Comparison of a Miniaturized Implantable Two‐Stage Rotodynamic Blood Pump to Equivalent Single‐Stage Concepts

We and others have recently reported that prolonged sitting impairs endothelial function in the leg vasculature; however, the mechanism(s) remain unknown. Herein, we tested the hypothesis that a sustained reduction in flow-induced shear stress is the underlying mechanism by which sitting induces leg endothelial dysfunction. Specifically, we examined whether preventing the reduction in shear stress during sitting would abolish the detrimental effects of sitting on popliteal artery endothelial function. In 10 young healthy men, bilateral measurements of popliteal artery flow-mediated dilation were performed before and after a 3-h sitting period during which one foot was submerged in 42°C water (i.e., heated) to increase blood flow and thus shear stress, whereas the contralateral leg remained dry and served as internal control (i.e., nonheated). During sitting, popliteal artery mean shear rate was reduced in the nonheated leg (pre-sit, 42.9 ± 4.5 s(-1); and 3-h sit, 23.6 ± 3.3 s(-1); P < 0.05) but not in the heated leg (pre-sit, 38.9 ± 3.4 s(-1); and 3-h sit, 63.9 ± 16.9 s(-1); P > 0.05). Popliteal artery flow-mediated dilation was impaired after 3 h of sitting in the nonheated leg (pre-sit, 7.1 ± 1.4% vs. post-sit, 2.8 ± 0.9%; P < 0.05) but not in the heated leg (pre-sit: 7.3 ± 1.5% vs. post-sit, 10.9 ± 1.8%; P > 0.05). Collectively, these data suggest that preventing the reduction of flow-induced shear stress during prolonged sitting with local heating abolishes the impairment in popliteal artery endothelial function. Thus these findings are consistent with the hypothesis that sitting-induced leg endothelial dysfunction is mediated by a reduction in shear stress.

Following an extended sitting challenge of 1-6 hours, endothelial function measured via flow-mediated dilation (FMD) is impaired in the leg. Further, this impairment has been shown to be mediated by the reduction in shear stress that occurs in the legs with prolonged sitting. Interestingly, previous findings have demonstrated that prolonged periods of sitting result in a reduction in shear rate as early as 10 minutes into the sitting period. However, it is unknown whether this acute reduction in shear stress is sufficient to alter conduit artery endothelial function or if the decline in shear stress must be maintained for a longer period. PURPOSE: We tested the hypothesis that 10 minutes of sitting would result in a reduction in popliteal artery shear stress and an impairment in FMD. METHODS: Popliteal artery diameter and blood velocity were continuously recorded via duplex Doppler ultrasound in ten healthy men before, during, and after a 10 minute sitting period. In addition, popliteal artery FMD was performed before and after the acute sitting period. Shear rate was calculated as [8 x mean blood velocity/diameter]. FMD was calculated as [(peak diameter – base diameter)/base diameter x 100] and was ANCOVA-corrected for hyperemic shear rate AUC. RESULTS: Popliteal artery shear rate was significantly reduced with 10 minutes of sitting (PreSit: 57.1±11.2 s-1 vs. PostSit: 37.4±5.1 s-1; P = 0.034); however popliteal artery FMD was unaffected (PreSit: 4.5±0.6% vs. PostSit: 4.6±0.8%; P = 0.738). ANCOVA-corrected FMD yielded similar results (P = 0.715). Interestingly, reactive hyperemia, a measure of microvascular dilator function, tended to be lower following the acute bout of sitting (PreSit: 59,243±9,642 a.u. vs. PostSit: 41,201±6,578 a.u.; P = 0.06). CONCLUSIONS: These preliminary findings demonstrate that shear rate is diminished within the first 10 minutes of sitting, yet this stimulus is not sufficient to affect conduit artery endothelial function. However, microvascular function may be more sensitive to this brief reduction in shear stress, suggestive of a distinction between sitting-induced impairments in macrovascular and microvascular responsiveness. Supported by UTA College of Nursing and Health Innovation.

