Vessel Distensibility Research Articles

EFFECT OF TOBACCO AND ELECTRONIC CIGARETTES ON HEART RATE AND CARDIOVASCULAR SYSTEM IN SMOKERS

Smoking is widespread among the young working population in Russia. Moreover, e-cigarettes are very popular among smokers as an alternative to traditional ones. The purpose of the study was to establish the effect of traditional cigarettes and modern e-cigarettes on the physiological characteristics of smokers, namely young people aged 18–21. Materials and Methods. The study involved young people agd 18–21 with at least 1 year of smoking experience and non-smokers. The trial participants were organized into three groups: a control group (non-smokers) and two experimental groups (traditional cigarette smokers and e-cigarette smokers). The research methods included physical tests, such as a breathing test, pressure measurements at rest, at load and after smoking, and calculation of cardiovascular state parameters. Results. During the experiment, no changes in blood pressure were observed in e-cigarette smokers.In traditional cigarette smokers, an increase in systolic blood pressure was observed at load. However, diastolic blood pressure was normal. It indicated a decrease in the distensibility of arterial vessels. An increase in heart rate was noted in both cigarette and e-cigarette smokers at load and immediately after smoking. The predominance of the sympathetic influence on the cardiovascular system was determined in all trial subjects. The obtained data indicated a violation in cardiovascular system activity in all subjects before and after exercise, and after smoking. At the same time, cardiovascular system activity deteriorated in the experimental groups after smoking. Under normal conditions and after exercise, all trial subjects showed tension in their adaptation mechanisms. After smoking in both experimental groups cardiovascular system adaptation potential was unsatisfactory. Conclusion. An assessment of physical parameters in smokers revealed a negative impact of tobacco and e-cigarettes on the cardiovascular system, namely on heart rate, regulation of cardiovascular system activity, adaptation mechanisms, which was likely to increase with smoking history.

Therapeutic inhibition of biomechanically-activated YAP-TAZ signaling prevents vein graft atherosclerosis

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Rembrandt Institute for Cardiovascular Sciences Background Venous bypass grafts may have limited patency due to excessive intimal hyperplasia and accelerated atherosclerosis. YAP-TAZ signaling regulates cellular responses to biomechanical cues, such as disturbed flow or vessel distention as seen in vein grafts. YAP activation leads to inflammation and angiogenesis, which both contribute to vein graft atherosclerosis. Inhibition of YAP-TAZ attenuates naive atherogenesis, but its potential to inhibit intraplaque angiogenesis and reduce vein graft atherosclerosis has not been explored. Methods Saphenous vein progenitor cells (SVPs) were subjected to mechanical strain in vitro to assess YAP activation. IHC to assess YAP-expression was performed on vein grafts from pigs as well as ex vivo cultured human saphenous veins. Furthermore, YAP-IHC was performed on murine vein grafts from hypercholesterolemic ApoE3*Leiden mice harvested at early, mid- and late-stage disease timepoints to assess optimal treatment window. In a separate experiment, mice (n=11-13/group) underwent bypass surgery and were treated with the FDA-approved YAP-TAZ inhibitor Verteporfin (50 mg/kg) or vehicle 3 times/week from day 10 until sacrifice (day 28). Ultrasound was used to longitudinally quantify vascular remodeling. Vein grafts were harvested and processed for morphometric and compositional analysis. Results Mechanical strain induced activation of YAP and its downstream targets (Ctgf, Cyr61) in SVPs, which was inhibited by Verteporfin (confirmed by WB, IP and qPCR). Moreover, YAP was abundantly expressed in pig vein graft lesions, whilst Verteporfin blocked YAP expression in ex vivo cultured human saphenous veins after exposure to disturbed flow. In addition, YAP was increasingly expressed during vein graft lesion development in mice, reaching its peak around day 14, which coincides with the initiation of intraplaque angiogenesis. Furthermore, YAP was predominantly expressed in luminal and adventitial endothelial cells. Analysis of ultrasound demonstrated that Verteporfin prevented vein graft thickening in mice over time. End-point histology revealed that the intima/media ratio was significantly decreased by Verteporfin treatment (37%, p=0.001). Intraplaque angiogenesis was also reduced (34%, p=0.002), whilst neovessel maturation was improved upon verteporfin treatment. The vessel wall ACTA2 content was reduced (42%, p=0.023), whilst collagen was not altered between both groups, indicating that Verteporfin diminished the fibroproliferative response without affecting vessel wall stability. Conclusion Verteporfin inhibited YAP-TAZ activation induced by mechanical strain in vitro (SVPs) as well as ex vivo (cultured human saphenous veins). In vivo, Verteporfin treatment resulted in a significant decrease of vein graft atherosclerosis and intraplaque angiogenesis. Therefore, therapeutic targeting of YAP-TAZ using Verteporfin might be a new candidate to improve vein graft patency.

