Ashkan Javadzadegan

Pathologic shear triggers shedding of vascular receptors: a novel mechanism for down-regulation of platelet glycoprotein VI in stenosed coronary vessels.

Ligand-induced ectodomain shedding of glycoprotein VI (GPVI) is a metalloproteinase-dependent event. We examined whether shear force, in the absence of GPVI ligand, was sufficient to induce shedding of GPVI. Human-citrated platelet-rich plasma or washed platelets were subjected to increasing shear rates in a cone-plate viscometer, and levels of intact and cleaved GPVI were examined by Western blot and ELISA. Pathophysiologic shear rates (3000-10 000 seconds(-1)) induced platelet aggregation and metalloproteinase-dependent appearance of soluble GPVI ectodomain, and GPVI platelet remnant. Shedding of GPVI continued after transient exposure to shear. Blockade of α(IIb)β(3), GPIbα, or intracellular signaling inhibited shear-induced platelet aggregation but minimally affected shear-induced shedding of GPVI. Shear-induced GPVI shedding also occurred in platelet-rich plasma or washed platelets isolated from a von Willebrand disease type 3 patient with no detectable VWF, implying that shear-induced activation of platelet metalloproteinases can occur in the absence of GPVI and GPIbα ligands. Significantly elevated levels of sGPVI were observed in 10 patients with stable angina pectoris, with well-defined single vessel coronary artery disease and mean intracoronary shear estimates at 2935 seconds(-1) (peak shear, 19 224 seconds(-1)). Loss of GPVI in platelets exposed to shear has potential implications for the stability of a forming thrombus at arterial shear rates.

Flow recirculation zone length and shear rate are differentially affected by stenosis severity in human coronary arteries

Flow recirculation zones and shear rate are associated with distinct pathogenic biological pathways relevant to thrombosis and atherogenesis. The interaction between stenosis severity and lesion eccentricity in determining the length of flow recirculation zones and peak shear rate in human coronary arteries in vivo is unclear. Computational fluid dynamic simulations were performed under resting and hyperemic conditions on computer-generated models and three-dimensional (3-D) reconstructions of coronary arteriograms of 25 patients. Boundary conditions for 3-D reconstructions simulations were obtained by direct measurements using a pressure-temperature sensor guidewire. In the computer-generated models, stenosis severity and lesion eccentricity were strongly associated with recirculation zone length and maximum shear rate. In the 3-D reconstructions, eccentricity increased recirculation zone length and shear rate when lesions of the same stenosis severity were compared. However, across the whole population of coronary lesions, eccentricity did not correlate with recirculation zone length or shear rate (P = not signficant for both), whereas stenosis severity correlated strongly with both parameters (r = 0.97, P < 0.001, and r = 0.96, P < 0.001, respectively). Nonlinear regression analyses demonstrated that the relationship between stenosis severity and peak shear was exponential, whereas the relationship between stenosis severity and recirculation zone length was sigmoidal, with an apparent threshold effect, demonstrating a steep increase in recirculation zone length between 40% and 60% diameter stenosis. Increasing stenosis severity and lesion eccentricity can both increase flow recirculation and shear rate in human coronary arteries. Flow recirculation is much more sensitive to mild changes in the severity of intermediate stenoses than is peak shear.

Correlation between Reynolds number and eccentricity effect in stenosed artery models

BACKGROUND Flow recirculation and shear strain are physiological processes within coronary arteries which are associated with pathogenic biological pathways. Distinct Quite apart from coronary stenosis severity, lesion eccentricity can cause flow recirculation and affect shear strain levels within human coronary arteries. OBJECTIVE The aim of this study is to analyse the effect of lesion eccentricity on the transient flow behaviour in a model of a coronary artery and also to investigate the correlation between Reynolds number (Re) and the eccentricity effect on flow behaviour. METHODS A transient particle image velocimetry (PIV) experiment was implemented in two silicone based models with 70% diameter stenosis, one with eccentric stenosis and one with concentric stenosis. RESULTS At different times throughout the flow cycle, the eccentric model was always associated with a greater recirculation zone length, maximum shear strain rate and maximum axial velocity; however, the highest and lowest impacts of eccentricity were on the recirculation zone length and maximum shear strain rate, respectively. Analysis of the results revealed a negative correlation between the Reynolds number (Re) and the eccentricity effect on maximum axial velocity, maximum shear strain rate and recirculation zone length. CONCLUSIONS As Re number increases the eccentricity effect on the flow behavior becomes negligible.

