Atheroprone flow activates inflammation via endothelial ATP-dependent P2X7-p38 signalling

Objective: Atherosclerosis is a focal disease occurring at arterial sites of disturbed blood flow that generates low oscillating shear stress. Endothelial inflammatory signalling is enhanced at sites of disturbed flow via mechanisms that are incompletely understood. The influence of disturbed flow on endothelial ATP receptors and downstream signalling was assessed. Methods and Results: Cultured human endothelial cells were exposed to atheroprotective (high uniform) or atheroprone (low oscillatory) shear stress for 72 hours prior to assessment of ATP responses. Imaging of cells loaded with a calcium-sensitive fluorescent dye revealed that atheroprone flow enhanced extracellular calcium influx in response to 300µM BzATP. Pretreatment with pharmacological inhibitors demonstrated that this process required P2X7 receptors. The mechanism involved altered expression of P2X7, which was induced by atheroprone flow conditions in cultured cells. Similarly, en face staining of the murine aorta revealed enriched P2X7 expression at an atheroprone site. Functional studies in cultured endothelial cells showed that atheroprone flow induced p38 phosphorylation and upregulation of E-selectin and IL-8 secretion via a P2X7-dependent mechanism. Moreover, genetic deletion of P2X7 significantly reduced E-selectin at atheroprone regions of the murine aorta. Conclusions: These findings reveal that P2X7 is regulated by shear forces leading to its accumulation at atheroprone sites that are exposed to disturbed patterns of blood flow. P2X7 promotes endothelial inflammation at atheroprone sites by transducing ATP signals into p38 activation. Thus P2X7 integrates vascular mechanical responses with purinergic signalling to promote endothelial dysfunction and may provide an attractive potential therapeutic target to prevent or reduce atherosclerosis

Endothelial repair in stented arteries is accelerated by inhibition of Rho-associated protein kinase.

AIMS: Stent deployment causes endothelial cell (EC) denudation, which promotes in-stent restenosis and thrombosis. Thus endothelial regrowth in stented arteries is an important therapeutic goal. Stent struts modify local hemodynamics, however the effects of flow pertubation on EC injury and repair are incompletely understood. By studying the effects of stent struts on flow and EC migration we identified an intervention that promotes endothelial repair in stented arteries. METHODS AND RESULTS: In vitro and in vivo models were developed to monitor endothelialization under flow and the influence of stent struts. A 2D parallel-plate flow chamber with 100 μm ridges arranged perpendicular to the flow was used. Live cell imaging coupled to computational fluid dynamic simulations revealed that EC migrate in the direction of flow upstream from the ridges but subsequently accumulate downstream from ridges at sites of bidirectional flow. The mechanism of EC trapping by bidirectional flow involved reduced migratory polarity associated with altered actin dynamics. Inhibition of Rho-associated protein kinase (ROCK) enhanced endothelialization of ridged surfaces by promoting migratory polarity under bidirectional flow (p<0.01). To more closely mimic the in vivo situation we cultured EC on the inner surface of polydimethylsiloxane tubing containing Coroflex Blue stents (65 μm struts) and monitored migration. ROCK inhibition significantly enhanced EC accumulation downstream from struts under flow (p<0.05). We investigated the effects of ROCK inhibition on re-endothelialization in vivo using a porcine model of EC denudation and stent placement. En face staining and confocal microscopy revealed that inhibition of ROCK using fasudil (30 mg/day via osmotic minipump) significantly increased re-endothelialization of stented carotid arteries (p<0.05). CONCLUSIONS: Stent struts delay endothelial repair by generating localised bidirectional flow which traps migrating EC. ROCK inhibitors accelerate endothelial repair of stented arteries by enhancing EC polarity and migration through regions of bidirectional flow

Towards accurate and precise T1 and extracellular volume mapping in the myocardium: a guide to current pitfalls and their solutions

Mapping of the longitudinal relaxation time (T1) and extracellular volume (ECV) offers a means of identifying pathological changes in myocardial tissue, including diffuse changes that may be invisible to existing T1-weighted methods. This technique has recently shown strong clinical utility for pathologies such as Anderson- Fabry disease and amyloidosis and has generated clinical interest as a possible means of detecting small changes in diffuse fibrosis; however, scatter in T1 and ECV estimates offers challenges for detecting these changes, and bias limits comparisons between sites and vendors. There are several technical and physiological pitfalls that influence the accuracy (bias) and precision (repeatability) of T1 and ECV mapping methods. The goal of this review is to describe the most significant of these, and detail current solutions, in order to aid scientists and clinicians to maximise the utility of T1 mapping in their clinical or research setting. A detailed summary of technical and physiological factors, issues relating to contrast agents, and specific disease-related issues is provided, along with some considerations on the future directions of the field. Towards accurate and precise T1 and extracellular volume mapping in the myocardium: a guide to current pitfalls and their solutions. Available from: https://www.researchgate.net/publication/317548806_Towards_accurate_and_precise_T1_and_extracellular_volume_mapping_in_the_myocardium_a_guide_to_current_pitfalls_and_their_solutions [accessed Jun 13, 2017]