A load-transfer function for the side resistance of drilled shafts in soft rock

Introduction: Pulmonary arterial obstruction due to acute thromboembolism causes local reduction or cessation of blood flow. Under normal conditions, pulmonary blood flow exerts shear stress on endothelial cells, known to play an important role in maintaining vascular homeostasis. We hypothesized that pulmonary microvascular endothelial cells exposed to abrupt reductions in shear stress would demonstrate attenuated phosphatidylinositol 3-kinase (PI3K)-dependent signaling and phosphorylation of downstream effectors Akt and endothelial nitric oxide synthase (eNOS). Methods: We tested our hypothesis in primary cultures of human lung microvascular endothelial cells (hLMVECs). We cultured early passage (p≤8) hLMVECs from 5 unique donor lots in standard 6-well culture plates and exposed cells to shear stress using an orbital shaker. Using a fixed depth (volume) and viscosity of tissue culture media, we adjusted the magnitude of shear stress exerted on hLMVECs by changing the angular velocity of orbital rotation. We acclimatized hLMVECs to physiologically-relevant shear stress (~12 dyn/cm2) for 24 hours, then exposed cells to low shear stress (~3 dyn/cm2) or no shear stress (0 dyn/cm2) for 30 minutes. Control cells were maintained at 12 dyn/cm2 of shear stress. In some experiments, PI3K activity was inhibited throughout the acclimatization and shear stress manipulation period by including LY294002 (10 μM) or vehicle (DMSO, 0.1% v/v) in culture media. We prepared whole cell lysates and used western blot to evaluate the expression and phosphorylation of Akt (ser473) and eNOS (ser1177). Results: We found that phosphorylation of Akt, but not Akt expression, decreased significantly (p&lt;0.05) when shear stress was acutely reduced (~3 dyn/cm2) or removed (0 dyn/cm2). Inhibition of PI3K activity with LY294002 further diminished shear-mediated changes in Akt phosphorylation in all 3 groups. Conversely, eNOS phosphorylation was not modified by acute reductions in shear stress, but eNOS expression was markedly attenuated by PI3K inhibition under all conditions. Conclusions: Our results indicate that phosphorylation of Akt, but not its downstream target eNOS, is rapidly attenuated by abrupt reductions in shear stress in hLMVECs. However, shear stress appears to regulate eNOS expression in a PI3K-dependent manner. Taken together, these findings suggest that acute disruption of flow, as seen in pulmonary embolism, may disrupt human lung microvascular endothelial cell homeostasis and nitric oxide bioavailability via multiple PI3K-dependent signaling pathways. This work is supported by HL126514 and HL159906. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background/Objectives: The similarities and differences from a rheological perspective between significant short focal and mild long coronary lesions warrant investigation to elucidate wall shear stress (WSS) angiographic discrepancies. Methods: Patients who underwent coronary computed tomography angiography (CCTA) between 1 January 2023 and 1 September 2024 were selected for computational fluid dynamics (CFD) analysis. The selection criteria included either a focal (≤20 mm) hemodynamically significant stenosis, defined as ≥75% lumen narrowing, or a long (30–40 mm) non-hemodynamically significant lesion showing ≤50% stenosis of the left anterior descending (LAD) artery. Patient-specific models were reconstructed from ECG-gated CCTA images. Wall shear stress (WSS, measured in Pascals) and residence time (RT) were evaluated for each patient. Results: The LAD arteries of 30 patients (mean age 54 years, 63.3% men) were evaluated: 16 with focal, hemodynamically significant coronary stenosis, while 14 with diffuse, long, non-hemodynamically significant coronary lesions. Both groups exhibited a lower mean WSS compared to the non-stenosed segment, with no significant difference in mean WSS between the two groups (p = 0.84). Conversely, both groups demonstrated a higher mean residence time (RT) compared to the non-stenosed segments (0.2 ± 0.06 vs. 0.60 ± 0.03, p < 0.001 and 0.2 ± 0.006 vs. 0.59 ± 0.02, p < 0.001, respectively), and no significant difference in mean RT (p = 0.82). Conclusions: Long, angiographically mild coronary stenoses show similar WSS and RT characteristics compared to short hemodynamically significant coronary stenosis.

Drugs with prolonged, on-target residence time often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here, we demonstrate progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Utilizing an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrate biochemical residence times spanning from minutes to 7 days. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK more than 18 hours after clearance from the circulation. The inverted cyanoacrylamide strategy was further utilized to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating generalizability of the approach. Targeting noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates “residence time by design”, the ability to modulate and improve the duration of target engagement in vivo.

