Peak Shear Rate Research Articles

Fluid-structure interaction analysis of eccentricity and leaflet rigidity on thrombosis biomarkers in bioprosthetic aortic valve replacements.

This work intends to study the effect of aortic annulus eccentricity and leaflet rigidity on the performance, thrombogenic risk and calcification risk in bioprosthetic aortic valve replacements (BAVRs). To address these questions, a two-way immersed fluid-structure interaction (FSI) computational model was implemented in a high-performance computing (HPC) multi-physics simulation software, and validated against a well-known FSI benchmark. The aortic valve bioprosthesis model is qualitatively contrasted against experimental data, showing good agreement in closed and open states. Regarding the performance of BAVRs, the model predicts that increasing eccentricities yield lower geometric orifice areas (GOAs) and higher normalized transvalvular pressure gradients (TPGs) for healthy cardiac outputs during systole, agreeing with in vitro experiments. Regions with peak values of residence time are observed to grow with eccentricity in the sinus of Valsalva, indicating an elevated risk of thrombus formation for eccentric configurations. In addition, the computational model is used to analyze the effect of varying leaflet rigidity on both performance, thrombogenic and calcification risks with applications to tissue-engineered prostheses. For more rigid leaflets it predicts an increase in systolic and diastolic TPGs, and decrease in systolic GOA, which translates to decreased valve performance. The peak shear rate and residence time regions increase with leaflet rigidity, but their volume-averaged values were not significantly affected. Peak solid stresses are also analyzed, and observed to increase with rigidity, elevating risk of valve calcification and structural failure. To the authors' knowledge this is the first computational FSI model to study the effect of eccentricity or leaflet rigidity on thrombogenic biomarkers, providing a novel tool to aid device manufacturers and clinical practitioners.

Effect of Acute Isometric Handgrip Exercise on Vascular Function in Children with Congenital Heart Disease

ObjectiveThe reactivity of conduit vessels such as the brachial artery is important in influencing arterial diameter, and subsequently, blood flow. Flow‐mediated dilation (FMD) measures vessel reactivity. The increase in shear stimuli from transient arterial occlusion enhances arterial diameter in an endothelial‐dependent manner, and this is thought to be impaired in individuals with congenital heart disease (CHD). Isometric handgrip (IHG) exercise is a proposed intervention to improve vessel reactivity by optimizing the shear stimuli to provoke changes in arterial diameter. Indeed, IHG training has been found to improve FMD in healthy adults and children. Whether IHG training improves endothelial dysfunction in CHD remains unknown. Improving vessel reactivity in the young becomes increasingly important in optimizing vascular health into adulthood. The effects of acute IHG exercise on the brachial artery were examined in children with CHD.HypothesisWe tested the hypothesis that acute IHG exercise would increase FMD in children with CHD.MethodsFour subjects with CHD (mean, 13 ± 1 year, 3 female) completed a single session of 4 × 2 mins of acute IHG (30% maximum voluntary contraction using the right hand) with 1‐min rest intervals between bouts. Before and after IHG exercise, the right brachial artery was imaged with Duplex ultrasound using a 1‐min baseline, 5 mins of forearm circulatory occlusion, followed by 3 mins of cuff deflation. Blood pressure and heart rate were measured continuously.ResultsPre‐FMD (baseline) mean arterial pressure (pre: 102 ± 17 mmHg vs. post: 110 ± 16 mmHg, p = 0.496) and heart rate (pre: 75 ± 13 bpm vs. post: 66 ± 5 bpm, p = 0.253) were not different. Baseline brachial artery diameter increased following acute IHG in 3 of 4 subjects (pre: 3.11 ± 0.45 mm vs. post: 3.23 ± 0.39 mm, Cohen’s d = 0.3). Peak shear rate was greater post‐IHG in 3 of 4 subjects (pre: 995 ± 346 sec‐1vs. post: 1158 ± 501 sec‐1, Cohen’s d = 0.4). FMD% (4.7% vs. 6.3% and 8.2% vs. 10.5%) and FMD% normalized to shear rate area under the curve (AUC) ratio (2.2E‐5 vs. 7.4E‐5 a.u. and 3.1E‐5 vs. 4.3E‐5 a.u., Cohen’s d = 2.0) increased post‐IHG in 2 of 4 subjects. When brachial artery diameter increased, peak shear rate, FMD%, and FMD% normalized to shear rate AUC improved post‐IHG in 2/3 subjects whereas subject four showed a decrease in brachial artery diameter, FMD% and FMD% normalized to shear rate AUC, with the exception of peak shear rate post‐IHG.ConclusionFavorable changes in brachial artery diameter, peak shear rate, FMD% and FMD% normalized to shear rate AUC following acute IHG may be a promising intervention for improving vascular tone and endothelial function in children with CHD.

