Genotype-guided therapy for atrial fibrillation

房颤（AF）是一种日益严重的流行病，到2050年约有1600万美国人受到影响。尽管最近 尽管基于导管的治疗取得了进展，但抗血小板药物（AAD）仍然常用于治疗患有血小板减少性紫癜的患者。 然而，个体患者的反应是高度可变的，并且可能与 严重的毒性。抗心律失常药物治疗房颤的成功有限，部分原因是抗心律失常药物的异质性。 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 是预测哪些房颤患者可能对抗心律失常治疗有反应。新出现的证据 支持了这里要检验的总体假设，即对AAD反应的变异性是由 单核苷酸多态性（SNP）与AF相关。尽管遗传学方法已经揭示了AF 对治疗的敏感性和反应是由底层基质调节的， 对病人床边护理的发现一直受到限制，部分原因是对病人的健康状况缺乏了解。 风险等位基因导致AF的潜在机制，与确定治疗相关的挑战， 有效性和缺乏前瞻性基因型指导研究。目标1将检验假设， 染色体（chr）4q25 AF SNP使用负荷调节症状性AF患者对AAD的反应 作为治疗效果的量度。这一建议的科学前提是基于我们发表的研究 这表明chr4q25 SNP不仅能预测房颤的成功症状控制， 携带风险等位基因的人对Na+通道的反应比K+通道阻滞剂AAD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。我们提出 一项随机交叉研究，患者将接受氟卡尼/索他洛尔治疗， 通过植入可插入的心脏监测器进行评估。虽然我们发现携带chr4q25的房颤患者 AF风险等位基因比携带野生型（WT）等位基因的患者更可能对氟卡尼有反应， 对AAD的这种差异反应的潜在机制知之甚少。目标2将阐明 chr4q25风险SNP差异调节对AAD应答的潜在细胞机制 使用人心房诱导多能干细胞衍生的心肌细胞（hiPSC-CM）的AF患者。第一、 我们将从chr4q25风险和WT等位基因携带者产生心房iPSC-CM。第二，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 体内相关细胞-细胞、细胞-细胞外基质和细胞可溶性因子的微环境工程 交互.第三，我们将从chr4q25 AF风险和 WT等位基因携带者，并检查离体氟卡尼和索他洛尔的作用。这些研究不仅将 改善AF患者对AAD反应的预测，并为基因型指导方法铺平道路 而且还促进了个性化医疗的实践。

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.