Functional restoration of ventriculo-arterial coupling in cardiogenic shock via dual mechanical support

项目摘要 心源性休克是一种高度病态-心脏功能受损导致多器官衰竭和死亡。 即使及时的药物治疗也常常是不够的，支持血液循环的机械手段也是不够的。 越来越进化。体外膜氧合（ECMO）已迅速被接受，以提供 机械循环支持但对其对左心室功能影响的了解有限限制了其使用。 ECMO通过引入 逆行灌注与来自衰竭心脏的顺行血流碰撞， 分水岭区域，其对终末器官灌注和临床结局的影响未知。 最近的临床研究报告，ECMO患者与经皮 心室辅助装置（pVAD），以提供双重机械支持。有趣的是，这个想法反映了我们自己的想法。 临床观察结果，其中添加pVAD允许左心室卸载并改善临床医生 控制灌注。我们最近利用心脏（宿主）和pVAD（器械）之间相互作用的指标 在心源性休克中，提供对衰竭心脏的生理状态和参数的深入了解， 用于追踪器官功能的变化。我们已经将pVAD支持与ECMO联系起来，并发现 pVAD操作的变化识别器官恢复或疾病进展。我们进一步调查了 ECMO对血流的影响，利用计算流体动力学模型量化诱导的血流中断 通过引入逆行灌注。 我们假设动态分水岭区域影响终末器官灌注，pVAD允许临床医生- 循环的受控调节，从而在功能上恢复心室-动脉耦合。我们调查 该假设通过：（1）确定ECMO对左心室功能的影响;（2）量化血管流量 动力学在ECMO衰竭的心脏循环;和（3）调查双重机械支持的效果， ECMO和pVAD对LV功能和血管血流动力学的影响。我们应用多尺度多模态方法， 评估我们的假设我们将研究ECMO和双机械支持对左室功能的影响， 完整的猪和心源性休克患者的研究。我们将研究血管动力学， 计算流体动力学和ECMO衰竭心脏循环的台式模型。我们的发现会让 深入了解ECMO支持的应用和优化，以改善临床结局和器械设计。 这个项目充分利用了我对休克和机械支持的临床兴趣，工程背景， 和多尺度病理生理系统的研究。在启蒙导师和咨询师的指导下， 在委员会的帮助下，我制定了一个五年计划，以提供我成为一名教师所需的教学和研究培训 成功的独立调查员专注于发展先进的机械支持的末期 心肺疾病

PROJECT SUMMARY Cardiogenic shock is a highly morbid condition - impaired heart function leads to multi-organ failure and death. Even prompt medical therapy is frequently insufficient and mechanical means of supporting the circulation are increasingly evolving. Extracorporeal membrane oxygenation (ECMO) has rapidly been embraced to provide mechanical circulatory support but limited understanding of its impact on left ventricular function restricts its use. ECMO profoundly disrupts coupling between the left ventricle and the arterial system through introduction of retrograde perfusion that collides with antegrade blood flow from the failing heart to generate a dynamic watershed region whose impact on end-organ perfusion and clinical outcomes is unknown. Recent clinical studies report improved outcomes for ECMO patients when paired with a percutaneous ventricular assist device (pVAD) to provide for dual mechanical support. Intriguingly this idea mirrors our own clinical observations in which addition of a pVAD allows for offloading of the left ventricle and improved clinician control of perfusion. We recently harnessed metrics of interactions between the heart (host) and pVAD (device) in cardiogenic shock to provide insight into the physiological state of the failing heart and parameters that can be utilized to track changes in organ function. We have linked pVAD support to ECMO and have discovered that changes in pVAD operation identify organ recovery or disease progression. We have further investigated the effects of ECMO on blood flow utilizing computational fluid dynamic modeling to quantify flow disruptions induced by the introduction of retrograde perfusion. We hypothesize that dynamic watershed regions affect end-organ perfusion and that pVADs allow for clinician- controlled modulation of the circulation thereby functionally restoring ventriculo-arterial coupling. We investigate this hypothesis by: (1) determining ECMO effects on left ventricular function; (2) quantifying vascular flow dynamics in the ECMO-failing heart circulation; and (3) investigating the effect of dual mechanical support with ECMO and a pVAD on LV function and vascular flow dynamics. We apply multiscale multimodal methods to evaluate our hypothesis. We will study the effects of ECMO and then dual mechanical support on LV function in the intact pig and in studies of patients with cardiogenic shock. We will investigate vascular dynamics utilizing computational fluid dynamics and benchtop models of the ECMO-failing heart circulation. Our findings will yield insight into the application and optimization of ECMO support to improve clinical outcomes and device design. This project makes the most of my clinical interest in shock and mechanical support, engineering background, and research in multiscale pathophysiologic systems. With the guidance of enlightened mentors and an advisory committee, I have developed a five-year plan to provide the didactic and research training I need to become a successful independent investigator focused on the development of advanced mechanical support of end-stage cardiopulmonary disease.