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Over 90% of cancer deaths result not from primary tumor development, but from metastatic tumors that arise after cancer cells circulate to distal sites via the circulatory system. While it is known that metastasis is an inefficient process, the effect of hemodynamic parameters such as fluid shear stress (FSS) on the viability and efficacy of metastasis is not well understood. Recent work has shown that select cancer cells may be able to survive and possibly even adapt to FSS in vitro. The current research seeks to characterize the effect of FSS on the mechanical properties of suspended cancer cells in vitro. Nontransformed prostate epithelial cells (PrEC LH) and transformed prostate cancer cells (PC-3) were used in this study. The Young's modulus was determined using micropipette aspiration. We examined cells in suspension but not exposed to FSS (unsheared) and immediately after exposure to high (6,400 dyn/cm2) and low (510 dyn/cm2) FSS. The PrEC LH cells were ∼140% stiffer than the PC-3 cells not exposed to FSS. Post-FSS exposure, there was an increase of ∼77% in Young's modulus after exposure to high FSS and a ∼47% increase in Young's modulus after exposure to low FSS for the PC-3 cells. There was no significant change in the Young's modulus of PrEC LH cells post-FSS exposure. Our findings indicate that cancer cells adapt to FSS, with an increased Young's modulus being one of the adaptive responses, and that this adaptation is specific only to PC-3 cells and is not seen in PrEC LH cells. Moreover, this adaptation appears to be graded in response to the magnitude of FSS experienced by the cancer cells. This is the first study investigating the effect of FSS on the mechanical properties of cancer cells in suspension, and may provide significant insights into the mechanism by which some select cancer cells may survive in the circulation, ultimately leading to metastasis at distal sites. Our findings suggest that biomechanical analysis of cancer cells could aid in identifying and diagnosing cancer in the future. [ABSTRACT FROM AUTHOR]

Introduction: Left ventricular assist devices (LVAD) play an increasingly important role for the medical-therapy refractory end-stage heart failure (HF) patient population, in the context of stagnant donor heart availability. Thromboembolic and hemorrhagic complications such as strokes, however, remain high, and in some cases have seen increased incidence. There are a lack of guidelines governing LVAD surgical implantation configurations, which have been shown to have a strong influence on the thrombogenicity of LVAD therapy. Methods: We use a platelet-focused approach to simulate the thrombogenicity of virtual LVAD implantations under a wide range of clinically-relevant parameters. We investigate the hemodynamic microenvironment in the LVAD inflow (left ventricle inflow cannula angulation, inflow cannula insertion depth, left ventricle size) and outflow (outflow graft anastomoses angles, outflow graft diameters and partial intermittent aortic valve opening) regions, analyzing platelet biomechanics. Rigorous statistical methods are used to analyze hundreds of thousands of platelet trajectories to characterize thrombogenic indices such as residence time (RT), shear history (SH) and shear loading (SL) for platelet activation. Results: An unfavorable hemodynamic microenvironment in the left ventricle due to malangulation of the inflow cannula predisposes platelets, to activate and agglomerate before entering the LVAD. Similarly, small left ventricles pose a markedly elevated thrombosis risk, especially in the presence of deep inflow cannula insertion depths. These intraventricular hemodynamics, coupled with non-optimal outflow graft anastomosis angles, represent an additional risk of stroke, via flow-mediated platelet activation. Thrombogenic risk can be mitigated to a significant extent by optimizing surgical configurations and patient management strategies for LVAD speed, conducive to intermittent aortic valve flow. Conclusions: The novel comprehensive simulation approach followed in this study to evaluate thrombogenicity via platelet-based metrics can be implemented in surgical implantation guidelines to reduce the rate of thromboembolic complications, improving long-term outcomes of LVAD therapy. [ABSTRACT FROM AUTHOR]

Congenital heart defects (CHDs) represent the most common form of human birth defects; approximately one-third of heart defects involve malformations of the outflow tract (OFT). Maternal diabetes increases the risk of CHD by 3-5 fold. During heart organogenesis, little is known about the effects of hyperglycemia on hemodynamics, which are critical to normal heart development. Heart development prior to septation in the chick embryo was studied under hyperglycemic conditions. Sustained hyperglycemic conditions were induced, raising the average plasma glucose concentration from 70 mg/dL to 180 mg/dL, akin to the fasting plasma glucose of a patient with diabetes. The OFTs were assessed for structural and hemodynamic alterations using optical coherence tomography (OCT), confocal microscopy, and microcomputed tomography. In hyperglycemic embryos, the endocardial cushions of the proximal OFT were asymmetric, and the OFTs curvature and torsion were significantly altered. The blood flow velocity through the OFT of hyperglycemic embryos was significantly decreased, including flow reversal in 30% of the cardiac cycle. Thus, hyperglycemia at the onset of gestation results in asymmetric proximal endocardial cushions, abnormal OFT curvature, and altered hemodynamics in the developing heart. If present in humans, these results may identify early developmental alterations that contribute to the increased risk for cardiac malformations in babies from diabetic mothers.

We analyzed heart wall motion and blood flow dynamics in chicken embryos using in vivo optical coherence tomography (OCT) imaging and computational fluid dynamics (CFD) embryo-specific modeling. We focused on the heart outflow tract (OFT) region of day 3 embryos, and compared normal (control) conditions to conditions after performing an OFT banding intervention, which alters hemodynamics in the embryonic heart and vasculature. We found that hemodynamics and cardiac wall motion in the OFT are affected by banding in ways that might not be intuitive a priori . In addition to the expected increase in ventricular blood pressure, and increase blood flow velocity and, thus, wall shear stress (WSS) at the band site, the characteristic peristaltic-like motion of the OFT was altered, further affecting flow and WSS. Myocardial contractility, however, was affected only close to the band site due to the physical restriction on wall motion imposed by the band. WSS were heterogeneously distributed in both normal and banded OFTs. Our results show how banding affects cardiac mechanics and can lead, in the future, to a better understanding of mechanisms by which altered blood flow conditions affect cardiac development leading to congenital heart disease.