Superior Vena Cava Syndrome Associated with Left Subclavian Thrombosis Secondary to Anaplastic Thyroid Carcinoma: A Case Report

Superior vena cava syndrome results from obstruction of the venous flow or the return of the superior vena cava. Increased venous pressure in the upper body causes edema of the face, neck, and upper extremities occasionally accompanied by vessel distension, cyanosis, cough, dyspnea, stridor, and dysphagia. Cerebral edema causes headaches, confusion, coma, and even death. Lung cancer and non-Hodgkin lymphoma are the most frequent malignant causes (85%) of superior vena cava syndrome, and thyroid cancer is a rare cause (< 5%).

Beta-adrenergic blockade increases pulmonary vascular resistance and causes exaggerated hypoxic pulmonary vasoconstriction at high altitude: a physiological study.

An increasing number of hypertensive persons travel to high altitude (HA) while using antihypertensive medications such as beta-blockers. Nevertheless, while hypoxic exposure initiates an increase in pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR), the contribution of the autonomic nervous system is unclear. In animals, beta-adrenergic blockade has induced pulmonary vasoconstriction in normoxia and exaggerated hypoxic pulmonary vasoconstriction (HPV) and both effects were abolished by muscarinic blockade. We thus hypothesized that in humans, propranolol (PROP) increases Ppa and PVR in normoxia and exaggerates HPV, and that these effects of PROP are abolished by glycopyrrolate (GLYC). In seven healthy male lowlanders, Ppa was invasively measured without medication, with PROP and PROP+GLYC, both at sea level (SL, 488m) and after a 3-week sojourn at 3454m altitude (HA). Bilateral thigh-cuff release manoeuvres were performed to derive pulmonary pressure-flow relationships and pulmonary vessel distensibility. At SL, PROP increased Ppa and PVR from (mean±SEM) 14±1 to 17±1mmHg and from 69±8 to 108±11 dyn s cm-5 (21% and 57% increase, P=0.01 and P<0.0001). The PVR response to PROP was amplified at HA to 76% (P<0.0001, P[interaction]=0.05). At both altitudes, PROP+GLYC abolished the effect of PROP on Ppa and PVR. Pulmonary vessel distensibility decreased from 2.9±0.5 to 1.7±0.2 at HA (P<0.0001) and to 1.2±0.2 with PROP, and further decreased to 0.9±0.2% mmHg-1 with PROP+GLYC (P=0.01). Our data show that beta-adrenergic blockade increases, and muscarinic blockade decreases PVR, whereas both increase pulmonary artery elastance. Future studies may confirm potential implications from the finding that beta-adrenergic blockade exaggerates HPV for the management of mountaineers using beta-blockers for prevention or treatment of cardiovascular conditions.

Vascular Ultrasound for In Vivo Assessment of Arterial Pathologies in a Murine Model of Atherosclerosis and Aortic Aneurysm.

Vascular diseases like atherosclerosis and abdominal aortic aneurysm (AAA) are common pathologies in the western world, promoting various potentially fatal conditions. Here, we evaluate high-resolution (HR) ultrasound in mouse models of atherosclerosis and AAA as a useful tool for noninvasive monitoring of early vascular changes in vivo. We used Apolipoprotein E-deficient (ApoE-/-) mice as an atherosclerosis model and induced AAA development by the implementation of Angiotensin II-releasing osmotic minipumps. HR ultrasound of the carotid artery or the abdominal aorta was performed to monitor vascular remodeling in vivo. Images were analyzed by speckle tracking algorithms and correlated to histological analyses and subsequent automated collagen quantification. Consistent changes were observed via ultrasound in both models: Global radial strain (GRS) was notably reduced in the AAA model (23.8 ± 2.8% vs. 12.5 ± 2.5%, p = 0.01) and in the atherosclerotic mice (20.6 ± 1.3% vs. 15.8 ± 0.9%, p = 0.02). In mice with AAA, vessel distensibility was significantly reduced, whereas intima-media thickness was increased in atherosclerotic mice. The area and collagen content of the tunica media were increased in diseased arteries of both models as measured by automated image analysis of Picrosirius Red-stained aortic sections. Correlation analysis revealed a strong correlation of multiple parameters, predicting early vascular damage in HR ultrasound and histological examinations. In conclusion, our findings underscore the potential of HR ultrasound in effectively tracing early alterations in arterial wall properties in murine models of atherosclerosis and AAA.