Inorganic nitrate attenuates endothelial dysfunction consequent to systemic inflammation

Abstract Introduction Chronic cardiovascular diseases are characterised by low-grade systemic inflammation and attenuated nitric oxide (NO) bioavailability resulting in endothelial dysfunction. Inorganic nitrate augments NO bioavailability and improves markers of vascular dysfunction in patients with cardiovascular risk factors. However, the exact mechanism of this effect is uncertain. Purpose To determine whether inorganic nitrate supplementation alters systemic inflammation-induced endothelial dysfunction. Methods 62 healthy male volunteers were randomised 1:1 to receive ∼8–10 mmol of dietary inorganic nitrate in beetroot juice or nitrate-free beetroot juice (placebo) once daily for 6 days. Measures of brachial artery flow-mediated dilatation (FMD), brachial blood pressure (BP), pulse wave analysis and carotid-femoral pulse wave velocity (PWV) by Vicorder were taken prior to and at 8 hours after a typhoid vaccine (to induce mild systemic inflammation). Plasma, urine and saliva samples were also collected. Clinicaltrials.gov: NCT02715635. Results Baseline characteristics were similar between the two groups. Inorganic nitrate significantly elevated plasma nitrite (placebo = Δ0.02±0.5 μM, inorganic nitrate = Δ0.63±1.2 μM; p=0.01) and nitrate levels (p<0.0001) compared to placebo. There were significant increases in urine nitrite (p<0.0001) and nitrate (p<0.0001) in addition to salivary nitrite (p<0.0001) and nitrate (p<0.0001) compared to placebo. After 8 hours, typhoid vaccine induced an increase in circulating white cells (placebo = Δ3.34±3.37x109/L, inorganic nitrate = Δ2.9±2.78x109/L; p=0.58) that was similar in in both arms. However, there was a significant reduction in the FMD response in the placebo group at 8-hours post vaccine; an effect that was absent in volunteers treated with inorganic nitrate (placebo = Δ−1.33±1.53%, inorganic nitrate = Δ−0.07±1.84%, p=0.005). Importantly, there were no statistically significant differences in baseline vessel diameter (p=0.78), time to peak diameter in response to flow (p=0.87) and peak shear rate (p=0.57) between the groups. When comparing change from baseline to 8 hours after the vaccine, there were no significant differences in brachial systolic BP (p=0.12), central systolic BP (p=0.12) and PWV (p=0.60) between groups, but a significant reduction in brachial diastolic BP in the inorganic nitrate group (p=0.048). Conclusions Inflammation-induced endothelial dysfunction was prevented in those receiving dietary inorganic nitrate suggesting that elevating circulating nitrite and delivering NO to the blood vessel wall, through dietary approaches may offer potential therapeutic benefit in those cardiovascular diseases which typically exhibit low grade inflammation and deficiencies in bioavailable NO. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): British Heart Foundation

Abstract P323: Impact Of Diminished Pulsatility On Unravelling Of Von Willebrand Factor (VWF) In Patients With Continuous Flow Ventricular Assisted Devices (CF-VADs)

Introduction: Patients implanted with Continuous Flow Ventricular Assisted Devices (CF VADs) exhibit diminished pulsatility and are at a high risk for developing acquired von Willebrand Factor syndrome (AVWS) and non-surgical bleeding. This study aimed to understand how diminished pulsatility due to CF VAD impacts unravelling and patient plasma levels of von Willebrand Factor (vWF). A microfluidic approach was used to study unravelling of vWF under normal pulsatile flow and flow with diminished pulsatility. In addition, vWF levels in CF-VAD patients was measured to determine vWF levels in circulation. Hypothesis: We hypothesized that diminished pulsatility increases vWF unravelling, likely leading to increased vWF degradation and elevated levels of low MW vWF fragments in circulation, this in turn leads to decreased endothelial vWF production in CF-VAD patients. Methods: vWF molecules were immobilized in a microfluidic device and subjected to either normal pulsatile flow or flow with diminished pulsatility (same mean flow). vWF unravelling behavior was observed using total internal reflection fluorescence (TIRF) microscopy. Patient blood samples were collected 1-2 days pre CF-VAD implant and monthly post-implant. Patient plasma vWF levels were measured using an ELISA kit. Results: TIRF imaging showed that vWF molecules undergo unravelling and significantly greater elongation (p<0.05) under diminished pulsatility than with normal physiological pulsatility, despite higher levels of peak shear rates with normal pulsatility ( Fig.1A ). Evaluation of plasma vWF levels in patients (n=9) showed that vWF levels decreased progressively following CF-VAD placement ( Fig.1B ). These results suggest that diminished pulsatility increased unravelling of vWF and exposure of ADAMTS13 binding sites, potentially leading to enhanced cleavage of vWF into low molecular weight (MW) multimers. Review of literature suggests that both low MW multimers and diminished pulsatility cause endothelial dysfunction and decreased endothelial vWF production, which was evident in patient samples. Conclusion: Diminished pulsatility may independently promote vWF degradation and lead to decreased production of vWF, thus contributing to AVWS.

