Non-invasive wave intensity analysis in common carotid artery of healthy humans

This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University LondonThe study of arterial wave propagation is essential to understand the physiopathology of the cardiovascular system, as waves carry clinically relevant information. Impedance analysis was used for such type of studies, where results were presented in the frequency domain, but it was difficult to relate specific events to time points within the cardiac cycle. Therefore, a mathematical tool called wave intensity analysis was developed, initially using measurements of pressure and velocity (PU approach). However, the need to acquire such measurements in a non-invasive, direct and simultaneous fashion led to the development of the DU approach, a type of wave intensity analysis carried out using vessel diameter and flow velocity waveforms, thus giving up the pressure measurement. It is the only available technique, at present, able to extract wave intensity information without relying on distally recorded pressure measurements and on non-simultaneous recordings. Due to its non-invasive nature for collecting the required measurements, this technique has a potential use in clinical and research settings to investigate physiological changes under rapid perturbations, such as the ones introduced by exercise. In this thesis, the DU approach is performed by only using an ultrasound device and to extract information about cardio-arterial interaction in the human common carotid artery. In the first experimental chapter of this thesis, a reproducibility study of common carotid DU-derived wave intensity parameters was conducted on a healthy young cohort, both at rest and during exercise (semi-recumbent cycling). Carotid diameter and blood flow velocity features, as well as wave intensity parameters such as forward compression, backward compression and forward expansion wave peaks and energies, were overall fairly reproducible. In particular, diameter variables exhibited higher reproducibility and lower dispersion than corresponding velocity variables, whereas wave intensity energy variables exhibited higher reproducibility and lower dispersion than corresponding peaks. Local wave speed, calculated via lnDU-loop, a technique based only on local measurements of diameter and velocity and often associated with the DU approach, was also reproducible. It is possible to conclude that the DU-derived wave intensity analysis is reliable both at rest and during exercise. In a subsequent study, DU-derived wave intensity analysis was performed on a young trained cohort to investigate the contribution of cardiac and peripheral vascular alterations to common carotid wave intensity parameters, under rapid physiological perturbations, such as semi-recumbent cycling at incremental workrates, and subsequent recovery. Judging by the increase in local wave speed, the common carotid artery stiffened substantially as workrate increased whilst peak and energy of the forward and backward compression waves also increased, due to enhanced ventricular contractility, which was associated with larger reflections from the cerebral microcirculation and other vascular beds in the head. However, the reflection indices remained unchanged during exercise, highlighting that the increased magnitude of reflections is mainly due to the enhanced contractility, rather than changes in vascular resistance, at least at the carotid artery in young healthy individuals. The forward expansion wave increased during exercise, as the left ventricle actively decelerated blood flow in late systole, potentially improving filling time during diastole. In the early recovery, the magnitude of all waves returned to baseline value. Finally, the X wave, attributed to the reflection of the backward compression wave, had a tendency to increase during exercise and to return to baseline value in early recovery. A further development of wave intensity analysis came with the reservoir-wave approach, able to separate, from the pressure and velocity waveforms, the component solely due to the reservoir volume, for the correct evaluation of backward- and forward-travelling waves. A number of issues, however, still remains, involving specifically the lack of consensus over the fitting technique and over the value of the asymptotic pressure value (P ∞),used for the determination of the reservoir waveform. Therefore, to give a contribution to the debate involving the more correct model for the pressure and velocity reservoir-wave approach, a study aimed to investigate various common carotid hemodynamic and wave intensity parameters, using different fitting techniques and values of P ∞ currently available in literature, was performed and described in the last chapter of this thesis. The study demonstrated that different fitting method and values of P ∞ could bring significant variations in values and trends of hemodynamic and wave intensity parameters. However, despite the changes in the shape of the reservoir pressure waveform, its peak and integral with respect to time tended to remain constant. This is an important feature, because both reservoir peak pressure and its integral have been used in clinical settings for the calculation of diagnostic indicators. The reservoir and excess velocity peaks, instead, changed more significantly. This outcome, together with the concomitant substantial change in excess pressure peak and integral, may greatly affect wave intensity parameters. Wave intensity parameters were, in fact, significantly more sensitive to fitting techniques and values of P ∞ than pressure parameters. Finally, the wave speed did not substantially change, leading to the conclusion that the calculation of local vessel distensibility and/or compliance, when calculated from the excess components of the waveforms, seemed insensitive to fitting techniques and values of P

Role of temperature on nonlinear cardiac dynamics.