Highly reproducible rat arterial injury model of neointimal hyperplasia.

Models of arterial injury in rodents have been invaluable to our current understanding of vessel restenosis and play a continuing role in the development of endovascular interventions for cardiovascular disease. Mechanical distention of the vessel wall and denudation of the vessel endothelium are the two major modes of vessel injury observed in most clinical pathologies and are critical to the reproducible modelling of progressive neointimal hyperplasia. The current models which have dominated this research area are the mouse wire carotid or femoral injury and the rat carotid balloon injury. While these elicit simultaneous distension of the vessel wall and denudation of the luminal endothelium, each model carries limitations that need to be addressed using a complementary injury model. Wire injuries in mice are highly technical and procedurally challenging due to small vessel diameters, while rat balloon injuries require permanent blood vessel ligation and disruption of native blood flow. Complementary models of vascular injury with reproducibility, convenience, and increased physiological relevance to the pathophysiology of endovascular injury would allow for improved studies of neointimal hyperplasia in both basic and translational research. In this study, we developed a new surgical model that elicits vessel distention and endothelial denudation injury using sequential steps using microforceps and a standard needle catheter inserted via arteriotomy into a rat common carotid artery, without requiring permanent ligation of branching arteries. After 2 weeks post-injury this model elicits highly reproducible neointimal hyperplasia and rates of re-endothelialisation similar to current wire and balloon injury models. Furthermore, evaluation of the smooth muscle cell phenotype profile, inflammatory response and extracellular matrix within the developing neointima, showed that our model replicated the vessel remodelling outcomes critical to restenosis and those becoming increasingly focused upon in the development of new anti-restenosis therapies.

Abstract TP99: Non-invasive Aortic Pulse Wave Velocity Is Related To Gold Standard Carotid-femoral Pulse Wave Velocity: Implications For Monitoring Large Artery Stiffness In The Clinic

Introduction: Aortic stiffness is an independent predictor of fatal stroke in both hypertensive populations and healthy subjects, but traditional monitoring methods have had difficulty being incorporated into routine practice. The gold standard, carotid-femoral pulse wave velocity (cfPWV), poses methodological challenges as this method bypasses the most distensible vessel, the proximal aorta. We propose a new method, aortic arch pulse wave velocity (aaPWV) assessed via ultrasound, which encompasses the proximal aorta and can be performed during standard cardiac echocardiography. We sought to determine if the two methods were related. Methods: We recruited 44 healthy volunteers (38.1y [SEM: 2.39], range 20-62y, 80% female) for this study. Both aaPWV and cfPWV were measured by the wave-foot method using a commercial Logic S8 Ultrasound system (GE Healthcare) with synchronous electrocardiogram. cfPWV was calculated by determining the time delay between the two vessels and dividing by the measured distance between the two sites. aaPWV was calculated by determining the time delay between onset of aortic ejection from the apical 5-chamber view and the arrival of the pulse wave at the start of descending aorta in the suprasternal view. Distance for aaPWV was estimated using regression equation from the literature. Results: Paired t-tests revealed cfPWV was significantly greater than aaPWV (5.98 ± 0.17m/s vs. 4.7 ± 0.29m/s; P&lt;0.001). Pearson correlation revealed the two methods were related (r=0.35, P=0.01) and intraclass correlation coefficient revealed good agreement within and between raters (0.75, 0.85 respectively; 0.75-0.9 indicate good agreement). Conclusion: We report that while aaPWV and cfPWV are correlated, significant differences exist, which was expected given the proximal segment is the most elastic portion of the aorta. The findings from this study suggest aaPWV could be a more feasible method to measure large artery stiffness in routinely in the clinic, but future studies are needed to determine if aaPWV is similarly predictive of adverse cardiovascular outcomes.

Abstract WP137: Carotid Distension And Remodeling Is Associated With The Aorta-carotid Stiffness Gradient