Prolonged sitting impairs endothelial function in the leg vasculature, and this impairment is thought to be largely mediated by a sustained reduction in blood flow-induced shear stress. Indeed, preventing the marked reduction of shear stress during sitting with local heating abolishes the impairment in popliteal artery endothelial function. Herein, we tested the hypothesis that sitting-induced reductions in shear stress and ensuing endothelial dysfunction would be prevented by periodic leg movement, or "fidgeting." In 11 young, healthy subjects, bilateral measurements of popliteal artery flow-mediated dilation (FMD) were performed before and after a 3-h sitting period during which one leg was subjected to intermittent fidgeting (1 min on/4 min off) while the contralateral leg remained still throughout and served as an internal control. Fidgeting produced a pronounced increase in popliteal artery blood flow and shear rate (prefidgeting, 33.7 ± 2.6 s(-1) to immediately postfidgeting, 222.7 ± 28.3 s(-1); mean ± SE; P < 0.001) that tapered off during the following 60 s. Fidgeting did not alter popliteal artery blood flow and shear rate of the contralateral leg, which was subjected to a reduction in blood flow and shear rate throughout the sitting period (presit, 71.7 ± 8.0 s(-1) to 3-h sit, 20.2 ± 2.9 s(-1); P < 0.001). Popliteal artery FMD was impaired after 3 h of sitting in the control leg (presit, 4.5 ± 0.3% to postsit: 1.6 ± 1.1%; P = 0.039) but improved in the fidgeting leg (presit, 3.7 ± 0.6% to postsit, 6.6 ± 1.2%; P = 0.014). Collectively, the present study provides evidence that prolonged sitting-induced leg endothelial dysfunction is preventable with small amounts of leg movement while sitting, likely through the intermittent increases in vascular shear stress.

The success of left ventricular assist device (LVAD) therapy is hampered by complications such as thrombosis and bleeding. Understanding blood flow interactions between the heart and the LVAD might help optimize treatment and decrease complication rates. We hypothesized that LVADs modify shear stresses and blood transit in the left ventricle (LV) by changing flow patterns and that these changes can be characterized using 2D echo color Doppler velocimetry (echo-CDV). We used echo-CDV and custom postprocessing methods to map blood flow inside the LV in patients with ongoing LVAD support (Heartmate II, N = 7). We compared it to healthy controls (N = 20) and patients with dilated cardiomyopathy (DCM, N = 20). We also analyzed intraventricular flow changes during LVAD ramp tests (baseline ± 400 rpm). LVAD support reversed the increase in blood stasis associated with DCM, but it did not reduce intraventricular shear exposure. Within the narrow range studied, the ventricular flow was mostly insensitive to changes in pump speed. Patients with significant aortic insufficiency showed abnormalities in blood stasis and shear indices. Overall, this study suggests that noninvasive flow imaging could potentially be used in combination with standard clinical methods for adjusting LVAD settings to optimize flow transport and minimize stasis on an individual basis.

The goal of this study was to quantify the reduction in velocity, vorticity, and shear stresses resulting from the sequential placement of stents across the neck of sidewall cerebral aneurysms. A digital particle image velocimetry (DPIV) system was used to measure the pulsatile velocity field within a flexible silicone sidewall intracranial aneurysm model and at the aneurysm neck-parent artery interface in this model. The DPIV system is capable of providing an instantaneous, quantitative two-dimensional measurement of the velocity vector field of "blood" flow inside the aneurysm pouch and the parent vessel, and its changes at varying stages of the cardiac cycle. The corresponding vorticity and shear stress fields are then computed from the velocity field data. Three Neuroform stents (Boston Scientific/Target), each with a strut thickness between 60 and 65 microm, were subsequently placed across the neck of the aneurysm model and measurements were obtained after each stent had been placed. The authors measured a consistent decrease in the values of the maximal averaged velocity, vorticity, and shear stress after placing one, two, and three stents. Measurements of the circulation inside the sac demonstrated a systematic reduction in the strength of the vortex due to the stent placement. The decrease in the magnitude of the aforementioned quantities after the first stent was placed was remarkable. Placement of two or three stents led to a less significant reduction than placement of the first stent. The use of multiple flexible intravascular stents effectively reduces the strength of the vortex forming in an aneurysm sac and results in a decrease in the magnitude of stresses acting on the aneurysm wall.

Hemodialysis catheters are used to support blood filtration, yet there are multiple fundamentally different approaches to catheter tip design with no clear optimal solution. Side-holes have been shown to increase flow rates and decrease recirculation but have been associated with clotting/increased infection rates. This study investigates the impact of changing the shape, size and number of side-holes on a simple symmetric tip catheter by evaluating the velocity, shear stress and shear rate of inflowing blood. A platelet model is used to examine the residence time and shear history of inflowing platelets. The results show that side-holes improve the theoretical performance of the catheters, reducing the maximum velocity and shear stress occurring at the tip compared to non-side-hole catheters. Increasing the side-hole area improved performance up to a point, past which not all inflow through the hole was captured, and instead a small fraction slowly ‘washed-out’ through the remainder of the tip resulting in greater residence times and increasing the likelihood of platelet adhesion. An oval shaped hole presents a lower chance of external fibrin formation compared to a circular hole, although this would also be influenced by the catheter material surface topology which is dependent on the manufacturing process. Overall, whilst side-holes may be associated with increased clotting and infection, this can be reduced when side-hole geometry is correctly implemented though; a sufficient area for body diameter (minimising residence time) and utilising angle-cut, oval shaped holes (reducing shear stress and chances of fibrin formation partially occluding holes).

