GENE TRANSFER APPROACHES TO ATRIAL FIBRILATION

描述（由申请人提供）：心房颤动（AF）是美国和其他发达国家最常见的心律失常。房颤严重影响患者的生活，引起心悸、疲劳、虚弱和活动不耐等症状，并大大增加中风、充血性心力衰竭和死亡的风险。对公共卫生的影响是巨大的，每年有40多万人住院，医疗保健费用为60亿至70亿美元。房颤引起的问题还包括缺乏安全有效的治疗方法。药物治疗AF的历史很长，疗效差，并有潜在的致命副作用。新的消融策略在阵发性房颤中取得了进展，但它们是一个漫长、困难的过程，成功率低于最佳水平，而且不良事件过于频繁。我们提出基因治疗作为治疗心律失常的新策略。在这一建议中，我们假设基因治疗诱导的心房传导和难治性质的改变将预防房颤。为了验证这一假设，我们将解决3个具体目标：(1)确定KCNH2-G628S基因转移导致房颤不应期延长的预防条件；(2)评估IKur和IKr对房颤期间心房复极和房颤预防的相对贡献；(3)通过延长心房难治性并增加心房连通和传导来消除房颤。这些目标的成功完成将进一步加深我们对AF维持机制的理解，并可能将这些发现转化为新的治疗方法。公共卫生相关性：心房颤动（AF）是美国和其他发达国家最常见的心律失常。房颤严重影响患者的生活，引起心悸、疲劳、虚弱和活动不耐等症状，并大大增加中风、充血性心力衰竭和死亡的风险。对公共卫生的影响是巨大的，每年有40多万人住院，医疗保健费用为60亿至70亿美元。房颤引起的问题还包括缺乏安全有效的治疗方法。药物治疗AF的历史很长，疗效差，并有潜在的致命副作用。新的消融策略在阵发性房颤中取得了进展，但它们是一个漫长、困难的过程，成功率低于最佳水平，而且不良事件过于频繁。本提案的重点是开发治疗和潜在治愈房颤的新疗法。我们有初步数据显示基因疗法可以消除房颤。在本提案中，我们将进一步了解这些疗法及其在房颤中的潜在应用。

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common rhythm disturbance in the US and other developed countries. AF significantly affects the lives of the afflicted, causing symptoms that range from palpitations to fatigue, weakness and activity intolerance, and substantially increasing the risks of stroke, congestive heart failure and death. The impact on public health is substantial, with more than 400,000 hospital admissions per year and $6-7 billion in healthcare costs. Adding to the problems caused by AF is the lack of safe and effective therapies for this rhythm disorder. Pharmacotherapy for AF has a long history of poor efficacy and potentially lethal side effects. Newer ablation strategies are making inroads in paroxysmal AF, but they are long, difficult procedures with less than optimal success rates and too frequent adverse events. We have proposed gene therapy as a new strategy to treat cardiac arrhythmias. In this proposal, we hypothesize that gene therapy-induced alterations in atrial conduction and refractory properties will prevent atrial fibrillation. To test this hypothesis, we will address 3 specific aims: (1) to define conditions for AF prevention with refractory period prolongation from KCNH2-G628S gene transfer; (2) to assess the relative contributions of IKur and IKr to atrial repolarization during AF and to AF prevention, and (3) to eliminate AF by prolonging atrial refractory properties in combination with increasing atrial connectivity and conduction. Successful completion of these aims will further our understanding of the mechanism responsible for sustaining AF and possibly allow translation of these findings into novel therapies. PUBLIC HEALTH RELEVANCE: Atrial fibrillation (AF) is the most common rhythm disturbance in the US and other developed countries. AF significantly affects the lives of the afflicted, causing symptoms that range from palpitations to fatigue, weakness and activity intolerance, and substantially increasing the risks of stroke, congestive heart failure and death. The impact on public health is substantial, with more than 400,000 hospital admissions per year and $6-7 billion in healthcare costs. Adding to the problems caused by AF is the lack of safe and effective therapies for this rhythm disorder. Pharmacotherapy for AF has a long history of poor efficacy and potentially lethal side effects. Newer ablation strategies are making inroads in paroxysmal AF, but they are long, difficult procedures with less than optimal success rates and too frequent adverse events. This proposal focuses on developing new therapies to treat and potentially cure AF. We have preliminary data showing that gene therapies can eliminate AF. In this proposal, we will further develop our understanding of these therapies and their potential use with AF.