Background: Recent studies have suggested that the arterial stiffness gradient between the aorta and cerebrovasculature, versus aortic stiffness alone, better predicts incidence of cerebrovascular disease, due to increased transmission of pulsatile energy to the cerebral microcirculation. Our aim was to evaluate the association of structural and functional alterations in the carotid artery with the aorta-carotid stiffness gradient versus using aortic stiffness alone. Methods: We evaluated vascular measures in 29 subjects (50±2.4 yrs, range 33–75 yrs, 65.5% women). Carotid pulse wave velocity (an index of stiffness, using the Bramwell-Hill equation), intima-media thickness (cIMT), cIMT-lumen ratio, and strain were calculated from Doppler ultrasound images. Carotid-femoral PWV (cfPWV) was calculated using the distance between the carotid and femoral sites and the timing of the velocity upstrokes relative to the R-wave on simultaneous electrocardiography. The aorta-carotid stiffness gradient (cf/c) was estimated as the ratio of cfPWV to carotid PWV. Blood pressures were taken as the average of two resting measurements prior to testing. The cf/c ratio was log-transformed to account for positive skewness. Results: In univariate analysis, both cfPWV and log(cf/c) were associated with carotid strain (β=-0.76 and β=-15.91 respectively; both p&lt;0.05). The cIMT-lumen ratio was associated with cfPWV (β=0.0049, p=0.019) but not with log(cf/c) (p=0.125). After adjustment for age, sex, BMI and SBP, the association between cfPWV and carotid strain was nonsignificant (p&gt;0.05) while log(cf/c) remained independently associated with carotid strain (β=-12.69, p&lt;0.05). In the adjusted model, both cfPWV and log(cf/c) were independently associated with cIMT-lumen ratio (β=0.0059 and β=0.082 respectively, both p&lt;0.05). Conclusion: After adjustment, cfPWV and cf/c were associated with increases in the cIMT-lumen ratio, an indicator of inward remodeling. However, only cf/c was associated with carotid strain, a measure of vessel distension and an index of vessel stiffness. These results suggest that, compared to aortic stiffness alone, the aorta-carotid stiffness gradient may be a more robust indicator of alterations in carotid structure and function.

Comparison of Approximated and Actual Bramwell-Hill Equation Implementation for Local Pulse Wave Velocity: Ex-vivo Study.

Bramwell-Hill (BH) equation is widely adopted for the evaluation of local pulse wave velocity (PWV), primarily for its theoretical association with the vessel's distensibility. Its implementation, however, requires arterial pressure and diameter waveforms simultaneously from a single site. Owing to the challenges associated with such a noninvasive recording, an approximated BH equation is adopted without requiring the entire pressure waveform but only the diastolic and systolic values. The approximated BH method yields a single value of local PWV as opposed to the actual method that provides instantaneous PWV within a cardiac cycle. This study aims to provide the currently lacking insights into how the approximate versus actual BH implementations compare. The study also addresses the pivotal question of which instantaneous value within the cardiac cycle corresponds to the approximated BH. An ex-vivo study was conducted for this purpose, emulating different flow conditions (changing mean and pulse pressures) to vary the local PWV within the range of 4.4 to 8.9 m/s. The results revealed the expected (pressure-dependent) incremental nature of local PWV due to hyper-elastic behavior of the artery, with systolic BH-PWV > diastolic BH-PWV by 13.6%. The approximate BH-PWV was similar to actual BH-PWV obtained from mean pressure level. It further underestimated the systolic, and overestimated the diastolic PWVs by 8.5% and 6.6%, respectively. Clinical Relevance - When estimated BH-PWV estimates are compared to normal values for patient classification or utilized as a reference standard in validation studies these findings become extremely important.

Computational Fluid–Structure Interactions in the Human Cerebrovascular System: Part 1—A Review of the Current Understanding of Cerebrovascular Biomechanics

Abstract Computational fluid–structure interaction (FSI) modeling is a technique used in engineering to understand the effect that fluid flow and surrounding structures have on one another. Used in the aerospace and turbine industries, when applied in the appropriate scenarios, the outcome of fluid–solid interaction analyses may yield more precise results than computational fluid dynamics or mechanical structural testing/analysis alone. For biological systems, such as the cerebrovascular system in humans, the inherent complexity of the system makes performing clinically accurate predictive computational modeling challenging. An isolated computational fluid dynamic analysis of the blood flow to predict cerebral aneurysm rupture or an isolated structural analysis of the cerebral aneurysm dome may be only part of the answer to predicting whether an aneurysm will rupture and over what time span. The variable pressures and flow rate of blood through vessels cause blood vessel walls to change shape, rebound, and move within the adjacent tissue. This rebounding movement, in turn, alters the flow pattern of blood. In pathologies such as cerebral aneurysms or cerebral arteriovenous malformations (AVMs) with unpredictable rupture profiles, these small interactions between blood flow and vessel distension may potentially explain the difference between a catastrophic hemorrhage and an entirely quiescent lesion. This two-part review evaluates (1) the current understanding of cerebrovascular fluid and structure mechanical properties and (2) the state of fluid–structure interaction models in the cerebrovascular systems. Additionally, as the cardiovascular FSI literature is much more extensive than the cerebrovascular literature, future potential studies that glean insight from that work are discussed.

