Antiplatelet therapy and clinical outcomes in cardiovascular diseases

Cardiovascular diseases (CVD) is a leading cause of death in the world. Despite effective treatment regimens for ischaemic heart disease (IHD) and ischaemic stroke, mortality and recurrence rates remain high. Antiplatelet therapy is on effective treatment and reduces the risk of recurrent heart attack and stroke. Nevertheless, there are patients who stopped or interrupted their antiplatelet therapy for certain reasons or some patients may be resistant or poor responders to antiplatelet therapy. Furthermore, there is evidence of rebound effect in platelet activity after antiplatelet cessation and this may associate with increased risk of cardiovascular event. This thesis is divided into five main chapters (chapters 3 to 7) which attempt to provide data to help resolve the uncertainty. Chapter 1 highlights the background of cardiovascular diseases and the global burden of cardiovascular and cerebrovascular diseases. The metabolism of platelets, antiplatelet therapy and current antiplatelet therapy guidelines are described, followed by discussion of the risk of cardiovascular event and changes in antiplatelet therapy. Chapter 2 describes the data source from Virtual International Stroke Trial Archive (VISTA) and National Health Service Greater Glasgow and Clyde (NHSGGC) Safe Haven, followed by definition of outcome measures. In chapter 3, Virtual International Stroke Trial Archive (VISTA) data was examined to test whether continue with the same antiplatelet therapy or changing to a new antiplatelet regimen reduces the risk of subsequent events in patients who experience a stroke whilst taking antiplatelet therapy. The findings indicate that subjects who switch to a new antiplatelet regimen after stroke did not have a lower early recurrence rate than subjects who continued with the same antiplatelet therapy. Observations on bleeding complications were similar in both groups. However, changing antiplatelet regimen after stroke was associated with more favourable functional outcome across a full scale modified Rankin Scale (mRS) at 90 days. In chapter 4, association between early or later initiation of antiplatelet with a recurrent ischaemic stroke and bleeding complications was assessed using VISTA data. The findings indicate that there was no association between a recurrent ischaemic stroke and timing of initiation of antiplatelet drug after stroke. However, early initiation was associated with increased risk of bleeding. In terms of functional outcomes, this study demonstrated that the mid-time and late initiation of antiplatelet therapy after acute stroke are associated with better functional outcomes compared with early initiation. In chapter 5, a nested case-control study was performed to explore the rate of antiplatelet cessation and interruption in a sample of patients with recent ischaemic stroke and to assess the risk of cardiovascular events associated with cessation and interruption of antiplatelet. It was found that there was no increased risk of cardiovascular event among patients who had early cessation or interrupted/stopped antiplatelet therapy within 90 days following acute ischaemic stroke. In chapter 6, the incidence and predictors of cardiovascular events after DAPT cessation were evaluated. The incidence of cardiovascular event while taking DAPT and following discontinuation of DAPT was 15.7% and 16.7% respectively. This study found that increasing age was associated with an increased risk of cardiovascular event, whereas, revascularization-treated patients and longer duration of DAPT, were each associated with a decreased risk. The duration of DAPT six months and less was associated a significantly higher risk for cardiovascular event. In chapter 7, an untargeted metabolomics analysis was performed while on DAPT (aspirin plus ticagrelor) and once they stopped ticagrelor to identify metabolite changes associated with cardiovascular events after stopping DAPT. Ten ACS patients were recruited in this study and data were analysed for seven patients. Three hundred eleven putative metabolites were identified. This study found 16 putative metabolites significantly altered following ticagrelor cessation. Of these, seven metabolites were from lipid pathway and down-regulated some up to 3-fold. On the other hand, adenosine, from nucleotide metabolism was upregulated up to 2.6-fold. It concluded that there are changes in numerous pathways following DAPT discontinuation and whether these changes differ in patients who have cardiovascular event after stopping DAPT warrant further investigation. In chapter 8, a summary of the findings of this thesis are presented as well as the future directions of research in this area.

Quantification of variable palmar ligaments around the triquetrum-hamate joint determined by lunate type

The ligaments of the wrist are highly variable and poorly described, which is more obvious on the ulnar side of the wrist. Previous studies highlighted the potential differences within the ligaments of the wrist but no consensus has been reached. Poor tissue description and inconsistent use of terminology hindered the reproducibility of the results. Improved understanding of the morphological variations between carpal bones may facilitate improved understanding of the ligamentous structure within the wrist. This study aims to identify the potential variations between carpal bones that could be used to separate palmar ligamentous patterns around the triquetrum-hamate joint into subgroups within the sample population. Investigations were performed following a detailed nomenclature and a clear definition of ligamentous structures to facilitate detailed description and reproducible results. Quantitative analyses were conducted using 3D modelling technique. Histological sections were then analysed to identify the structure of each ligamentous attachment. Variable patterns of ligamentous attachments were identified. Differences were not only obvious between samples but also between the right and left hands of the same person. These identifications suggested that the palmar ligamentous patterns around the triquetrum-hamate joint are best described as a spectrum with a higher affinity of the triquetrum-hamate-capitate ligament and the lunate-triquetrum ligament to be associated with type I lunate wrists on one extreme and type II lunate wrists with the palmar triquetrum-hamate ligament, triquetrum-hamate-capitate ligament and palmar radius-lunate-triquetrum ligament attachments at the other extreme. Histological analyses confirmed pervious established work regarding the mechanical role of ligaments in wrist joint biomechanics. Also, there were no significant differences between the quantitative data obtained from the Genelyn-embalmed and unembalmed specimens (p>0.05). The current study demonstrated variable ligamentous patterns that suggest different bone restraints and two different patterns of motion. These findings support previous suggestions regarding separating the midcarpal joint into two distinct functional types. Type I wrists were identified with ligamentous attachments that are suggestive of rotating/translating hamate whilst type II wrists identified with ligamentous attachments that are suggestive of flexing/extending hamate motion based upon the patterns of the ligamentous attachments in relation to the morphological features of the underlying lunate type of the wrist. This opens the horizon for particular consideration and/or modification of surgical procedures, which may enhance the clinical management of wrist dysfunction.

