Genotype-guided therapy for atrial fibrillation

心房颤动的基因型引导治疗

• 批准号: 10453452
• 负责人: Dawood Darbar
• 金额: $ 69.8万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453452
• 关键词: 4q25; Acids; Adherent Culture; Adopted; Adverse effects; Adverse event; Affect; Alleles; American; Anti-Arrhythmia Agents; Arrhythmia; Atrial Fibrillation; Atrial Function; Cardiac; Cardiac Myocytes; Catheters; Cell Culture Techniques; Cell Line; Cells; Cessation of life; Chromosomes; Clinical; Cross-Over Studies; Data; Development; Electrophysiology (science); Engineering; Epidemic; Ethnic Origin; Ethnic group; Extracellular Matrix; Feasibility Studies; Flecainide; Genetic; Genotype; Heart Abnormalities; Heart Atrium; Heart failure; Heterogeneity; Human; Implant; Knowledge; Level of Evidence; Measures; Membrane; Modeling; Monitor; Morbidity - disease rate; Patient Care; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Pilot Projects; Potassium Channel; Pre-Clinical Model; Preclinical Testing; Predisposition; Proteins; Protocols documentation; Publishing; Race; Randomized; Recurrence; Reporting; Risk; Single Nucleotide Polymorphism; Sotalol; Surrogate Markers; Symptoms; Testing; Toxic effect; Translations; Treatment Efficacy; Tretinoin; base; channel blockers; experience; genetic approach; genetic variant; heart rhythm; human embryonic stem cell; implantation; improved; in vivo; individual patient; individual response; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; mortality; mouse model; novel; outcome prediction; personalized medicine; predicting response; prospective; response; risk minimization; risk variant; stroke risk; success; therapeutic target; treatment response

Atrial fibrillation (AF) is a growing epidemic with ~16 million Americans affected by 2050. Despite recent advances in catheter-based therapy, antiarrhythmic drugs (AADs) are still commonly used to treat patients with symptomatic AF. However, response in an individual patient is highly variable and can be associated with significant toxicities. The limited success of AADs in treating AF is due in part to heterogeneity of the underlying substrate and our inability to predict individual responses to therapy. Thus, a major knowledge gap is predicting which patients with AF are likely to respond to antiarrhythmic therapy. Emerging evidence supports the overarching hypothesis to be tested here that variability in response to AADs is modulated by a single nucleotide polymorphism (SNP) associated with AF. Although genetic approaches to AF have revealed that susceptibility to and response to therapy is modulated by the underlying substrate, the translation of these discoveries to the bedside care of patients has been limited in part because of poor understanding of the underlying mechanisms by which risk alleles cause AF, challenges associated with determining the therapeutic efficacy and lack of prospective genotype-guided studies. Aim 1 will test the hypothesis that a common chromosome (chr) 4q25 AF SNP modulates response to AADs in patients with symptomatic AF using burden as a measure of therapeutic efficacy. The scientific premise for this proposal is based on our published study which showed that a chr4q25 SNP not only predicted successful symptom control of AF but that patients who carried the risk allele responded better to Na+-channel than K+-channel blocker AADs; a recent study that confirmed our clinical observation; and preliminary data generated in our pilot and feasibility study. We propose a randomized cross-over study whereby patients will be given flecainide/sotalol and therapeutic efficacy will be assessed by implanting insertable cardiac monitors. While we showed that AF patients who carry the chr4q25 AF risk allele are more likely to respond to flecainide than those who carry the wild-type (WT) allele, the underlying mechanism for this differential response to AADs is poorly understood. Aim 2 will elucidate the underlying cellular mechanisms by which a chr4q25 risk SNP differentially modulates response to AADs in patients with AF using human atrial induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). First, we will generate atrial iPSC-CMs from chr4q25 risk and WT allele carriers. Second, we will test the hypothesis that the electrophysiologic (EP) and structural maturity of atrial iPSC-CMs can be enhanced by precise microenvironmental engineering of in-vivo relevant cell-cell, cell-extracellular matrix, and cell-soluble factor interactions. Third, we will determine the EP phenotypes of mature atrial iPSC-CMs from chr4q25 AF risk and WT allele carriers and examine the effects of flecainide and sotalol ex-vivo. The proposed studies will not only improve the prediction of response to AADs for AF patients and pave the way for a genotype-guided approach but also facilitate the practice of personalized medicine.

心房颤动（AF）是一种日益流行的流行病，约有1600万美国人受到2050年影响。尽管最近 基于导管的疗法的进步，抗心律失常药物（AADS）仍然通常用于治疗患者 有症状的AF。但是，单个患者的反应是高度可变的，可以与 显着的毒性。 AAD在治疗AF方面的成功有限，部分原因是 潜在的底物以及我们无法预测个人对治疗的反应。因此，一个主要的知识差距 正在预测哪些AF患者可能对抗心律失常治疗有反应。新兴证据 支持这里要测试的总体假设，即对AADS的可变性由A调制 与AF相关的单核苷酸多态性（SNP）。尽管对AF的遗传方法已经揭示了 对治疗的敏感性和对治疗的反应受到基础的调节，这些底物的翻译 患者的床边护理发现受到限制，部分原因是对 风险等位基因引起AF的基本机制，与确定治疗相关的挑战 功效和缺乏前瞻性基因型引导研究。 AIM 1将检验一个普遍的假设 染色体（CHR）4Q25 AF SNP使用负担调节有症状AF患者的AADS的反应 作为治疗功效的量度。该提案的科学前提是基于我们已发表的研究 这表明CHR4Q25 SNP不仅预测了AF的成功症状控制，还可以预测 与K+通道阻滞剂AADS相比，对Na+通道的反应更好。最近的一项研究 证实了我们的临床观察；以及我们的试点和可行性研究中产生的初步数据。我们建议 一项随机跨界研究，将为患者提供氟卡尼/索他洛尔和治疗功效 通过植入可插入的心脏监护仪进行评估。当我们证明携带CHR4Q25的AF患者 与携带野生型（WT）等位基因的AF风险等位基因相比 对AAD的这种不同反应的基本机制知之甚少。 AIM 2将阐明 CHR4Q25风险SNP差异调节对AADS的响应的潜在细胞机制 使用人类心房诱导多能干细胞衍生的心肌细胞（HIPSC-CMS）的AF患者。第一的， 我们将从CHR4Q25风险和WT等位基因载体中生成心房IPSC-CM。其次，我们将检验假设 可以通过精确增强心房IPSC-CM的电生理（EP）和结构成熟度 体内相关的细胞细胞，细胞 - 细胞基质和细胞溶因子的微环境工程 互动。第三，我们将确定来自CHR4Q25 AF风险的成熟心房IPSC-CM的EP表型 WT等位基因载体并检查氟卡因和索托洛尔的效果。拟议的研究不仅将 改善对AF患者对AADS的反应的预测，并为基因型引导的方法铺平道路 而且还促进了个性化医学的实践。