ORIGINAL PRE-CLINICAL SCIENCE
Evaluation of flow-modulation approaches in ventricular assist devices using an in-vitro endothelial cell culture model

https://doi.org/10.1016/j.healun.2018.10.007Get rights and content

BACKGROUND

Continuous-flow ventricular assist devices (CF-VADs) produce non-physiologic flow with diminished pulsatility, which is a major risk factor for development of adverse events, including gastrointestinal (GI) bleeding and arteriovenous malformations (AVMs). Introduction of artificial pulsatility by modulating CF-VAD flow has been suggested as a potential solution. However, the levels of pulsatility and frequency of CF-VAD modulation necessary to prevent adverse events are currently unknown and need to be evaluated.

METHODS

The purpose of this study was to use human aortic endothelial cells (HAECs) cultured within an endothelial cell culture model (ECCM) to: (i) identify and validate biomarkers to determine the effects of pulsatility; and (ii) conclude whether introduction of artificial pulsatility using flow-modulation approaches can mitigate changes in endothelial cells seen with diminished pulsatile flow. Nuclear factor erythroid 2–related factor 2 (Nrf-2)–regulated anti-oxidant genes and proteins and the endothelial nitric oxide synthase/endothelin-1 (eNOS/ET-1) signaling pathway are known to be differentially regulated in response to changes in pulsatility.

RESULTS

Comparison of HAECs cultured within the ECCM (normal pulsatile vs CF-VAD) with aortic wall samples from patients (normal pulsatile [n = 5] vs CF-VADs [n = 5]) confirmed that both the Nrf-2–activated anti-oxidant response and eNOS/ET-1 signaling pathways were differentially regulated in response to diminished pulsatility. Evaluation of 2 specific CF-VAD flow-modulation protocols to introduce artificial pulsatility, synchronous (SYN, 80 cycles/min, pulse pressure 20 mm Hg) and asynchronous (ASYN, 40 cycles/min, pulse pressure 45 mm Hg), suggested that both increased expression of Nrf-2–regulated anti-oxidant genes and proteins along with changes in levels of eNOS and ET-1 can potentially be minimized with ASYN and, to a lesser extent, with SYN.

CONCLUSIONS

HAECs cultured within the ECCM can be used as an accurate model of large vessels in patients to identify biomarkers and select appropriate flow-modulation protocols. Pressure amplitude may have a greater effect in normalizing anti-oxidant response compared with frequency of modulation.

Section snippets

Endothelial cell culture model

The ECCM setup used for generation of normal and CF-VAD flow conditions consists of a pulsatile flow pump with adjustable frequency and stroke volume (Model 1407, Harvard Apparatus, Holliston, MA), a compliance element to adjust the level of pulsatility under CF-VAD support conditions, a cell-culture chamber with a compliant thin membrane that mimics a section of the vessel wall, a one-way flow control valve, a tunable flow resistance element to adjust systemic arterial resistance, and a

Nrf-2–regulated anti-oxidant response and ET-1/eNOS signaling in ECCM (NF vs CF) and aortic wall samples (normal vs CF-VAD)

Evaluation of HAECs within the ECCM for 7 days under conditions of normal (NF; heart rate 80 beats/min, pulse pressure 40 mm Hg) and CF-VAD flow (CF; heart rate 80 beats/min, pulse pressure 5 mm Hg) showed transcriptional upregulation of Nrf-2‒dependent anti-oxidant genes involved in glutathione metabolism and a significant increase in transcript levels of associated genes, including Gclc, Gclm, Gpx1, catalase, Sod1, Sod2, and G6pd, in relation to normal pulsatile flow conditions (Figure 2A).

Discussion

Physically, normal and CF-VAD flow induce different stress profiles on cultured HAECs. Cells subject to CF-VAD flow constantly undergo fluid flow and stretch, whereas cells subject to normal flow have a refractory period in which they relax and have no fluid flow. Endothelial cells subject to normal pulsatile flow also undergo higher peak stretch and shear stress when compared with CF-VAD flow. Results from our previous study demonstrate that diminished pulsatility influenced HAEC morphology

Disclosure statement

The authors have no conflicts of interest to disclose.

We thank the staff of the Comprehensive Cardiovascular Center at the University of Alabama at Birmingham, and the Center for Free Radical Biology for support and help with this project. Dr. Gobinath Shanmugam is also acknowledged for help with gene and protein expression studies.

This project was supported by start-up funds from the Division of Cardiovascular Disease (to P.S.), a pilot grant from the Comprehensive Cardiovascular Center, the

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    T.A.H. and N.S.R. contributed equally to this work as co‒first authors.

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