Haemodynamic assessment of human coronary arteries is affected by degree of freedom of artery movement

Abstract Abnormal haemodynamic parameters are associated with atheroma plaque progression and instability in coronary arteries. Flow recirculation, shear stress and pressure gradient are understood to be important pathogenic mediators in coronary disease. The effect of freedom of coronary artery movement on these parameters is still unknown. Fluid–structure interaction (FSI) simulations were carried out in 25 coronary artery models derived from authentic human coronaries in order to investigate the effect of degree of freedom of movement of the coronary arteries on flow recirculation, wall shear stress (WSS) and wall pressure gradient (WPG). Each FSI model had distinctive supports placed upon it. The quantitative and qualitative differences in flow recirculation, maximum wall shear stress (MWSS), areas of low wall shear stress (ALWSS) and maximum wall pressure gradient (MWPG) for each model were determined. The results showed that greater freedom of movement was associated with lower MWSS, smaller ALWSS, smaller flow recirculation zones and lower MWPG. With increasing percentage diameter stenosis (%DS), the effect of degree of freedom on flow recirculation and WSS diminished. Freedom of movement is an important variable to be considered for computational modelling of human coronary arteries, especially in the setting of mild to moderate stenosis. Abbreviations: 3D: Three-dimensional; 3DR: Three-dimensional Reconstruction; 3D-QCA: Three-dimensional quantitative coronary angiography; ALWSS: Areas of low wall shear stress; CAD: Coronary artery disease; CFD: Computational fluid dynamics; %DS: Diameter stenosis percentage; EPCS: End point of counter-rotating streamlines; FSI: Fluid–structure interaction; IVUS: Intravascular ultrasound; LAD: Left anterior descending; MWSS: Maximum wall shear stress; SST: Shear stress transport; TAWSS: Time-averaged wall shear stress; WSS: wall shear stress; WPG: Wall pressure gradient; MWPG: Maximum wall pressure gradient; FFR: Fractional flow reserve; iFR: Instantaneous wave-free ratio

Flow observations in elastic stenosis biomodel with comparison to rigid-like model

BACKGROUND Plaques in blood vessels exhibit a wide range of stiffness depending on disease conditions: stiffness is an important factor in plaque behavior. The geometrical change in plaque based on its behavior can affect blood flow patterns. Thus, it is important to study both blood flow and deformation of plaques and blood vessels. OBJECTIVE This study aims to identify the differences in flow conditions between in vitro models to discuss experimental materials for arterial wall and flow observation. METHODS In order to observe the blood flow pattern and plaque deformation simultaneously, a PVA-H stenosis model was used. In addition, a silicone model was also used as a rigid-like model for comparison with the PVA-H model. PIV was employed to measure the flow velocity distribution and determine the flow levels in the models. RESULTS PVA-H model exhibits expansion with an increase in upstream pressure and silicone model maintains the diameter. The expansion depends on their mechanical properties and influences flow conditions such as velocity changes and RAP in the parent artery. The balance between the expansion and change in flow conditions determines the final geometries of PVA-H model and flow pattern. CONCLUSIONS The results suggest that the stiffness measurement for blood vessels and plaques such as ultrasound measurements would be important for accurate treatments.

Intracoronary upregulation of platelet extracellular matrix metalloproteinase inducer (CD147) in coronary disease.

BACKGROUND CD147, also known as extracellular matrix metalloproteinase inducer, is present on circulating platelets and leukocytes in patients with coronary disease and is implicated in atherogenesis, and plaque rupture. We investigated whether CD147 (platelet, leukocyte and soluble) is upregulated within the coronary circulation in patients with stable coronary disease, and whether CD147 levels are associated with coronary shear stress levels. METHODS A total of 25 patients undergoing intervention of a single coronary lesion had blood sampled within the coronary (n=15) and peripheral circulation (n=10). Platelet and leukocyte CD147 expression was measured by flow cytometry. Soluble CD147 was measured by enzyme-linked immunosorbent assays. Shear stress was calculated using computational fluid dynamics analysis. The effect of shear on platelet CD147 expression in vitro was investigated using a cone-plate viscometer. RESULTS Platelet CD147 was higher in the coronary sinus (CS) compared to femoral vein (mean ± SD fluorescence intensity: 3.1 ± 0.7 vs. 2.2 ± 0.5, p=0.01). There was a significant linear trend for increased platelet CD147 expression from the proximal artery to the distal artery, and subsequently to the CS (p=0.01), indicating trans-lesion and transmyocardial upregulation. There were no differences between the various sites for monocyte, granulocyte or soluble CD147 levels (all p=ns). Trans-lesion gradients of CD147 did not correlate with shear stress (all p=ns). Blood subjected to shear in vitro had higher levels of platelet P-selectin (p=0.04) but similar levels of platelet CD147 (p=0.46) compared to rested blood. CONCLUSION Platelet CD147 expression is upregulated in the coronary circulation in patients with stable coronary disease, but its upregulation is independent of shear stress.