Computational Fluid Dynamics Simulations at Micro-Scale Stenosis for Microfluidic Thrombosis Model Characterization

Platelet aggregation plays a central role in pathological thrombosis, preventing healthy physiological blood flow within the circulatory system. For decades, it was believed that platelet aggregation was primarily driven by soluble agonists such as thrombin, adenosine diphosphate and thromboxane A2. However, recent experimental findings have unveiled an intriguing but complementary biomechanical mechanism—the shear rate gradients generated from flow disturbance occurring at sites of blood vessel narrowing, otherwise known as stenosis, may rapidly trigger platelet recruitment and subsequent aggregation. In our Nature Materials 2019 paper [1], we employed microfluidic devices which incorporated micro-scale stenoses to elucidate the molecular insights underlying the prothrombotic effect of blood flow disturbance. Nevertheless, the rheological mechanisms associated with this stenotic microfluidic device are poorly characterized. To this end, we developed a computational fluid dynamics (CFD) simulation approach to systematically analyze the hemodynamic influence of bulk flow mechanics and flow medium. Grid sensitivity studies were performed to ensure accurate and reliable results. Interestingly, the peak shear rate was significantly reduced with the device thickness, suggesting that fabrication of microfluidic devices should retain thicknesses greater than 50 µm to avoid unexpected hemodynamic aberration, despite thicker devices raising the cost of materials and processing time of photolithography. Overall, as many groups in the field have designed microfluidic devices to recapitulate the effect of shear rate gradients and investigate platelet aggregation, our numerical simulation study serves as a guideline for rigorous design and fabrication of microfluidic thrombosis models.

Using Continuous And Interval Exercise To Manipulate Shear Rate Patterns In The Common Femoral Artery

Vascular shear rate (SR) assessed via ultrasound represents frictional force of blood flowing over the endothelium. Low and oscillatory shear confers a pro-inflammatory phenotype, whereas greater shear has an anti-inflammatory phenotype decreasing CVD risk. Exercise increases SR, however the impact of continuous (CON) and interval (INT) exercise upon the balance of anterograde (ANT) and retrograde (RET) SR and thus the oscillatory shear index (OSI) is unknown. PURPOSE: To examine the impact of acute CON and INT (no active recovery) exercise on SR patterns and OSI in the common femoral artery (CFA) during exercise. METHODS: 10 healthy individuals (25±3 years, n=5 male) underwent two work-matched exercise sessions (CON and INT) on a supine cycle ergometer at 125% lactate threshold. In each protocol repetitive ultrasound scans were taken of the CFA during a brief cessation in exercise to determine in-exercise shears. Flow mediated dilatation (FMD) was measured before and after exercise to assess acute changes in endothelial function. RESULTS: FMD did not differ after exercise in either protocol (CON: 9.9±8.1% vs 8.4±6.2%; INT: 9.1±5.9% vs 6.6±3.4%: P>0.05). ANT and RET SR reached a plateau in each protocol. Total ANT SR was lower in CON than INT (CON: 861540±291534 vs INT: 1955615±674594 s-1: P<0.05), however total RET SR did not differ between protocols (CON: 76625±89390 vs INT: 78126±78697 s-1: P>0.05). Peak and mean SR were similar in CON and INT, respectively (peak ANT: 1258±403 vs 1480±510 s-1; RET: 107±123 vs 108±75 s-1: P>0.05; meanANT: 1171±372 vs 1358±469 s-1; RET: 61±81 vs 54±55 s-1: P>0.05). Mean and peak OSI were also similar in both types of exercise (peak CON: 0.07±0.08 vs INT: 0.08±0.0.06 AU; mean CON: 0.05±0.06 vs INT: 0.04±0.04 AU; P>0.05). No time was spent in pure oscillatory shear (>0.5 AU). CONCLUSION: During exercise matched for intensity and the duration of muscular work, using an INT approach ensured a similar OSI but a greater total ANT SR compared to CON. This would suggest that in the exercising limb INT exercise does not confer a negative oscillatory profile. GRANT FUNDING: Medical Research Council

Effects of Intermittent Pneumatic Compression on Leg Vascular Function in People with Spinal Cord Injury: A Pilot Study