Thermal effects affecting spatiotemporal behavior of cardiac tissue are discussed by relating temperature variations to proarrhythmic dynamics in the heart. By introducing a thermoelectric coupling in a minimal model of cardiac tissue, we are able to reproduce experimentally measured dynamics obtained simultaneously from epicardial and endocardial canine right ventricles at different temperatures. A quantitative description of emergent proarrhythmic properties of restitution, conduction velocity, and alternans regimes as a function of temperature is presented. Complex discordant alternans patterns that enhance tissue dispersion consisting of one wave front and three wave backs are described in both simulations and experiments. Possible implications for model generalization are finally discussed

The AXIOM software layers

AXIOM project aims at developing a heterogeneous computing board (SMP-FPGA).The Software Layers developed at the AXIOM project are explained.OmpSs provides an easy way to execute heterogeneous codes in multiple cores. People and objects will soon share the same digital network for information exchange in a world named as the age of the cyber-physical systems. The general expectation is that people and systems will interact in real-time. This poses pressure onto systems design to support increasing demands on computational power, while keeping a low power envelop. Additionally, modular scaling and easy programmability are also important to ensure these systems to become widespread. The whole set of expectations impose scientific and technological challenges that need to be properly addressed.The AXIOM project (Agile, eXtensible, fast I/O Module) will research new hardware/software architectures for cyber-physical systems to meet such expectations. The technical approach aims at solving fundamental problems to enable easy programmability of heterogeneous multi-core multi-board systems. AXIOM proposes the use of the task-based OmpSs programming model, leveraging low-level communication interfaces provided by the hardware. Modular scalability will be possible thanks to a fast interconnect embedded into each module. To this aim, an innovative ARM and FPGA-based board will be designed, with enhanced capabilities for interfacing with the physical world. Its effectiveness will be demonstrated with key scenarios such as Smart Video-Surveillance and Smart Living/Home (domotics).Peer ReviewedPostprint (author's final draft

Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment

Tumour-associated microglia/macrophages (TAM) are the most numerous non-neoplastic populations in the tumour microenvironment in glioblastoma multiforme (GBM), the most common malignant brain tumour in adulthood. The mTOR pathway, an important regulator of cell survival/proliferation, is upregulated in GBM, but little is known about the potential role of this pathway in TAM. Here, we show that GBM-initiating cells induce mTOR signalling in the microglia but not bone marrow-derived macrophages in both in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-κB activity promotes an immunosuppressive microglial phenotype. This hinders effector T-cell infiltration, proliferation and immune reactivity, thereby contributing to tumour immune evasion and promoting tumour growth in mouse models. The translational value of our results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model, whereby expanded-potential stem cells (EPSC)-derived microglia-like cells are conditioned by syngeneic patient-derived GBM-initiating cells. These results raise the possibility that microglia could be the primary target of mTOR inhibition, rather than the intrinsic tumour cells in GBM

The AXIOM platform for next-generation cyber physical systems

Cyber-Physical Systems (CPSs) are widely used in many applications that require interactions between humans and their physical environment. These systems usually integrate a set of hardware-software components for optimal application execution in terms of performance and energy consumption. The AXIOM project (Agile, eXtensible, fast I/O Module), presented in this paper, proposes a hardware-software platform for CPS coupled with an easy parallel programming model and sufficient connectivity so that the performance can scale-up by adding multiple boards. AXIOM supports a task-based programming model based on OmpSs and leverages a high-speed, inexpensive communication interface called AXIOM-Link. The board also tightly couples the CPU with reconfigurable resources to accelerate portions of the applications. As case studies, AXIOM uses smart video surveillance, and smart home living applicationsThis work is partially supported by the European Union H2020 program through the AXIOM project (grant ICT-01-2014 GA 645496) and HiPEAC (GA 687698), by the Spanish Government through Programa Severo Ochoa (SEV-2015-0493), by the Spanish Ministry of Science and Technology through TIN2015-65316-P project, and by the Generalitat de Catalunya (contracts 2014-SGR-1051 and 2014-SGR-1272). We also thank the Xilinx University Program for its hardware and software donations.Peer ReviewedPostprint (author's final draft

