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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：
10671651
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/10671651
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 Population Extracellular Matrix Feasibility Studies Flecainide Genetic Genetic Carriers 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 Prediction of Response to Therapy Predisposition Proteins Protocols documentation Publishing Race Randomized Recurrence Reporting Risk Single Nucleotide Polymorphism Sotalol Surrogate Markers Symptoms Testing Toxic effect Translations Treatment Efficacy Tretinoin 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 racial population 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）是一种日益增长的流行病，到2050年，约有1600万美国人受到影响。尽管最近