Abstract P162: Cardiovascular Disease And Periodontal Disease In Type 1 Diabetes

Type 1 diabetes (T1D) is a condition in which the body’s immune system destroys insulin-producing beta cells, resulting in hyperglycemia. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in those with T1D. Periodontal disease (PD) is the 6th major complication of T1D. Oral bacteria have been detected in atherosclerotic plaques. Thus, oral bacteria may play a causal role in cardiovascular disease. The aims of this study are to determine how subclinical measures of cardiovascular disease differ by diabetes status and how they are related to the extent of periodontal disease. It is hypothesized that people with T1D will have stiffer vessels with higher pulse wave velocity (PWV), lower brachial artery distensibility (BrachD), and higher carotid intima-media thickness (cIMT) compared to non-diabetic controls. It is also hypothesized that people with T1D will have a higher prevalence of PD compared to non-diabetic controls. Study visits were performed to assess cardiovascular and periodontal outcomes in people with T1D (n=144) and non-diabetic controls (n=147). Univariate analysis was performed using t-test and chi-square to test for significant differences in vascular measures and periodontal status between T1D and controls. Age and sex-adjusted multivariate linear and logistic regression was used to further examine differences in vascular measures and periodontal disease by diabetes status. PWV was significantly higher in people with T1D compared to controls (8.390 +/- 0.111 vs. 7.822 +/- 0.108, p=0.0003). BrachD was significantly lower in people with T1D compared to controls (5.795 +/- 0.095 vs. 6.413 +/- 0.094, p&lt;0.0001). cIMT was significantly higher in people with T1D compared to controls (0.679 +/- 0.009 vs. 0.626 +/- 0.009, p&lt;0.0001). Adults with T1D were significantly more likely to have moderate to severe PD compared to controls (OR = 2.759, 95% CI [1.310-5.811], p=0.0076). Adults with T1D have worse cardiovascular health as measured by stiffer central vessels, more subclinical atherosclerosis, and lower peripheral vessel distensibility. Adults with T1D had almost 3-fold higher risk of moderate to severe PD compared to non-diabetic adults. The relationship between PD and the increased CVD risk in people with T1D warrants further examination.

A mathematical model of maternal vascular growth and remodeling and changes in maternal hemodynamics in uncomplicated pregnancy.

The maternal vasculature undergoes tremendous growth and remodeling (G&R) that enables a > 15-fold increase in blood flow through the uterine vasculature from conception to term. Hemodynamic metrics (e.g., uterine artery pulsatility index, UA-PI) are useful for the prognosis of pregnancy complications; however, improved characterization of the maternal hemodynamics is necessary to improve prognosis. The goal of this paper is to develop a mathematical framework to characterize maternal vascular G&R and hemodynamics in uncomplicated human pregnancies. A validated 1D model of the human vascular tree from the literature was adapted and inlet blood flow waveforms at the ascending aorta at 4week increments from 0 to 40weeks of gestation were prescribed. Peripheral resistances of each terminal vessel were adjusted to achieve target flow rates and mean arterial pressure at each gestational age. Vessel growth was governed by wall shear stress (and axial lengthening in uterine vessels), and changes in vessel distensibility were related to vessel growth. Uterine artery velocity waveforms generated from this model closely resembled ultrasound results from the literature. The literature UA-PI values changed significantly across gestation, increasing in the first month of gestation, then dramatically decreasing from 4 to 20weeks. Our results captured well the time-course of vessel geometry, material properties, and UA-PI. This 1D fluid-G&R model captured the salient hemodynamic features across a broad range of clinical reports and across gestation for uncomplicated human pregnancy. While results capture available data well, this study highlights significant gaps in available data required to better understand vascular remodeling in pregnancy.

Deep Learning-Based Approach to Automatically Assess Coronary Distensibility Following Kawasaki Disease

