Toward a Mechanism-Based Approach to Treating Atrial Fibrillation

寻找基于机制的心房颤动治疗方法

• 批准号: 9068340
• 负责人: Bjorn C Knollmann
• 金额: $ 7.79万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9068340
• 关键词: 4q25; Ablation; Animals; Anti-Arrhythmia Agents; Arrhythmia; Atrial Fibrillation; Atrial Natriuretic Factor; Calsequestrin; Cardiac; Cells; Chromosomes; Chronic; Clinical; Clinical Markers; Clinical Trials; Controlled Clinical Trials; Data; Double-Blind Method; Electrophysiology (science); Etiology; Failure; Fibrosis; Flecainide; Functional disorder; Genetic; Genetic Markers; Health; Heart; Heart Atrium; Heterogeneity; Human; Human Genetics; Hypertrophy; Individual; Knockout Mice; Maps; Modeling; Molecular; Mus; Mutation; Optics; Patients; Pharmaceutical Preparations; Pharmacotherapy; Predisposition; Property; Publishing; Randomized; Recording of previous events; Recurrence; Research; Risk; RyR2; Ryanodine Receptor Calcium Release Channel; Single Nucleotide Polymorphism; Testing; Time; Tissues; Translating; Troponin T; Variant; Work; active control; base; channel blockers; comparative efficacy; design; drug efficacy; drug testing; enantiomer; genetic variant; homeodomain; individual patient; inhibitor/antagonist; insight; mouse model; predicting response; prevent; research study; response; risk variant; success; targeted treatment; tool; transcription factor

DESCRIPTION (provided by applicant): Although atrial fibrillation (AF) is the most prevalent cardiac arrhythmia requiring antiarrhythmic drug therapy, response in an individual patient is highly variable with frequent AF recurrence. The limited success of drug therapy has been attributed in part to failure to target therapy to underlying mechanisms. Recent experimental work from our group and others in mouse models suggests that Ca leak via type 2 ryanodine receptor (RyR2) Ca release channels is one important mechanism responsible for triggering paroxysmal AF. While Ca leak has been documented in atrial tissue from AF patients, the causal relationship to human AF remains controversial. Hence, proposed here will test our overarching hypothesis that leaky RyR2 channels confer AF risk that can be targeted therapeutically in humans. Our published and preliminary data demonstrate that the R-enantiomer of propafenone is the most potent inhibitor of RyR2 Ca release among clinically approved antiarrhythmic drugs. R-propafenone was strikingly effective in suppressing Ca-triggered focal AF in calsequestrin null mice (Casq2-/-), whereas S-propafenone that largely lacks RyR2 blocking properties was significantly less effective. Since R- and S-propafenone are equipotent Na channel blockers and racemic propafenone is used clinically, the two propafenone enantiomers can be used as tools to determine the contribution of leaky RyR2 channels to AF risk in humans, enabling us to translate findings from mice to patients. In humans, common AF-associated 4q25 single nucleotide polymorphisms (SNPs) near the paired-like homeodomain transcription factor 2 (PITX2) are currently the strongest genetic markers of AF risk. While the functional effects of the SNPs remain controversial, our published data show that individuals carrying 4q25 risk alleles respond better to Class IC drugs flecainide and propafenone, both of which also inhibit RyR2 channels. In contrast, Class III drugs that lack RyR2 blocking properties were less effective in 4q25 carriers. These results raise the exciting possibility to be tested below that 4q25 risk alleles are markers for leaky RyR2 channels in humans with AF. Hence, Aim 1 will determine whether Ca leak contributes to the underlying pro-arrhythmic mechanism in diverse mouse models with inducible AF: Pitx2 haploinsufficient mice (Pitx2+/-), mice carrying human AF mutations in the cardiac Na channel (Scn5a-D1275N) in the atrial natriuretic peptide (mut-NPPA), and in troponin T that causes atrial hypertrophy and fibrosis (TnT-F110I). Aim 2 will test the hypothesis that the underlying electrophysiological mechanisms predict response to drug therapy in mice. The clinical trial in Aim 3 will test whether results from murine AF models predict antiarrhythmic drug efficacy in humans with paroxysmal AF, and whether the 4q25 risk alleles can identify AF patients who will benefit from RyR2 channel block. Accomplishing the aims could provide proof of concept that mouse AF research is translatable to humans, and that drug testing at the time of AF ablation in the clinical EP lab may help individualize AF drug therapy.

描述（由申请人提供）：虽然房颤（AF）是最常见的需要抗心律失常药物治疗的心律失常，但个体患者的反应差异很大，AF复发频繁。药物治疗的有限成功部分归因于未能将治疗靶向于潜在机制。我们小组和其他人最近在小鼠模型中的实验工作表明，钙泄漏通过2型兰尼碱受体（RyR 2）钙释放通道是一个重要的机制，负责触发阵发性房颤。虽然钙泄漏已记录在心房组织房颤患者，人类房颤的因果关系仍然存在争议。因此，这里提出的将测试我们的总体假设，即泄漏的RyR 2通道赋予AF风险，可以在人类中进行治疗。我们已发表的和初步的数据表明，普罗帕酮的R-对映体是临床批准的抗心律失常药物中最有效的RyR 2 Ca释放抑制剂。R-普罗帕酮在抑制钙螯合蛋白缺失小鼠（Casq 2-/-）中的Ca触发的局灶性AF中显著有效，而在很大程度上缺乏RyR 2阻断特性的S-普罗帕酮的有效性显著降低。由于R-和S-普罗帕酮是等效的Na通道阻滞剂，外消旋普罗帕酮在临床上使用，这两种普罗帕酮对映体可用作确定RyR 2通道泄漏对人类AF风险的贡献的工具，使我们能够将研究结果从小鼠转化为患者。在人类中，常见的AF相关4 q25单核苷酸多态性（SNP）靠近配对样同源结构域转录因子2（PITX 2）是目前AF风险最强的遗传标记。虽然SNP的功能效应仍存在争议，但我们发表的数据显示，携带4 q25风险等位基因的个体对IC类药物氟卡尼和普罗帕酮的反应更好，这两种药物也抑制RyR 2通道。相比之下，缺乏RyR 2阻断特性的III类药物在4 q25携带者中效果较差。这些结果提出了下面要测试的令人兴奋的可能性，即4 q25风险等位基因是AF患者中渗漏RyR 2通道的标志物。因此，目标1将确定Ca渗漏是否有助于诱导型AF的不同小鼠模型中的潜在促排卵机制：Pitx 2单倍缺陷小鼠（Pitx 2 +/-），心脏Na通道中携带人AF突变的小鼠（Scn 5a-D1275 N）在心房利钠肽（mut-NPPA）和引起心房肥大和纤维化的肌钙蛋白T（TnT-F110 I）中。目的2将检验潜在的电生理机制预测小鼠对药物治疗的反应的假设。Aim 3中的临床试验将测试来自鼠AF模型的结果是否预测患有阵发性AF的人类中的抗心律失常药物疗效，以及4 q25风险等位基因是否可以识别将从RyR 2通道阻滞中受益的AF患者。实现这些目标可以提供概念证明，即小鼠AF研究可转化为人类，并且在临床EP实验室进行AF消融时的药物测试可能有助于个性化AF药物治疗。