti-Ro antibodies exhibit longer QTc intervals and those with low antibody titers show normal QTc. The pathogenesis of this autoimmune associated long QT syndrome and the variability in QTc values in patients positive to anti-Ro antibodies is not well understood The preliminary data suggest that anti-Ro antibodies are arrhythmogenic as a result of interference with the ventricular repolarization. The K channel HERG which conducts the rapidly activating delayed K current, IKr, plays a major role in ventricular repolarization and is the main target for drugs-induced QTc prolongation. We hypothesize that anti-Ro antibodies from patients with QTc prolongation specifically target and inhibit HERG channel function, prolong action potential duration in a dose-dependent manner resulting in delayed repolarization seen as QT prolongation on the surface electrocardiogram. This hypothesis will be tested via four aims: Aim#1: To investigate the electrophysiological basis of variability of QTc prolongation in anti-Ro antibody positive adult patients with connective tissue disease (CTD). Aim #2: To investigate the electrophysiological basis for the absence of QTc prolongation in a subset of CTD adult patients with anti-Ro antibodies. Aim#3: To elucidate the possible antigenic target of pathological antibodies on the HERG channel. Aim#4: To establish animal models of autoimmune-associated QTc prolongation. Significance to Veterans Health: Patients with connective tissue diseases have a high prevalence of QTc prolongation and high incidence of life threatening arrhythmias. QTc prolongation associated with anti-Ro antibodies per se confers an increased risk of developing cardiac arrhythmias and represents an additional risk factor for patients with pre-existing acquired or congenital long QTc. A major impact from this study is the potential recommendation that patients with moderate to high anti-Ro antibodies should benefit from routine ECG testing and those identified with anti-Ro antibodies associated QTc prolongation should receive counseling, including education about drugs that may put them at risk for life threatening arrhythmias. This is relevant to Veterans health because of the highly prevalent use of antipsychotic and antidepressant drugs that are known to prolong the QTc interval in both men and women Veterans.