Effects of Pulsatility on Arterial Endothelial and Smooth Muscle Cells

Abstract

Continuous flow ventricular assist device (CFVAD) support in advanced heart failure patients causes diminished pulsatility, which has been associated with adverse events including gastrointestinal bleeding, end organ failure, and arteriovenous malformation. Recently, pulsatility augmentation by pump speed modulation has been proposed as a means to minimize adverse events. Pulsatility primarily affects endothelial and smooth muscle cells in the vasculature. To study the effects of pulsatility and pulse modulation using CFVADs, we have developed a microfluidic co-culture model with human aortic endothelial (ECs) and smooth muscle cells (SMCs) that can replicate physiologic pressures, flows, shear stresses, and cyclical stretch. The effects of pulsatility and pulse frequency on ECs and SMCs were evaluated during (1) normal pulsatile flow (120/80 mmHg, 60 bpm), (2) diminished pulsatility (98/92 mmHg, 60 bpm), and (3) low cyclical frequency (115/80 mmHg, 30 bpm). Shear stresses were estimated using computational fluid dynamics (CFD) simulations. While average shear stresses (4.2 dynes/cm²) and flows (10.1 mL/min) were similar, the peak shear stresses for normal pulsatile flow (16.9 dynes/cm²) and low cyclic frequency (19.5 dynes/cm²) were higher compared to diminished pulsatility (6.45 dynes/cm²). ECs and SMCs demonstrated significantly lower cell size with diminished pulsatility compared to normal pulsatile flow. Low cyclical frequency resulted in normalization of EC cell size but not SMCs. SMCs size was higher with low frequency condition compared to diminished pulsatility but did not normalize to normal pulsatility condition. These results may suggest that pressure amplitude augmentation may have a greater effect in normalizing ECs, while both pressure amplitude and frequency may be required to normalize SMCs morphology. The co-culture model may be an ideal platform to study flow modulation strategies.