The relationship between coronary artery distensibility and fractional flow reserve

Discordance between angiography-based anatomical assessment of coronary stenosis severity and fractional flow reserve (FFR) has been attributed to several factors including lesion length and irregularity, and the myocardial territory supplied by the target vessel. We sought to examine if coronary arterial distensibility is an independent contributor to this discordance. There were two parts to this study. The first consisted of “in silico” models of 26 human coronary arteries. Computational fluid dynamics-derived FFR was calculated for fully rigid, partially distensible and fully distensible models of the 26 arteries. The second part of the study consisted of 104 patients who underwent coronary angiography and FFR measurement. Distensibility at the lesion site (DistensibilityMLA) and for the reference vessel (DistensibilityRef) was determined by analysing three-dimensional angiography images during end-systole and end-diastole. Computational fluid dynamics-derived FFR was 0.67±0.19, 0.70±0.18 and 0.75±0.17 (P<0.001) in the fully rigid, partially distensible and fully distensible models respectively. FFR correlated with both DistensibilityMLA (r = 0.36, P<0.001) and DistensibilityRef (r = 0.44, P<0.001). Two-way ANCOVA analysis revealed that DistensibilityMLA (F (1, 100) = 4.17, p = 0.031) and percentage diameter stenosis (F (1, 100) = 60.30, p < 0.01) were both independent predictors of FFR. Coronary arterial distensibility is a novel, independent determinant of FFR, and an important factor contributing to the discordance between anatomical and functional assessment of stenosis severity.

Spiral blood flow in aorta–renal bifurcation models

Abstract The presence of a spiral arterial blood flow pattern in humans has been widely accepted. It is believed that this spiral component of the blood flow alters arterial haemodynamics in both positive and negative ways. The purpose of this study was to determine the effect of spiral flow on haemodynamic changes in aorta–renal bifurcations. In this regard, a computational fluid dynamics analysis of pulsatile blood flow was performed in two idealised models of aorta–renal bifurcations with and without flow diverter. The results show that the spirality effect causes a substantial variation in blood velocity distribution, while causing only slight changes in fluid shear stress patterns. The dominant observed effect of spiral flow is on turbulent kinetic energy and flow recirculation zones. As spiral flow intensity increases, the rate of turbulent kinetic energy production decreases, reducing the region of potential damage to red blood cells and endothelial cells. Furthermore, the recirculation zones which form on the cranial sides of the aorta and renal artery shrink in size in the presence of spirality effect; this may lower the rate of atherosclerosis development and progression in the aorta–renal bifurcation. These results indicate that the spiral nature of blood flow has atheroprotective effects in renal arteries and should be taken into consideration in analyses of the aorta and renal arteries.

Particle image velocimetry study of aorta-renal bifurcation

BACKGROUND Haemodynamic parameters such as separated flow regions play a key role in the progression and development of atherosclerotic lesions in renal arteries, which typically originate at the renal ostium. OBJECTIVE The aim of this study was to analyse the flow dynamics in a two-dimensional model of aorta-renal bifurcation, with a particular focus on the effect of aorta-to-renal flow ratio on flow separation regions. METHOD A particle image velocimetry (PIV) experiment was conducted in an acrylic model of the aorta-renal ostium and the relationship between renal-to-aorta flow ratio and separated flow region was investigated. RESULTS For high flow ratios, a stagnation region was observed near the cranial side of the aorta. With a decrease in the flow ratio, however, this stagnation region disappeared. Furthermore, our results showed that an increase in the renal flow rate was associated with an increase in the length of the separated flow region, but a decrease in the width of the separation regions. CONCLUSIONS As the renal-to-aorta flow ratio increased a longer separation region was observed on the cranial side of the renal channel.

Flow visualisation study of spiral flow in the aorta–renal bifurcation

Abstract The aim of this study was to analyse the flow dynamics in an idealised model of the aorta–renal bifurcation using flow visualisation, with a particular focus on the effect of aorta-to-renal flow ratio and flow spirality. The recirculation length was longest when there was low flow in the renal artery and smaller in the presence of spiral flow. The results also indicate that patients without spiral flow or who have low flow in the renal artery due to the presence of stenosis may be susceptible to heightened development of atherosclerotic lesions.