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，其影响具有抗Ro抗体的母亲的胎儿和/或新生儿。抗Ro抗体不被认为是成人心脏传导系统的致病性，但新出现的临床证据表明，校正QT（QTc）的患病率和复杂室性心律失常的频率在各种自身免疫性疾病患者中高得惊人。抗Ro抗体水平中至高（e50 U/ml）的患者QTc间期较长，抗体滴度低的患者QTc间期正常。这种自身免疫相关的长QT综合征的发病机制和抗Ro抗体阳性患者的QTc值的变异性尚不清楚。初步数据表明，抗Ro抗体是干扰心室复极的结果。传导快速激活的延迟钾电流IKr的K通道HERG在心室复极中起主要作用，并且是心室肌细胞的主要功能。 靶向药物诱导QTc延长。我们假设来自QTc延长患者的抗Ro抗体特异性靶向并抑制HERG通道功能，以剂量依赖性方式延长动作电位时程，导致复极延迟，表现为体表心电图上的QT延长。将通过四个目的检验该假设：目的1：研究抗Ro抗体阳性结缔组织病（CTD）成人患者QTc延长变异性的电生理学基础。目的#2：研究抗Ro抗体CTD成人患者亚组中不存在QTc延长的电生理学基础。目的#3：阐明HERG通道上病理抗体的可能抗原靶标。目的4：建立自身免疫相关QTc延长的动物模型。对退伍军人健康的意义：结缔组织病患者QTc间期延长的患病率较高，危及生命的心律失常的发生率较高。与抗Ro抗体本身相关的QTc延长可增加发生心律失常的风险，是既存获得性或先天性长QTc患者的额外风险因素。本研究的一个主要影响是潜在的建议，即抗Ro抗体中度至高度的患者应受益于常规ECG检查，而抗Ro抗体相关QTc延长的患者应接受咨询，包括有关可能使其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，因为抗精神病药和抗抑郁药的使用非常普遍，已知这些药物会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.