Objective: The purpose of this pilot study was to determine whether 60 mins of intermittent pneumatic compression therapy (IPC) could acutely increase leg blood flow-induced shear stress and enhance vascular endothelial function in persons with spinal cord injury (SCI).Design: Pretest with multiple posttests, within subject randomized control design.Setting: University of Southern Mississippi, Spinal Cord Injury Research Program within the School of Kinesiology, recruiting from the local community in Hattiesburg, Jackson, and Gulfport, MS.Participants: Eight adults with SCI (injury level: T3 and below; ASIA class A-C; age: 41±17 yrs).Interventions: A 60-min IPC session was performed in one leg (experimental leg; EXP), with the other leg serving as a control (CON).Outcomes Measures: Posterior-tibial artery shear rate (Doppler-ultrasound) was examined at rest, and at 15 and 45 mins during IPC. Endothelial function was assessed using the flow-mediated dilation (FMD) technique, before and after IPC.Results: Resting FMD (mm) was similar between legs at rest. A two-way repeated measures ANOVA (leg x time) revealed that during IPC, peak shear rate increased in the EXP leg (215±137 to 285±164 s−1 at 15 mins; +39±29%, P = 0.03), with no change occurring in the CON. In addition, FMD significantly increased in the EXP leg (Pre IPC: 0.36±0.14 vs. Post IPC: 0.47±0.17 mm; P = 0.011, d = 0.66), with no change occurring in the CON leg.Conclusion: These preliminary findings suggests that IPC therapy may acutely increase leg shear stress within 15 mins, with a resultant moderate-large improvement in vascular endothelial function after 60 mins in people with SCI.

Shear rates in engines and implications for lubricant design

By combining shear rate range data in engine components with measured viscosity shear rate curves on lubricants (at different temperatures), useful insights have been obtained on how the viscosity shear rate curve of a lubricant should be “designed” to give low friction (and hence improved fuel economy). A brief review is carried out of typical shear rates in key engine components, which is backed up by the authors’ own calculations (using in-house lubrication software that includes realistic viscosity/temperature/shear rate data). It is found that shear rates in journal bearings are typically in the range of 105 to 5 × 106 s−1, whilst peak shear rates for the piston rings can be as high as 2 × 107 s−1, and for the valve train, peak shear rates can reach 2 × 108 s−1. Accurate viscosity shear rate curves have been measured for different temperatures using a range of viscometers, including a novel mid-shear capillary viscometer that is capable of measuring viscosities in the shear rate range of 104 to 106 s−1. The use of such a viscometer is crucial to obtain good fits to the measured data (since usually, viscosity data are only usually available at low shear rates, 102–103 s−1, and extremely high shear rates, &gt; 106 s−1, and such data are difficult to use for accurate viscosity/temperature/shear rate fits). The implications of the above data are then discussed for the design of low friction lubricants which give improved fuel economy. It is highlighted that the traditional high temperature high shear viscosity, HTHS150, measured at 150 ℃ and a shear rate of 106 s−1, although adequate for bearing durability purposes, is probably not the ideal parameter to use for estimating the fuel economy potential of an oil (since shear rates in engines are usually much greater than 106 s−1, and also because oil temperatures in fuel economy engine tests are usually much lower than 150 ℃). Other possible high shear viscosity parameters are discussed which may be an improvement on HTHS150. The work also highlights that the choice of viscosity modifier, and the amount used, can have a substantial impact on the fuel economy performance of a lubricant.

Impaired Arterial Smooth Muscle Cell Vasodilatory Function In Methamphetamine Users

Objectives: Methamphetamine use is a strong risk factor for stroke. This study was designed to evaluate arterial function and structure in methamphetamine users ultrasonographically.Methods: In a cross-sectional study, 20 methamphetamine users and 21 controls, aged between 20 and 40years, were enrolled. Common carotid artery intima-media thickness (CCA-IMT) marker of early atherogenesis, flow-mediated dilatation (FMD) determinants of endothelium-dependent vasodilation, and nitroglycerine-mediated dilatation (NMD) independent marker of vasodilation were measured in two groups.Results: There were no significant differences between the two groups regarding demographic and metabolic characteristics. The mean (±SD) CCA-IMT in methamphetamine users was 0.58±0.09mm, versus 0.59±0.07mm in the controls (p=0.84). Likewise, FMD% was not significantly different between the two groups [7.6±6.1% in methamphetamine users vs. 8.2±5.1% in the controls; p=0.72], nor were peak flow and shear rate after hyperemia. However, NMD% was considerably decreased in the methamphetamine users [8.5±7.8% in methamphetamine users vs. 13.4±6.2% in controls; p=0.03].Conclusion: According to our results, NMD is reduced among otherwise healthy methamphetamine users, which represents smooth muscle dysfunction in this group. This may contribute to the high risk of stroke among methamphetamine users.