High performance MRI simulations of motion on multi-GPU systems

Background: MRI physics simulators have been developed in the past for optimizing imaging protocols and for training purposes. However, these simulators have only addressed motion within a limited scope. The purpose of this study was the incorporation of realistic motion, such as cardiac motion, respiratory motion and flow, within MRI simulations in a high performance multi-GPU environment. Methods: Three different motion models were introduced in the Magnetic Resonance Imaging SIMULator (MRISIMUL) of this study: cardiac motion, respiratory motion and flow. Simulation of a simple Gradient Echo pulse sequence and a CINE pulse sequence on the corresponding anatomical model was performed. Myocardial tagging was also investigated. In pulse sequence design, software crushers were introduced to accommodate the long execution times in order to avoid spurious echoes formation. The displacement of the anatomical model isochromats was calculated within the Graphics Processing Unit (GPU) kernel for every timestep of the pulse sequence. Experiments that would allow simulation of custom anatomical and motion models were also performed. Last, simulations of motion with MRISIMUL on single-node and multi-node multi-GPU systems were examined. Results: Gradient Echo and CINE images of the three motion models were produced and motion-related artifacts were demonstrated. The temporal evolution of the contractility of the heart was presented through the application of myocardial tagging. Better simulation performance and image quality were presented through the introduction of software crushers without the need to further increase the computational load and GPU resources. Last, MRISIMUL demonstrated an almost linear scalable performance with the increasing number of available GPU cards, in both single-node and multi-node multi-GPU computer systems. Conclusions: MRISIMUL is the first MR physics simulator to have implemented motion with a 3D large computational load on a single computer multi-GPU configuration. The incorporation of realistic motion models, such as cardiac motion, respiratory motion and flow may benefit the design and optimization of existing or new MR pulse sequences, protocols and algorithms, which examine motion related MR applications

Accelerated MR physics simulations on multi-GPU systems

A multi-GPU approach of MRISIMUL, a recently developed step-by-step comprehensive MR physics simulator of the Bloch equation, is presented in this study. The specific aim was to apply MRISIMUL on multi-GPU systems so as to achieve even shorter execution times. We hypothesized that such a simulation platform could achieve a scalable performance with the increasing number of available GPU cards on single node, multi-GPU computer systems. A parallelization strategy was employed using the MATLAB single-program-multiple- data (spmd) statement and an almost linear speedup was observed with the increasing number of available GPU cards on two separate systems: a single computer of 2 quad-core processors and two Tesla C2070 GPU cards and a single computer of 2 hexa-core processors and four Tesla C2075 GPU cards. © 2013 IEEE

MRISIMUL: A GPU-Based Parallel Approach to MRI Simulations

A new step-by-step comprehensive MR physics simulator (MRISIMUL) of the Bloch equations is presented. The aim was to develop a magnetic resonance imaging (MRI) simulator that makes no assumptions with respect to the underlying pulse sequence and also allows for complex large-scale analysis on a single computer without requiring simplifications of the MRI model. We hypothesized that such a simulation platform could be developed with parallel acceleration of the executable core within the graphic processing unit (GPU) environment. MRISIMUL integrates realistic aspects of the MRI experiment from signal generation to image formation and solves the entire complex problem for densely spaced isochromats and for a densely spaced time axis. The simulation platform was developed in MATLAB whereas the computationally demanding core services were developed in CUDA-C. The MRISIMUL simulator imaged three different computer models: a user-defined phantom, a human brain model and a human heart model. The high computational power of GPU-based simulations was compared against other computer configurations. A speedup of about 228 times was achieved when compared to serially executed C-code on the CPU whereas a speedup between 31 to 115 times was achieved when compared to the OpenMP parallel executed C-code on the CPU, depending on the number of threads used in multithreading (2-8 threads). The high performance of MRISIMUL allows its application in large-scale analysis and can bring the computational power of a supercomputer or a large computer cluster to a single GPU personal computer