Kawasaki disease is an acute vasculitis affecting children, which can lead to coronary artery (CA) aneurysms. Optical coherence tomography (OCT) has identified CA wall damage in KD patients, but it is unclear if these findings correlate with any distensibility changes in the CA and how these changes evolve over time. This paper seeks to establish the link between OCT findings and vessel distensibility with a novel deep learning coronary artery segmentation system and use the segmentation framework to automatically analyze the temporal evolution of coronary stiffness over many years. 27 KD patients underwent catheterization with coronary angiography of the left coronary artery (LCA), followed by OCT of proximal and distal segments of the LCA. Changes in the CA caliber over the cardiac cycle were measured automatically and compared against OCT findings suggestive of KD-related vascular damage. In addition, 34 KD patients with regressed or persistent CA aneurysms were followed with serial CA angiography over an average of 14.5years. Distensibility changes were calculated using adeep learning coronary artery segmentation framework and evaluated longitudinally. Distensibility in the coronary arteries after KD negatively correlated with increasing severity of OCT findings of KD-related vessel damage. KD patients have a significant increase in CA wall stiffness at 1year after diagnosis, which then plateaus subsequently, compared to controls. Also, patients with persistent CA aneurysms have a statistically significant increase in wall stiffness over time in comparison to those with regressed CA aneurysms. Distensibility changes in the CA of KD patients calculated using our automated deep learning approach correlates with the severity of OCT findings of KD-related CA damage. This decreased distensibility peaks at 1year in KD patients when following longitudinally and is more severe in those with persistent CA aneurysms.

Wireless Monitoring of Vascular Pressure Using CB-PDMS Based Flexible Strain Sensor.

Rising pressure within a vascular graft can signal impending failure caused by stenosis or thrombosis, and early detection can improve surgical salvage outcomes. To enable regular graft pressure monitoring, we developed a thin flexible pulsation sensor (FPS) with wireless data readout. A conductive polymer sensing layer is attached to a flexible circuit board and then encapsulated by polydimethylsiloxane (PDMS) for biocompatibility. Due to the FPS' outstanding flexibility in comparison to natural arteries, veins, and synthetic vascular grafts, it can be wrapped around target conduits to monitor blood pressure for short-term surgical and long-term implantation purposes. In this study, we analyze the power spectrum of the FPS data to determine the ideal bandwidth of the wireless FPS device to preserve heart rate and hemodynamic waveforms while rejecting noise. The strain response of FPS wrapped around silicone tube, vascular graft and artery was simulated using COMSOL®, showing a linear relationship between pressure and FPS strain. The optimized bandpass filter of 0.2-10 Hz was simulated and implemented on a flexible polyimide circuit board. The circuit board also included a low- power microcontroller for data conversion and transmission via simple 4-MHz on-off keying. The performance of the prototype was evaluated by recording wireless data from a vascular phantom under different pressure and flow settings. The results indicate that the peak-to-peak FPS voltage responds linearly to RMS blood pressure and systolic-diastolic pressure.Clinical Relevance- Early detection of a failing vascular graft could leverage sensors for near real-time monitoring. The presented wireless flexible sensor measures and transmits vessel distension data as a proxy for internal lumen pressure.

Differences in human placental mesenchymal stromal cells may impair vascular function in FGR.

Placentae from pregnancies with foetal growth restriction (FGR) exhibit poor oxygen and nutrient exchange, in part due to impaired placental vascular development. Placental mesenchymal stromal cells (pMSCs) reside in a perivascular niche, where they may influence blood vessel formation/function. However, the role of pMSCs in vascular dysfunction in FGR is unclear. To elucidate the mechanisms by which pMSCs may impact placental vascularisation we compared the transcriptomes of human pMSCs isolated from FGR (<5th centile) (n = 7) and gestation-matched control placentae (n = 9) using Affymetrix microarrays. At the transcriptome level, there were no statistically significant differences between normal and FGR pMSCs; however, several genes linked to vascular function exhibited notable fold changes, and thus the dataset was used as a hypothesis-generating tool for possible dysfunction in FGR. Genes/proteins of interest were followed up by real-time PCR, western blot and immunohistochemistry. Gene expression of ADAMTS1 and FBLN2 (fibulin-2) were significantly upregulated, whilst HAS2 (hyaluronan synthase-2) was significantly downregulated, in pMSCs from FGR placentae (n = 8) relative to controls (n = 7, P < 0.05 for all). At the protein level, significant differences in the level of fibulin-2 and hyaluronan synthase-2, but not ADAMTS1, were confirmed between pMSCs from FGR and control pregnancies by Western blot. All three proteins demonstrated perivascular expression in third-trimester placentae. Fibulin-2 maintains vessel elasticity, and its increased expression in FGR pMSCs could help explain the increased distensibility of FGR blood vessels. ADAMTS1 and hyaluronan synthase-2 regulate angiogenesis, and their differential expression by FGR pMSCs may contribute to the impaired angiogenesis in these placentae.

