GENE TRANSFER APPROACHES TO ATRIAL FIBRILATION

描述（由申请人提供）：房颤（AF）是美国和其他发达国家最常见的心律失常。AF严重影响患者的生活，引起从心悸到疲劳、虚弱和活动不耐受的症状，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，医疗费用为60亿至70亿美元。除了房颤引起的问题外，还缺乏针对这种节律紊乱的安全有效的治疗方法。房颤的药物治疗具有疗效差和潜在致命副作用的悠久历史。较新的消融策略正在阵发性房颤中取得进展，但它们是长期的，困难的手术，成功率低于最佳水平，不良事件太频繁。我们提出基因治疗作为一种新的策略来治疗心律失常。在这个建议中，我们假设基因治疗引起的心房传导和不应特性的改变将预防心房颤动。为了验证这一假设，我们将提出3个具体目标：（1）确定通过KCNH 2-G628 S基因转移延长不应期来预防AF的条件;（2）评估IKur和IKr对AF期间心房复极和AF预防的相对贡献;（3）通过延长心房不应期并增加心房连通性和传导来消除AF。这些目标的成功完成将进一步加深我们对持续性房颤机制的理解，并可能将这些发现转化为新的治疗方法。公共卫生相关性：房颤（AF）是美国和其他发达国家最常见的心律失常。AF严重影响患者的生活，引起从心悸到疲劳、虚弱和活动不耐受的症状，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，医疗费用为60亿至70亿美元。除了房颤引起的问题外，还缺乏针对这种节律紊乱的安全有效的治疗方法。房颤的药物治疗具有疗效差和潜在致命副作用的悠久历史。较新的消融策略正在阵发性房颤中取得进展，但它们是长期的，困难的手术，成功率低于最佳水平，不良事件太频繁。该提案的重点是开发新的疗法来治疗和潜在地治愈AF。我们有初步的数据表明，基因疗法可以消除AF。在该提案中，我们将进一步发展我们对这些疗法及其对AF的潜在用途的理解。

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.