GENE TRANSFER APPROACHES TO ATRIAL FIBRILATION

描述(申请人提供)：房颤(房颤)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，导致从心悸到疲劳、虚弱和活动不耐受等一系列症状，并大幅增加中风、充血性心力衰竭和死亡的风险。这对公共健康的影响是巨大的，每年有40多万人入院，医疗成本高达60-70亿美元。房颤造成的问题是缺乏安全有效的治疗这种节律紊乱的方法。房颤的药物治疗有很长的历史，疗效不佳，而且有潜在的致命性副作用。较新的消融策略在阵发性房颤中取得了进展，但它们是漫长而困难的手术，成功率不高，不良事件太频繁。我们提出了基因治疗作为治疗心律失常的新策略。在这项建议中，我们假设基因治疗引起的心房传导和难治性改变将预防心房颤动。为了验证这一假设，我们将解决三个具体目标：(1)明确KCNH2-G628S基因转移不应期延长预防房颤的条件；(2)评估IKUR和IKR在房颤时心房复极和预防房颤中的相对贡献；(3)通过延长心房不应性结合增加心房连接和传导来消除房颤。这些目标的成功完成将进一步加深我们对房颤持续机制的理解，并可能将这些发现转化为新的治疗方法。公共卫生相关性：在美国和其他发达国家，房颤是最常见的节律紊乱。房颤严重影响患者的生活，导致从心悸到疲劳、虚弱和活动不耐受等一系列症状，并大幅增加中风、充血性心力衰竭和死亡的风险。这对公共健康的影响是巨大的，每年有40多万人入院，医疗成本高达60-70亿美元。房颤造成的问题是缺乏安全有效的治疗这种节律紊乱的方法。房颤的药物治疗有很长的历史，疗效不佳，而且有潜在的致命性副作用。较新的消融策略在阵发性房颤中取得了进展，但它们是漫长而困难的手术，成功率不高，不良事件太频繁。这项建议的重点是开发新的治疗方法来治疗和潜在地治愈房颤。我们有初步数据表明，基因疗法可以消除房颤。在这份提案中，我们将进一步加深我们对这些疗法的理解，以及它们对房颤的潜在用途。

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.