Six weeks of high-intensity interval training enhances contractile activity induced vascular reactivity and skeletal muscle perfusion in older adults

Impairments in muscle microvascular function are associated with the pathogenesis of sarcopenia and cardiovascular disease. High-intensity interval training (HIIT) is an intervention by which a myriad of beneficial skeletal muscle/cardiovascular adaptations have been reported across age, including capillarisation and improved endothelial function. Herein, we hypothesised that HIIT would enhance muscle microvascular blood flow and vascular reactivity to acute contractile activity in older adults, reflecting HIIT-induced vascular remodelling. In a randomised controlled-trial, twenty-five healthy older adults aged 65–85 years (mean BMI 27.0) were randomised to 6-week HIIT or a no-intervention control period of an equal duration. Measures of microvascular responses to a single bout of muscle contractions (i.e. knee extensions) were made in the m. vastus lateralis using contrast-enhanced ultrasound during a continuous intravenous infusion of Sonovue™ contrast agent, before and after the intervention period, with concomitant assessments of cardiorespiratory fitness and resting blood pressure. HIIT led to improvements in anaerobic threshold (13.2 ± 3.4 vs. 15.3 ± 3.8 ml/kg/min, P < 0.001), dynamic exercise capacity (145 ± 60 vs. 159 ± 59 W, P < 0.001) and resting (systolic) blood pressure (142 ± 15 vs. 133 ± 11 mmHg, P < 0.01). Notably, HIIT elicited significant increases in microvascular blood flow responses to acute contractile activity (1.8 ± 0.63 vs. 2.3 ± 0.8 (arbitrary contrast units (AU), P < 0.01)), with no change in any of these parameters observed in the control group. Six weeks HIIT improves skeletal muscle microvascular responsiveness to acute contractile activity in the form of active hyperaemia-induced by a single bout of resistance exercise. These findings likely reflect reports of enhanced large vessel distensibility, improved endothelial function, and muscle capillarisation following HIIT. Moreover, our findings illustrate that HIIT may be effective in mitigating deleterious alterations in muscle microvascular mediated aspects of sarcopenia.

Sodium Nitroglycerin and Hypercapnic Stimuli Reduce Cerebral Vascular Bed Compliance in Humans

Human cerebral arteries dilate to various stimuli and this change in contractile state is often quantified as a steady-state change in vascular resistance. In oscillatory blood flow, compliance of the vascular bed also contributes to the regulation of cerebral perfusion. However, very little is known about the impact of cerebral dilation on cerebral vascular bed compliance. Therefore, the present study examined the impact of cerebral vasodilatory stimuli on cerebrovascular compliance in humans. Fifteen young, healthy adults (27 ± 5 years, 7 females) participated in the present study. Participants completed a sodium nitroglycerin (SNG) protocol involving a 2-minute baseline period, administration of one 0.4 mg sublingual spray of SNG, followed by 10 minutes of data collection. Following the completion of the SNG protocol, participants rested for at least 5 minutes after which the hypercapnia protocol was completed. Following a 2-minute baseline period, participants breathed a low percentage (5-6%) carbon dioxide (CO2)gas mixture for 4 minutes followed by a 3-minute recovery period breathing room air. Throughout the experimental protocols, blood pressure (BP) waveforms (finger photoplethysmography; Finapres Medical Systems) and middle cerebral artery blood velocity (BV) waveforms (transcranial Doppler ultrasound; Multigon Industries) were collected in the supine position. Five individual BP and corresponding BV waveforms were extracted during each protocol's baseline period, at each minute of SNG and CO2, and during the last minute of the CO2 recovery period. The waveforms were input into a modified Windkessel model and an index of cerebrovascular compliance (Ci) was calculated. During the SNG protocol, Ci was 5.0e-4 ± 2.3e-4 cm·s-1·mmHg-1 at baseline and decreased significantly by minute 7 of SNG administration (P = 0.01, d = 1.07). Overall, Ci decreased by 29% to its nadir, 3.6e-4 ± 1.2e-4 cm·s-1·mmHg-1, at minute 10 of the protocol (P = 0.01, d = 0.98). During the hypercapniaprotocol, Ci was 4.4e-4 ± 2.0e-4 cm·s-1·mmHg-1 at baseline and decreased significantly by minute 1 of breathing CO2 (P = 0.003, d = 1.04). Overall, Ci was reduced by 30% to its lowest value of 3.1e-4 ± 1.4e-4 cm·s-1·mmHg-1 by minute 4 of hypercapnia (P < 0.001, d = 1.56). However, following 3 minutes of recovery, Ci increased to 4.2e-4 ± 1.5e-4 cm·s-1·mmHg-1, which was not different from baseline values (P = 0.86). BP remained unchanged during the SNG protocol (BSL: 87 ± 8 mmHg, Min 10: 89 ± 8 mmHg; P = 0.99), while it increased by 5 mmHg during the hypercapnia protocol (BSL: 86 ± 10 mmHg, Min 4: 91 ± 10 mmHg; P < 0.001, d = 1.44). However, no significant relationship was observed between the change in BP and the change in Ci with hypercapnia (r = -0.09, P = 0.75). Both vasodilatory stimuli reduced Ci by approximately 30% from supine baseline values. The attenuation of Ci likely relates to the predominance of collagen fibers in supporting wall tension during vessel distension.