A Shear Micro-Gradient Microfluidic to Monitor Platelet Aggregation Dynamics in the Context of Von Willebrand Disease

Background:Virchow's triad identifies the three principle parameters driving haemostasis and thrombosis as: i. Changes in vessel wall properties and exposure of subendothelial matrix proteins; ii. Presentation of blood borne chemical activators (hypercoaguability); and iii.Blood-flow dependent mechanical factors (haemodynamics). Studies identifying a key role for micro-scale shear gradients in driving the earliest stages of platelet thrombus formation have informed the development of a novel set of microfluidic devices that have potential utility as rapid and efficient screening tools of shear dependent platelet function.Aim:The aim of this project was to undertake a small scale clinical and laboratory based characterisation study of a microfluidic platform designed by us and to assess its ability to identify differences in platelet aggregation dynamics in citrated whole blood taken from control subjects and subjects with clinically diagnosed or undiagnosed von Willebrand disease (Types 1, 2 and 3).Method:Patients with VWD were recruited from the haemophilia outpatient clinic, Alfred hospital. Whole blood samples (250mL) or samples treated ex vivo to block the canonical platelet amplification loop pathways were perfused at a defined flow rate (45ml/mL) through a set of well defined micro-shear gradient geometries pre-coated with purified VWF to initiate platelet capture. Microfluidic geometries were characterised by an entry shear rate of 1,800.s-1, that was accelerated to a peak shear rate of either 45,000.s-1 or 150,000.s-1, returning to an exit shear rate of 1,800.s-1. The rate of initial shear acceleration was varied using a series of geometries with contraction entry angles varying from 15 - 85o.Results:The microfluidic platform was able to identify patients with Types 1 (VWF antigen < 30%), 2A and 3 VWD. ROC analysis of control versus VWD samples determined that the device sensitivity approached 94.4%, with a specificity of 100% for VWD. A statistically significant difference (p< 0.05) was observed when comparing control blood samples to type 1VWD (p< 0.001) and type 2A VWD samples (p=0.004), with both subtypes showing minimal to no platelet aggregation in the device. Patients presenting with bleeding symptoms but found not to have VWD (normal VWF:Ag levels) showed no significant difference (p=0.907) to controls. Furthermore, exogenous titration of Type 3 (n=2) VWD blood samples with purified VWF (10 - 100mg/mL) recapitulated platelet aggregation in a concentration dependent manner. Head to head comparison with standard laboratory based tests including, VWF:Ag, VWF:CB and VWF:RCo demonstrated a strong linear correlation with device output. In addition, time-course (0, 2 and 4 Hrs) trials demonstrate that the device is a sensitive measure of DDAVP treatment of VWD.Conclusion:The Studies presented demonstrate that haemodynamically sensitive platelet aggregation within our prototype platform is critically dependent on blood VWF antigen levels and demonstrates good proof-of-concept that the microfludic can selectively identify VWD dependent defects in whole blood platelet aggregation. Taken together these data suggest that a microfluidic platform with discrete haemodynamic control can operate as a sensitive screen for VWD. Future studies will focus on defining the particle and key haemodynamic parameters that shift both device selectivity and sensitivity. DisclosuresNo relevant conflicts of interest to declare.

Impaired arterial smooth muscle cell vasodilatory function in methamphetamine users

ObjectivesMethamphetamine use is a strong risk factor for stroke. This study was designed to evaluate arterial function and structure in methamphetamine users ultrasonographically. MethodsIn a cross-sectional study, 20 methamphetamine users and 21 controls, aged between 20 and 40years, were enrolled. Common carotid artery intima-media thickness (CCA-IMT) marker of early atherogenesis, flow-mediated dilatation (FMD) determinants of endothelium–dependent vasodilation, and nitroglycerine-mediated dilatation (NMD) independent marker of vasodilation were measured in two groups. ResultsThere were no significant differences between the two groups regarding demographic and metabolic characteristics. The mean (±SD) CCA-IMT in methamphetamine users was 0.58±0.09mm, versus 0.59±0.07mm in the controls (p=0.84). Likewise, FMD% was not significantly different between the two groups [7.6±6.1% in methamphetamine users vs. 8.2±5.1% in the controls; p=0.72], nor were peak flow and shear rate after hyperemia. However, NMD% was considerably decreased in the methamphetamine users [8.5±7.8% in methamphetamine users vs. 13.4±6.2% in controls; p=0.03]. ConclusionAccording to our results, NMD is reduced among otherwise healthy methamphetamine users, which represents smooth muscle dysfunction in this group. This may contribute to the high risk of stroke among methamphetamine users.

Reactivity to low-flow as a potential determinant for brachial artery flow-mediated vasodilatation.

