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

项目总结 心源性休克是一种高度病态--心脏功能受损会导致多器官衰竭和死亡。 即使是及时的药物治疗也常常是不够的，支持循环的机械手段是 不断演变。体外膜氧合(ECMO)已迅速被接受，以提供 机械循环支持，但对其对左心功能影响的了解有限，限制了其应用。 ECMO通过引入血管紧张素转换酶来严重破坏左心室和动脉系统之间的连接 逆行灌注与衰竭心脏的顺行血流发生碰撞，从而产生动态血流 分水岭地区，其对终末器官灌注和临床结果的影响尚不清楚。 最近的临床研究报告了ECMO患者在配合经皮穿刺术时的预后改善。 提供双重机械支持的脑室辅助装置(PVAD)。耐人寻味的是，这个想法反映了我们自己的想法 添加PVAD可减轻左心室负荷的临床观察和改善临床医生的情况 控制灌流。我们最近利用了心脏(主机)和PVAD(设备)之间的交互指标 在心源性休克中提供对衰竭心脏的生理状态的洞察以及可以 用于跟踪器官功能的变化。我们已将PVAD支持与ECMO联系起来，并发现 PVAD手术中的变化可确定器官恢复或疾病进展。我们进一步调查了 应用计算流体动力学模型量化ECMO对血流的影响 通过引入逆行灌流。 我们假设动态分水岭区域影响终末器官灌流，而pVADs允许临床医生- 可控制的循环调节，从而从功能上恢复脑室-动脉连接。我们在调查 这一假设是通过：(1)确定ECMO对左心功能的影响；(2)量化血管流量 ECMO衰竭心脏循环的动力学；以及(3)研究双重机械支持对心脏循环的影响。 ECMO和PVAD对左心功能和血管血流动力学的影响。我们将多尺度多模式方法应用于 评估我们的假设。我们将研究ECMO和双机械支持对左心功能的影响。 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利用 ECMO衰竭心脏循环的计算流体力学和台式模型。我们的发现将会产生 深入了解ECMO支持的应用和优化，以改善临床结果和设备设计。 这个项目最大限度地利用了我在休克和机械支持、工程背景、 以及多尺度病理生理系统的研究。在开明导师的指导下和一位顾问 委员会，我已经制定了一个五年计划，为我提供成为一名 成功的独立研究人员专注于开发先进的末期机械支架 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.