Genotype-guided therapy for atrial fibrillation

心房颤动的基因型引导治疗

基本信息

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
项目类别：
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

项目摘要

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) 是一种日益严重的流行病，到 2050 年将有约 1600 万美国人受到影响。尽管基于导管的治疗取得了进展，但抗心律失常药物 (AAD) 仍然常用于治疗患有以下疾病的患者有症状的房颤。然而，个体患者的反应差异很大，并且可能与显着的毒性。 AAD 在治疗 AF 方面取得的成功有限，部分原因是药物的异质性潜在的底物和我们无法预测个体对治疗的反应。因此，一个重大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。新出现的证据支持这里要测试的总体假设，即对 AAD 的反应的变异性是由与 AF 相关的单核苷酸多态性 (SNP)。尽管 AF 的遗传方法已揭示对治疗的敏感性和反应是由潜在的底物调节的，这些底物的翻译对患者床边护理的发现受到限制，部分原因是对患者床边护理的了解不足。风险等位基因引起 AF 的潜在机制，与确定治疗方法相关的挑战功效和缺乏前瞻性基因型引导研究。目标 1 将检验以下假设：染色体 (chr) 4q25 AF SNP 使用负荷调节有症状 AF 患者对 AAD 的反应作为治疗效果的衡量标准。该提案的科学前提基于我们发表的研究结果表明，chr4q25 SNP 不仅可以预测 AF 症状的成功控制，而且还可以预测患者携带风险等位基因对 Na+ 通道的反应优于 K+ 通道阻断剂 AAD；最近的一项研究表明证实了我们的临床观察；以及我们的试点和可行性研究中生成的初步数据。我们建议一项随机交叉研究，患者将接受氟卡尼/索他洛尔治疗，治疗效果将通过植入可插入心脏监测器进行评估。虽然我们表明携带 chr4q25 的 AF 患者 AF 风险等位基因比携带野生型 (WT) 等位基因（即对 AAD 的这种差异反应的潜在机制尚不清楚。目标 2 将阐明 chr4q25 风险 SNP 差异调节对 AAD 反应的潜在细胞机制使用人心房诱导多能干细胞衍生的心肌细胞（hiPSC-CM）治疗房颤患者。第一的，我们将从 chr4q25 风险和 WT 等位基因携带者生成心房 iPSC-CM。其次，我们将检验假设心房 iPSC-CM 的电生理 (EP) 和结构成熟度可以通过精确的方法来增强体内相关细胞-细胞、细胞-细胞外基质、细胞可溶性因子的微环境工程互动。第三，我们将根据 chr4q25 AF 风险确定成熟心房 iPSC-CM 的 EP 表型 WT 等位基因携带者并检查氟卡尼和索他洛尔的离体作用。拟议的研究不仅将改善 AF 患者对 AAD 反应的预测，并为基因型引导方法铺平道路也有利于个体化医疗的实践。