Previous studies have reported a vasoconstrictor response in the radial artery during a cuff‐induced low‐flow condition, but a similar low‐flow condition in the brachial artery results in nonuniform reactivity. This variable reactivity to low‐flow influences the subsequent flow‐mediated dilatation (FMD) response following cuff‐release. However, it is uncertain whether reactivity to low‐flow is important in data interpretation in clinical populations and older adults. This study aimed to determine the influence of reactivity to low‐flow on the magnitude of brachial artery FMD response in middle‐aged and older individuals with diverse cardiovascular risk profiles. Data were analyzed from 165 individuals, divided into increased cardiovascular risk (CVR: n = 115, 85M, 67.0 ± 8.8 years) and healthy control (CTRL: n = 50, 30M, 63.2 ± 7.2 years) groups. Brachial artery diameter and blood velocity data obtained from Doppler ultrasound were used to calculate FMD, reactivity to low‐flow and estimated shear rate (SR) using semiautomated edge‐detection software. There was a significant association between reactivity to low‐flow and FMD in overall (r = 0.261), CTRL (r = 0.410) and CVR (r = 0.189, all P < 0.05) groups. Multivariate regression analysis found that reactivity to low‐flow, peak SR, and baseline diameter independently contributed to FMD along with sex, the presence of diabetes, and smoking (total R 2 = 0.450). There was a significant association between reactivity to low‐flow and the subsequent FMD response in the overall dataset, and reactivity to low‐flow independently contributed to FMD. These findings suggest that reactivity to low‐flow plays a key role in the subsequent brachial artery FMD response and is important in the interpretation of FMD data.

Ultrasound-mediated drug release from nanoscale liposomes using nanoscale cavitation nuclei

We have previously presented a liposomal formulation of mean size 140 nm, manufactured using DSPE, cholesterol, DSPC and DSPE-PEG at ratios of 65:25:3:7, which exclusively releases encapsulated doxorubicin in the presence of inertial cavitation nucleated by microbubbles (SonoVue®, Bracco) at peak rarefactional pressures in excess of 1.2 MPa at 0.5 MHz (Graham et al., J. Controlled Release, 2014). However, the benefits of cavitation-sensitive liposomes small enough to pass through the leaky tumor vasculature can only be fully realized if they can be triggered by cavitation nuclei which are also small enough to extravasate into the tumor mass. In the present work, we demonstrate that liposomal release comparable to that mediated by SonoVue® microbubbles can be achieved using gas-stabilizing polymeric nanocups of mean diameter 400 nm, at peak rarefactional pressure amplitudes in excess of 1.5 MPa at 0.5 MHz or 4 MPa at 1.6 MHz. Mechanistically, we hypothesize that release occurs once a threshold peak shear rate is exceeded in the fluid surrounding the collapsing microbubble, thus exceeding the critical shear stress on the liposomal surface. This is confirmed experimentally by demonstrating a correlation between release and the maximum power of broadband acoustic emissions received by a passive cavitation detector.

Resting brachial artery shear rate is associated with exercise habituation in middle aged and older adults

Hemodynamic shear stress, a frictional force of blood on the arterial wall, decreases with aging. The reduction in shear stress involved in development and progression of vascular endothelial dysfunction, a risk factor of cardiovascular disease. Habitual exercise is an effective strategy to improve vascular endothelial function. However, the effect of habitual exercise on the resting shear stress is unknown. The aim of this study was to determine whether brachial artery shear stress correlates with exercise habituation in middle aged and older adults.A total of 112 healthy middle aged and older adults (50–76 years) participated in this study. We measured peak and mean brachial artery shear rates, as indices of shear stress, at rest. Daily step counts and maximum oxygen consumption (VO2max) were measured as an index of exercise habituation. Subjects were divided into the inactive group (&lt; 7500 steps/day) and the active group (蠅 7500 steps/day).VO2max was significantly higher in the active group than in the inactive group (P &lt; 0.01). Peak shear rate and mean shear rate in the active group were significantly higher than in the inactive group (P &lt; 0.01 and P &lt; 0.05). VO2max correlated significantly with peak (r = 0.362, P &lt; 0.01) and mean shear rates (r = 0.302, P &lt; 0.05). These associations were remained significant even when adjusted for age.These results suggest that habitual exercise may increase resting brachial artery shear stress in middle‐aged and older adults.

Systemic sclerosis induces pronounced peripheral vascular dysfunction characterized by blunted peripheral vasoreactivity and endothelial dysfunction.

