The Maintenance of Human Atrial Fibrillation

描述（由申请人提供）：心房颤动（AF）是美国最常见的心律失常，影响2-5百万患者，可导致中风、心悸、心力衰竭，甚至死亡。不幸的是，房颤的治疗是有限的。抗心律失常或控制心率的药物耐受性差，副作用频繁，不能降低中风风险。消融术是一种新兴的微创治疗方法，因为它可以消除房颤，引起了相当大的关注。不幸的是，房颤消融术在技术上具有挑战性，只有50- 70%的成功率（相比之下，其他心律失常的成功率为90%），而且风险严重。这些限制的一个主要原因是人类房颤的机制尚不清楚，因此消融不能针对它们。因此，房颤消融是经验性的，导致心房的广泛破坏。在本次面向患者研究的职业中期指导奖中，申请人为临床医生和科学家提出了一个指导培训计划，应用生物工程原理来解决人类房颤维持的机制假设。从培训的角度来看，每位学员将接受申请人和一个由心律医学、生物工程、计算机建模和生物物理学专家组成的跨学科研究委员会的持续指导。通过正式的合作，学员也将能够在细胞电生理学培训。结构化的教学训练也被概述。从科学上讲，我们的中心假设是人类房颤是由局部来源维持的，而不是广泛分散的机制（多小波重入）。我们将创建消融患者房颤激活和恢复（复极）的详细图，然后使用计算分析和近实时的药理学干预来研究维持房颤的机制。个性化计算机模型的独特之处在于，预测将直接针对同一患者观察到的房颤进行测试，差异将用于直接设计进一步的临床研究。由于该项目是在消融中进行的，结果将很容易转化为实践。该候选人具有使用生物工程原理，信号处理和计算机模型来解决心律失常患者导向研究中的机制假设的记录。他还培养了一批临床科学家，他们继续从事以患者为导向的研究，其中许多人获得了校外资助。拟议的研究有三个目的：1)确定局部来源是否维持人类房颤；2)确定复极交替、传导减慢或解剖因素是否可以解释纤颤的紊乱；3)确定潜在局部源消融对AF的影响。我们的目标的成功完成将导致人类房颤机制理解的范式改变，以及其消融的方法。学员将在丰富的跨学科环境中接受培训，完成本课程后，将为从事心律失常患者导向研究的职业做好充分准备。

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most prevalent heart rhythm disorder in the U.S., affecting 2-5 million individuals in whom it may cause stroke, palpitations, heart failure, and even death. Unfortunately, therapy for AF is limited. Anti-arrhythmic or rate-controlling drugs are poorly tolerated, with frequent side effects and do not reduce stroke risk. Ablation is an emerging minimally invasive therapy that has attracted considerable attention because it may eliminate AF. Unfortunately, AF ablation is technically challenging, with a success of only 50-70 % (versus >90% for other arrhythmias), and serious risks. A major cause of these limitations is that the mechanisms for human AF are not known and thus ablation cannot be directed to them. As a result, AF ablation is empiric and results in extensive destruction of the atrium. In this Mid-Career Mentoring Award in Patient Oriented Research, the applicant proposes a mentored training program for clinician-scientists, applying bioengineering principles to address mechanistic hypotheses on the maintenance of human AF. From a training perspective, each mentee will receive continuous mentoring by the applicant and an interdisciplinary research committee comprising experts in heart rhythm medicine, bioengineering, computer modeling and biological physics. Through formalized collaborations, mentees will also be able to train in cellular electrophysiology. Structured didactic training is also outlined. Scientifically, our central hypothesis is that human AF is maintained by localized sources, as opposed to widely dispersed mechanisms (multi-wavelet reentry). We will create detailed maps of atrial activation and recovery (repolarization) in AF in patients at ablation, and then use computational analysis and pharmacologic interventions in near-real-time to study mechanisms that maintain AF. Personalized computer models will be unique in that predictions will be tested directly against observed AF in the same patient, with discrepancies used to directly design further clinical studies. Because the project is performed at ablation, results will be easily translated to practice. The candidate has a track-record of using bioengineering principles, signal processing and computer models to address mechanistic hypotheses in arrhythmia-focused patient oriented research. He also has a track record of training clinician-scientists who continue to pursue patient oriented research, many of whom have secured extramural funding. Proposed studies address three Aims: 1) To determine if localized sources maintain human AF; 2) To determine if repolarization alternant, conduction slowing or anatomic factors explain disorganization to fibrillation; 3) to determine the impact on AF of ablating at potential localized sources. Successful completion of our Aims will lead to a paradigm-change in the mechanistic understanding of human AF, and approaches to its ablation. Mentees will be trained in a rich interdisciplinary environment and, on completing this program, will be well prepared to embark upon careers in patient-oriented research in heart rhythm disorders. PUBLIC HEALTH RELEVANCE: fibrillation (AF) is an enormous public health problem that affects 2-5 million Americans, causing morbidity or death from stroke, rapid heartbeats and heart failure. Through this Mid-Career Mentoring Award in Patient Oriented Research, the applicant will perform research and train junior physician-researchers to better understand AF, and determine if abnormal activity in small regions or more widespread regions of the heart cause AF. By performing these studies in patients during clinical procedures, this project may lead to a paradigm-shift in understanding and treating AF.