Selection of Flow Modulation Protocols for Patients on Continuous Flow Ventricular Assist Devices (CF-VADs)

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PROJECT SUMMARY A major concern with continuous flow ventricular assist devices (CF-VADs) is the resulting non-physiological flow with diminished pulsatility which has been shown to be a major risk factor for development of arteriovenous malformations (AVMs) and gastrointestinal (GI) bleeding. To address this issue, flow modulation via rapid changes in pump impeller speed has been proposed as a technique to introduce ‘artificial pulsatility’. However, given the inadequacy of large animal models with recreating CF-VAD associated non-surgical bleeding events, it is still unclear if artificial pulsatility can prevent these adverse events or what level of artificial pulsatility is even necessary. To evaluate the effects of pulsatility and identify promising flow modulation approaches we developed a vascular pulse perfusion model (VPPM) to culture Human Aortic Endothelial Cells (HAECs) under conditions of normal pulsatile flow or flow with diminished pulsatility (CF-VAD support). Our rationale for modeling arterial vessels is because pulsatility primarily affects the arterial side of the circulatory system and its effects are transduced by endothelial cells that line the large arterial vessels. The VPPM was validated as relevant model via direct comparison with aortic samples of patients with and without CF-VADs. Our published data also shows that loss of pulsatility is associated with an increase in production of pro-angiogenic/inflammatory cytokines. The relevance of these results is further strengthened by supporting data from patients that experience AVMs and GI bleeding events (both CF-VAD related and due to other conditions) showing similar elevated levels of pro- angiogenic/inflammatory cytokines. The VPPM therefore provides a powerful model to evaluate artificial pulsatility in the context of CF-VAD flow modulation and determine if restoring pulse pressure and/or pulse frequency can mitigate non-surgical bleeding events. Based on recent studies that suggest that pulse pressure < 35 mmHg is a major risk factor for development of GI bleeds, we hypothesize that “Diminished pulsatility associated with ‘CF-VAD support’ results in endothelial dysfunction and pro-inflammatory/pro-angiogenic soluble factor production. These changes can be mitigated via introduction of artificial pulsatility using flow modulation strategies where pulse pressure is preserved at > 35 mmHg”. Aim1 will evaluate response of patient derived endothelial cells within the VPPM to CF-VAD flow and quantify angiogenic/inflammatory soluble factor production, Aim2 will follow patients for up to 36 months to evaluate serum levels of pro-angiogenic/pro- inflammatory cytokines and non-surgical bleeding events which will then be compared to results from in-vitro studies within the VPPM and Aim3 will evaluate different flow modulation strategies using patient-derived endothelial cells to determine most promising patient-specific approaches via comparison of hemodynamic profiles and cytokine biomarkers using deep learning approaches. Successful completion of this project will enable identification of device-based strategies to prevent non-surgical bleeding in patients on CF-VAD support.