Systemic sclerosis (SSc) vasculopathy can result in a digital ulcer (DU) and/or pulmonary arterial hypertension (PAH). We hypothesized that bedside brachial artery flow-mediated dilation (FMD) testing with duplex ultrasound could be used in SSc patients to identify features of patients at risk for DU or PAH. Thirty-eight SSc patients were compared to 52 age-matched healthy controls from the VAMC Utah Vascular Research Laboratory. Peripheral hemodynamics, arterial structure, and endothelial function were assessed by duplex ultrasound. A blood pressure cuff was applied to the forearm and 5-min ischemia was induced. Post-occlusion, brachial artery vascular reactivity (peak hyperemia/area under the curve [AUC]), shear rate, and endothelial function (FMD) were measured. SSc patients had smaller brachial artery diameters (p < 0.001) and less reactive hyperemia (p < 0.001), peak shear rate (p = 0.03), and brachial artery FMD (p < 0.001) compared with healthy controls. Brachial artery FMD was lower (p < 0.05) in SSc patients with DU. Tertile analysis suggested the 2 lower FMD tertiles (<5.40 %) had a 40-50 % chance of presenting with DU while the SSc patients with highest FMD tertile (>5.40 %) had less than 15 % chance of DU. All brachial artery FMD measurements were similar between SSc patients with and without PAH (all p > 0.05). Compared to healthy controls, SSc patients had significantly smaller brachial artery diameter and blunted peripheral vascular reactivity and endothelial function. SSc patients with DU have even greater impairments in endothelial function compared to those without DU. FMD testing has clinical utility to identify SSc patients at risk for DU.

Flow-mediated dilation is associated with endothelial oxidative stress in human venous endothelial cells.

Flow-mediated dilation (FMD) is recognized as a non-invasive endothelial function bioassay. However, FMD's relationship with endothelial cell oxidative stress in humans is yet to be determined. Here, we sought to determine if FMD was associated with endothelial nitric oxide synthase (eNOS) and endothelial oxidative stress in humans. Twenty-seven apparently healthy young men (26.5±5.9 years) underwent brachial artery FMD testing and endothelial cell biopsy from a forearm vein. Non-normalized FMD (%) and three different brachial artery FMD normalizations were performed: (1) peak shear rate (%/SR); (2) area under the SR curve until peak dilation (%/AUC); and (3) AUC 30 seconds before peak dilation (%/AUC30). Immunofluorescence quantification was used to assess eNOS expression and nitrotyrosine (NT), a criterion marker of endothelial oxidative stress. Values for eNOS and NT expression were reported as a ratio of endothelial cell to human umbilical vein endothelial cell average pixel intensity. NT expression was significantly correlated with FMD normalized by AUC30 (r = -0.402, p<0.05). Other FMD normalizations and non-normalized FMD were not significantly correlated with NT expression (r range = -0.364 to -0.142, all p>0.05). There were no significant correlations between eNOS expression and normalized and non-normalized FMD (r range = -0.168 to -0.066, all p>0.05). In conclusion, brachial artery FMD is associated with venous endothelial cell oxidative stress. However, this association is observed only when FMD is normalized by AUC30.

Platelet Adhesion to Polyurethane Urea Under Pulsatile Flow Conditions

Platelet adhesion to a polyurethane urea surface is a precursor to thrombus formation within blood-contacting cardiovascular devices, and platelets have been found to adhere strongly to polyurethane surfaces below a shear rate of approximately 500 s(-1). The aim of the current work is to determine the properties of platelet adhesion to the polyurethane urea surface as a function of time-varying shear exposure. A rotating disk system was used to study the influence of steady and pulsatile flow conditions (e.g., cardiac inflow and sawtooth waveforms) for platelet adhesion to the biomaterial surface. All experiments were conducted with the same root mean square angular rotation velocity (29.63 rad/s) and waveform period. The disk was rotated in platelet-rich bovine plasma for 2 h, with adhesion quantified by confocal microscopy measurements of immunofluorescently labeled bovine platelets. Platelet adhesion under pulsating flow was found to decay exponentially with increasing shear rate. Adhesion levels were found to depend upon peak platelet flux and shear rate, regardless of rotational waveform. In combination with flow measurements, these results may be useful for predicting regions susceptible to thrombus formation within ventricular assist devices.

Abstract P431: The Effect of Ten Days of Reduced Physical Activity (rPA) on Markers of Vascular Function

