Modulation of Ventricular-Vascular Coupling in Veno-Arterial Extracorporeal Membrane Oxygenation - Project Summary/Abstract Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) use in acute myocardial infarction (AMI) is increasing exponentially. Despite this, mortality rates remain high. A likely explanation is that VA-ECMO increases myocardial workload by increasing left ventricular (LV) afterload. Without mechanistic insight, physicians are empirically using additional devices to mitigate afterload, with associated increase in cost and adverse events. A critical barrier in the field is our lack of understanding of how VA-ECMO alters afterload and what interventions may mitigate these effects. In this proposal, we use the four-component model of afterload as arterial impedance, resistance, compliance and wave reflection to fully define how VA-ECMO changes afterload in an innovative and highly translational animal model of VA-ECMO in AMI. In exciting preliminary data, we identified a persistent increase in impedance after activation of VA-ECMO, which may represent a potential therapeutic target. Our central hypothesis is that VA-ECMO increases impedance through early wave reflection and that reducing early wave reflection will limit increases in ventricular work and myocardial injury imparted by VA-ECMO. To test this hypothesis, we will use our highly translational preclinical model of AMI to 1) determine how ventricular-arterial coupling is altered by VA-ECMO in the presence of cardiac dysfunction, 2) test whether pharmacologic or VA-ECMO device-based strategies can reduce impedance, LV work and myocardial injury, and 3) test whether concomitant use of intra-aortic balloon counterpulsation reduces impedance and myocardial injury due to VA-ECMO. These results will define the mechanisms by which VA- ECMO mediates afterload, identify novel strategies to limit increases in LV work and myocardial injury in VA- ECMO and provide critically needed mechanistic and highly translational insight into management of patients requiring VA-ECMO, with the ultimate goal to improve outcomes in AMI associated cardiogenic shock. Together with Dr. Everett’s quantitative medical engineering and cardiology background, scientific and career development mentorship from Dr. Navin Kapur and innovative Advisory Committee of physician-scientists, the fertile and supportive environment of the Tufts CardioVascular Center and Molecular Cardiology Research Institute, and proposed 5-year career development plan and training objectives, this work will provide Dr. Everett with critical 80% protected research time and expertise in the new disciplines of invasive ventricular and vascular hemodynamics, computational data methods for data-driven discovery, preclinical model design and development, expertise in mechanical circulatory support device function and skills in grant writing and career development. This additional training is crucial for Dr. Everett to reach her long-term goals to establish a distinctive clinical translational career path and successfully transition to R01 funding as an independent cardiologist-engineer who can change the paradigms and practice of cardiovascular medicine.
