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2-5百万人，可能导致中风、心悸、心力衰竭，甚至死亡。不幸的是，房颤的治疗方法有限。抗癫痫或心率控制药物耐受性差，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AF而引起了相当大的关注。不幸的是，AF消融术在技术上具有挑战性，成功率仅为50- 70%（而其他心律失常的成功率>90%），并且具有严重的风险。这些局限性的主要原因是人类AF的机制尚不清楚，因此消融无法针对它们。因此，房颤消融是经验性的，会导致心房的广泛破坏。 在这项以患者为导向的研究中期职业指导奖中，申请人为临床医生-科学家提出了一项指导培训计划，应用生物工程原理来解决人类AF维持的机制假设。从培训的角度来看，每位学员将获得申请人和由心律医学，生物工程，计算机建模和生物物理学。通过正式的合作，学员也将能够在细胞电生理学培训。还概述了结构化教学培训。科学上，我们的中心假设是，人类AF是由本地化的来源，而不是广泛分散的机制（多小波折返）。我们将在消融患者中创建详细的心房激活和恢复（复极）图，然后使用近实时的计算分析和药理学干预来研究维持AF的机制。个性化的计算机模型将是独一无二的，因为预测将直接针对同一患者中观察到的AF进行测试，差异用于直接设计进一步的临床研究。由于该项目是在消融时进行的，因此结果很容易转化为实践。候选人有使用生物工程原理，信号处理和计算机模型的跟踪记录，以解决以患者为中心的研究中的机械假说。他还拥有培训临床科学家的记录，他们继续追求以患者为导向的研究，其中许多人获得了校外资助。 拟定的研究有三个目的：1）确定局部源是否维持人类AF; 2）确定复极交替、传导减慢或解剖学因素是否解释了纤维性颤动的紊乱; 3）确定在潜在局部源消融对AF的影响。我们的目标的成功完成将导致人类AF的机械理解的范式变化，以及消融方法。学员将在丰富的跨学科环境中接受培训，并在完成该计划后，将为从事以患者为导向的心律失常研究事业做好充分准备。

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.