Impact of varying diastolic pressure fitting technique for the reservoir-wave model on wave intensity analysis

The reservoir-wave model assumes that the measured arterial pressure is made of two components: reservoir and excess. The effect of the reservoir volume should be excluded to quantify the effects of forward and backward traveling waves on blood pressure. Whilst the validity of the reservoir-wave concept is still debated, there is no consensus on the best fitting method for the calculation of the reservoir pressure waveform. Therefore, the aim of this parametric study is to examine the effects of varying the fitting technique on the calculation of reservoir and excess components of pressure and velocity waveforms. Common carotid pressure and flow velocity were measured using applanation tonometry and doppler ultrasound, respectively, in 1037 healthy humans collected randomly from the Asklepios population, aged 35 to 55 years old. Different fitting techniques to the diastolic decay of the measured arterial pressure were used to determine the asymptotic pressure decay, which in turn was used to determine the reservoir pressure waveform. The corresponding wave speed was determined using the PU-loop method, and wave intensity parameters were calculated and compared. Different fitting methods resulted in significant changes in the shape of the reservoir pressure waveform; however, its peak and time integral remained constant in this study. Although peak and integral of excess pressure, velocity components and wave intensity changed significantly with changing the diastolic decay fitting method, wave speed was not substantially modified. We conclude that wave speed, peak reservoir pressure and its time integral are independent of the diastolic pressure decay fitting techniques examined in this study. Therefore, these parameters are considered more reliable diagnostic indicators than excess pressure and velocity which are more sensitive to fitting techniques

Changes in Non-Invasive Wave Intensity Parameters with Variations of Savitzky-Golay Filter Settings

Ultrasound-measured waveforms, such as vessel diameter and blood flow velocity, are used to perform analysis of waves in the cardiovascular system. Wave intensity analysis is one of the tools used for this purpose. The waveforms are commonly filtered to eliminate high-frequency noise, however the filter settings affect the features of these signals and especially of their time derivatives, upon which wave intensity analysis is based. This study aims to investigate the alterations of wave intensity parameters with varying Savitzky-Golay filter settings, one of the most common smoothing algorithms used in this context. A broad spectrum of variations was observed in all the wave intensity variables. It is therefore important to always specify the filter settings applied to the signals in a wave intensity study, so that appropriate comparisons can be mad

COMMON CAROTID ARTERY DIAMETER, BLOOD FLOW VELOCITY AND WAVE INTENSITY RESPONSES AT REST AND DURING EXERCISE IN YOUNG HEALTHY HUMANS: A REPRODUCIBILITY STUDY

© 2017 The Authors. The aim of this study was to assess the reproducibility of non-invasive, ultrasound-derived wave intensity (WI) in humans at the common carotid artery (CCA). CCA diameter and blood velocity of twelve healthy young participants were recorded at rest and during mild cycling, to assess peak diameter, change in diameter, peak velocity, change in velocity, time derivatives, non-invasive wave speed and WI. Diameter, velocity and WI parameters were fairly reproducible. Diameter variables exhibited higher reproducibility than corresponding velocity variables (ICC = 0.79 vs. 0.73) and lower dispersion (CV = 5% vs. 9%). Wave speed presented fair reproducibility (ICC = 0.6, CV = 16%). WI energy variables exhibited higher reproducibility than corresponding peaks (ICC = 0.78 vs. 0.74) and lower dispersion (CV = 16% vs. 18%). The majority of variables had higher ICC and lower CV during exercise. We conclude that non-invasive WI analysis is reliable both at rest and during exercise