Flow-mediated dilation (FMD) is an early marker of cardiovascular disease. Circulating angiogenic cells (CAC) are hypothesized to support endothelial health and repair and have been related to Framingham risk score. Both FMD and CAC have been investigated as early biomarkers of vascular dysfunction and are related to physical activity. Low physical activity is a risk factor for cardiovascular disease however, the effect of a short-term reduction in physical activity on FMD and CACs is unclear. Purpose: To use a novel, objectively monitored model of rPA wherein participants maintain energy balance to evaluate changes in a physiological and cellular marker of vascular function. Hypothesis: rPA will result in lower FMD and CAC compared with baseline. Methods: Physical activity was measured via Actigraph GT3X before and during 10 days of rPA in healthy trained men (n=6). Baseline caloric intake was assessed and participants were instructed to reduce their intake to match the reduction in energy expenditure during rPA. FMD was assessed via duplex ultrasound of the brachial artery. Artery diameter and shear rate were analyzed with FMD Studio software (Quipu, Pisa). Data for baseline shear rate, baseline vessel diameter, peak shear rate, peak vessel diameter, absolute FMD, relative FMD, area under the curve (AUC), and normalized FMD were calculated for each subject. CAC colony forming units (CFU-EC) were measured before and after rPA. Paired T-tests were used to determine differences between variables before and after rPA. Results: Actigraph data revealed increased sedentary time (656 ± 42 to 758 ± 36 min/day, p=0.02) and decreased moderate to vigorous physical activity with rPA (MVPA, 87 ± 16 to 59 ± 9, p=0.03). Weight did not change with rPA. There was a 60 ± 27% increase in baseline shear rate (p=0.03) and a 22 ± 5% decrease in peak shear rate with rPA (p=0.003). We also found a 39% decrease in CAC with rPA (21 ± 5 to 14 ± 6, p=0.03). Conclusion: Our preliminary data show that short-term rPA results in significant changes in shear stress and CACs, two markers of vascular function. Future research should explore the independent influence of changes in physical activity and sedentary behavior on vascular function.

Impaired Vascular Function in Physically Active Premenopausal Women With Functional Hypothalamic Amenorrhea Is Associated With Low Shear Stress and Increased Vascular Tone

Exercise-trained hypoestrogenic premenopausal women with functional hypothalamic amenorrhea (ExFHA) exhibit impaired endothelial function. The vascular effects of an acute bout of exercise, a potent nitric oxide stimulus, in these women are unknown. Three groups were studied: recreationally active ExFHA women (n = 12; 24.2 ± 1.2 years of age; mean ± SEM), and recreationally active (ExOv; n = 14; 23.5 ± 1.2 years of age) and sedentary (SedOv; n = 15; 23.1 ± 0.5 years of age) ovulatory eumenorrheic women. Calf blood flow (CBF) and brachial artery flow-mediated dilation (FMD) were evaluated using plethysmographic and ultrasound techniques, respectively, both before and 1 hour after 45 minutes of moderate-intensity exercise. Endothelium-independent dilation was assessed at baseline using glyceryl trinitrate. Calf vascular resistance (CVR) and brachial peak shear rate, as determined by the area under the curve (SRAUCpk), were also calculated. FMD and glyceryl trinitrate responses were lower (P < .05) in ExFHA (2.8% ± 0.4% and 11.6% ± 0.7%, respectively) than ExOv (8.8% ± 0.7% and 16.7% ± 1.3%) and SedOv (8.0% ± 0.5% and 17.1% ± 1.8%). SRAUCpk was also lower (P < .05) in ExFHA. Normalization of FMD for SRAUCpk (FMD/SRAUCpk) did not alter (P > .05) the findings. CBF was lower (P < .05) and CVR higher (P < .05) in ExFHA. After exercise, FMD and SRAUCpk were augmented (P < .05), but remained lower (P < .05), in ExFHA. FMD/SRAUCpk no longer differed (P > .05) between the groups. CBF in ExFHA was increased (P < .05) and CVR decreased (P < .05) to levels observed in ovulatory women. Acute dynamic exercise improves vascular function in ExFHA women. Although the role of estrogen deficiency per se is unclear, our findings suggest that low shear rate and increased vasoconstrictor tone may play a role in impaired basal vascular function in these women.

Combining numerical and clinical methods to assess aortic valve hemodynamics during exercise

Computational simulations have the potential to aid understanding of cardiovascular hemodynamics under physiological conditions, including exercise. Therefore, blood hemodynamic parameters during different heart rates, rest and exercise have been investigated, using a numerical method. A model was developed for a healthy subject. Using geometrical data acquired by echo-Doppler, a two-dimensional model of the chamber of aortic sinus valsalva and aortic root was created. Systolic ventricular and aortic pressures were applied as boundary conditions computationally. These pressures were the initial physical conditions applied to the model to predict valve deformation and changes in hemodynamics. They were the clinically measured brachial pressures plus differences between brachial, central and left ventricular pressures. Echocardiographic imaging was also used to acquire different ejection times, necessary for pressure waveform equations of blood flow during exercise. A fluid-structure interaction simulation was performed, using an arbitrary Lagrangian-Eulerian mesh. During exercise, peak vorticity increased by 14.8%, peak shear rate by 15.8%, peak cell Reynolds number by 20%, peak leaflet tip velocity increased by 47% and the blood velocity increased by 3% through the leaflets, whereas full opening time decreased by 11%. Our results show that numerical methods can be combined with clinical measurements to provide good estimates of patient-specific hemodynamics at different heart rates.