Bond Graph Model of Cerebral Circulation: Toward Clinically Feasible Systemic Blood Flow Simulations

The primary paper Safaei et al. (2018) proposed an anatomically detailed model of the human cerebral circulation that runs faster than real-time on a desktop computer and is designed for use in clinical settings when the speed of response is important. Based on a one-dimensional formulation of the flow of an incompressible fluid in distensible vessels, a lumped parameter model was developed for 218 arterial segments. The proposed model improved simulation speed by approximately 200-fold while preserved accuracy. Bond graph formulation was used to ensure mass and energy conservation. The model predicted the pressure and flow signatures in the body.

Bond Graph Model of Cerebral Circulation: Toward Clinically Feasible Systemic Blood Flow Simulations

The primary paper Safaei et al. (2018) proposed an anatomically detailed model of the human cerebral circulation that runs faster than real-time on a desktop computer and is designed for use in clinical settings when the speed of response is important. Based on a one-dimensional formulation of the flow of an incompressible fluid in distensible vessels, a lumped parameter model was developed for 218 arterial segments. The proposed model improved simulation speed by approximately 200-fold while preserved accuracy. Bond graph formulation was used to ensure mass and energy conservation. The model predicted the pressure and flow signatures in the body.

The Effects of Prolonged Mechanical Ventilation on Structural and Material Properties of Diaphragm Arterioles

IntroductionIn skeletal muscle arterioles, cellular and vasoactive responses are influenced by the physiochemical milieu of the surrounding tissue. Understanding the mechanical properties of the blood vessel wall yields insight into vascular function in health and disease. In blood vessels, the endothelium mediates flow‐dependent vasodilation and contributes to the regulation of arterial mechanics. Prolonged mechanical ventilation (MV)(&gt;6 h) results in large, time‐dependent reductions in diaphragmatic blood flow and impaired endothelium‐dependent (and ‐independent) vasodilation of first‐order (1A) medial costal diaphragm arterioles. The purpose of this investigation was to determine if the severe reductions in diaphragmatic blood flow (and shear‐stress) with MV impair the structural and material properties (i.e. increased stress/stretch relation and/or circumferential stretch) of 1A arterioles from the medial costal diaphragm.MethodsFemale Sprague‐Dawley rats (~5 mo) were randomly divided into two groups, spontaneous breathing (SB, n = 6) and prolonged MV (6 h MV, n =5). Following SB and 6 h MV, 1A medial costal diaphragm arterioles (~200 μm diameter, ~2 mm in length) were isolated and cannulated. After cannulation, vessels were adjusted to a fixed length (L, 1.5 mm) and pressurized. Vessels that exhibited no leaks were subjected to a step‐wise passive‐pressure diameter test (0–140 cmH2O) in calcium‐free Ringer’s solution, at a single fixed axial length (L). Inner diameter (μm) and wall thickness (μm) were measured at each pressure step and used to calculate wall: lumen ratio, incremental distensibility (%/mmHg), Cauchy‐stress (μ), and circumferential stretch (λθ).ResultsFollowing 6 h MV, in the undeformed condition (0 mmHg) the wall: lumen ratio was significantly smaller compared to SB (1.04 ±0.21vs. 2.60 ±0.40; p&lt;0.05). There were no differences in incremental distensibility (%/mmHg) and the stress/stretch (μvs λθ) relation between groups (p&gt;0.05). At every pressure step, circumferential stretch (λθ; undeformed radius (r)/current deformed radius (R)) was significantly increased with 6 h MV versus SB (p&lt;0.05).ConclusionDespite no change in the distensibility and structural behavior (stress/stretch) of resistance vessels from the medial costal diaphragm, prolonged MV resulted in altered material properties (i.e. elevated circumferential stretch (λθ)) of medial costal diaphragm arterioles. Increased circumferential stretch can enhance superoxide generation in the endothelium and vascular smooth muscle cells. Therefore, elevated circumferential stretch of 1A diaphragm arterioles in combination with the severe reductions in blood flow may, in part, explain the previously demonstrated vascular dysfunction in the diaphragm following MV.Support or Funding InformationSupported by: NIH HL137156‐01A1