We and others recently reported that prolonged sitting impairs endothelial function in the leg vasculature; however, the mechanisms remain unknown. Herein, we tested the hypothesis that a sustained reduction in flow induced shear stress is the underlying mechanism by which sitting induces leg endothelial dysfunction. Specifically, we examined whether preventing the reduction in shear stress during sitting would abolish the detrimental effects of sitting on popliteal artery endothelial function. In 9 young healthy men, bilateral measurements of popliteal artery flow‐mediated dilation (FMD) were performed before and after a 3‐hour sitting period during which one foot was submerged in 42°C water (i.e. WETFOOT), while the contralateral leg remained dry and served as internal control (i.e., DRYFOOT). Local heating is an effective stimulus for dilating the skin circulation and increasing limb vascular conductance and thus, shear stress without producing systemic cardiovascular effects. During sitting, popliteal artery mean shear rate was significantly (P&lt;0.05) reduced in the leg of the DRYFOOT (pre sit: 44.1±4.9s−1, post sit: 25.4±3.8s−1) and sustained in the leg of the WETFOOT (pre sit: 39.6±3.7s−1, post sit: 40.7±5.5s−1). Popliteal artery FMD was impaired after 3 hours of sitting in the leg of the DRYFOOT (pre sit: 5.9±0.9% vs. post sit: 2.9±1.0%) but not WETFOOT (pre sit: 7.3±1.7% vs. post sit: 10.6±2.0%). Collectively, these data demonstrate that preventing the reduction of flow induced shear stress during sitting with local heating abolishes the impairment in popliteal artery endothelial function. Thus, a reduction in shear stress mediates sitting‐induced leg endothelial dysfunction.Support or Funding InformationSupport: NIH K01 HL‐125503 and R21 DK‐105368 (JP)

Effect of spew adhesive and beveling substrate geometrical shape on stresses in a bonded single lap joint

The research explores the effects of various geometric modifications on stress profiles within the adhesive layer of a single lap joint. The effects were numerically investigated by using the commercially available finite element code ABAQUS. Aerospace-grade aluminum alloy 6061-T6 adherends were bonded with Araldite 2011 adhesive. Geometric techniques ranging to external taper, internal taper, adherend rounding, adhesive fillets, and a combination of internal taper with adhesive fillet were examined. Optimum parameter of each geometric configuration was evaluated by following a parametric methodology. The best-performing parameter of each geometric configuration was then compared with the others for the reduction in peak peel and shear stresses. The reduction in peak stresses aims to increase the joint strength of lap joins by reducing the stress concentration points, hence delaying the crack initiation and propagation. The geometric configuration of internal taper with adhesive fillet showed the highest reduction in both peel and shear stresses of 88.58% and 39%, respectively, when compared to base geometry without any modification.

An important compensatory response to atherosclerosis is vascular remodeling, with maintenance of vessel lumen diameter and shear stress. Both hemodynamic and environmental factors contribute to vascular remodeling and shear stress regulation, and the process is probably also influenced by genetic factors. To establish an animal model for genetic analysis of shear stress regulation and vascular remodeling, we studied the effects of chronic flow alteration in four inbred rat strains. By ligating the left internal and external carotid arteries, we caused a approximately 90% decrease in left common carotid blood flow and a approximately 50% increase in right (contralateral) common carotid flow. After 4 weeks of altered flow, there were significant interstrain differences with respect to the change in carotid outer diameter (OD), the relationship between flow and shear stress, and the extent to which shear stress was normalized. Genetically hypertensive rats (GH) exhibited the greatest reduction in shear stress in response to increased flow, stroke-prone spontaneously hypertensive rats (SHR-SP) exhibited a smaller response, and Brown Norway (BN) rats exhibited the smallest response. SHR-SP and GH also differed significantly in outward remodeling (defined as an increase in lumen and vessel diameter) in increased flow arteries. In response to decreased flow, BN rats exhibited the smallest reduction in shear stress. These findings demonstrate significant strain-dependent differences in shear stress regulation and vascular remodeling in response to altered flow. This study emphasizes the important role of genetic factors in vascular remodeling and suggests that genetic analysis of these strains will provide novel insights into the underlying mechanisms.

Experimental and numerical analyses of the hemodynamics impact on real intracranial aneurysms: A particle tracking approach