A comparison of the physiological demands of rugby union match-play when determined by absolute (ABS) or individual (IND) velocity bands in Global Positioning System (GPS) analysis

Since turning professional in 1995 there have been considerable advances in the research on the demands of rugby union, largely using Global Positioning System (GPS) analysis over the last 10 years. A systematic review on the use of GPS, particularly the setting of absolute (ABS) and individual (IND) velocity bands in field based, intermittent, high-intensity (HI) team sports was undertaken. From 3669 records identified, 38 studies were included for qualitative analysis. Little agreement on the definition of movement intensities within team sports was found, only three papers, all on rugby union, had used IND bands, with only one comparing ABS and IND methods. Thus, the aim of this study was to determine if there is a difference in the demands within positions when comparing ABS and IND methods for GPS analysis and if these differences are significantly different between the forward and back positional groups. A total of 214 data files were recorded from 26 players in 17 matches of the 2015/2016 Scottish BT Premiership. ABS velocity zones 1-7 were set at 1) 0-6, 2) 6.1-11, 3) 11.1-15, 4) 15.1-18, 5) 18.1-21, 6) 21.1-15 and 7) 25.1-40km.h-1 while IND zones 1-7 were 1) <20, 2) 20-40, 3) 40-50, 4) 50-70, 5) 70-80, 6) 80-95 and 7) 95-100% of player’s individually determined maximum velocity (Vmax). A 40m sprint test measured Vmax using OptaPro S4 10 Hz (catapult, Australia) GPS units to derive IND bands. The same GPS units were worn during matches. GPS outputs analysed were % distance, % time, high intensity efforts (HIEs) over 18.1 km.h-1 / 70% max velocity and repeated high intensity efforts (RHIEs) which consists of three HIEs in 21secs. General linear model (GLM) analysis identified a significant difference in the measurement of % total distance covered, between the ABS and IND methods in all zones for forwards (p<0.05) and backs (p<0.05). This difference was also significant between forwards and backs in zones 1, shown as mean difference ± standard deviation (3.7±0.7%), 6 (1.2±0.4%) and 7 (1.0±0.0%) respectively (p<0.05). Percentage time estimations were significantly different between ABS and IND analysis within forwards in zones 1 (1.7±1.7%), 2 (-2.9±1.3%), 3 (1.9±0.8%), 4 (-1.4±0.8%) and 5 (0.2±0.4%), and within backs in zones 1 (-10±1.5%), 2 (-1.2±1.1%), 3 (1.8±0.9%) and 5 (0.6±0.5%) (p<0.05). The difference between groups was significant in zones 1, 2, 4 and 5 (p<0.05). The number of HIEs was significantly different between forwards and backs in zones 6 (6±2) and 7 (3±2). RHIEs were significantly different between ABS and IND for forwards (1±2, p<0.05) although not between groups. Until more research on the differences in ABS and IND methods is carried out, then neither can be deemed a criterion method. In conclusion, there are significant differences between the ABS and IND methods of GPS analysis of the physical demands of rugby union, which must be considered when used to inform training load and recovery to improve performance and reduce injuries.

Eulerian-Lagrangian definition of coarse bed-load transport: Theory and verification with low-cost inertial measurement units

Fluvial sediment transport is controlled by hydraulics, sediment properties and arrangement, and flow history across a range of time scales. This physical complexity has led to ambiguous definition of the reference frame (Lagrangian or Eulerian) in which sediment transport is analysed. A general Eulerian-Lagrangian approach accounts for inertial characteristics of particles in a Lagrangian (particle fixed) frame, and for the hydrodynamics in an independent Eulerian frame. The necessary Eulerian-Lagrangian transformations are simplified under the assumption of an ideal Inertial Measurement Unit (IMU), rigidly attached at the centre of the mass of a sediment particle. Real, commercially available IMU sensors can provide high frequency data on accelerations and angular velocities (hence forces and energy) experienced by grains during entrainment and motion, if adequately customized. IMUs are subjected to significant error accu- mulation but they can be used for statistical parametrisation of an Eulerian-Lagrangian model, for coarse sediment particles and over the temporal scale of individual entrainment events. In this thesis an Eulerian-Lagrangian model is introduced and evaluated experimentally. Absolute inertial accelerations were recorded at a 4 Hz frequency from a spherical instrumented particle (111 mm diameter and 2383 kg/m3 density) in a series of entrainment threshold experiments on a fixed idealised bed. The grain-top inertial acceleration entrainment threshold was approximated at 44 and 51 mg for slopes 0.026 and 0.037 respectively. The saddle inertial acceleration entrainment threshold was at 32 and 25 mg for slopes 0.044 and 0.057 respectively. For the evaluation of the complete Eulerian-Lagrangian model two prototype sensors are presented: an idealised (spherical) with a diameter of 90 mm and an ellipsoidal with axes 100, 70 and 30 mm. Both are instrumented with a complete IMU, capable of sampling 3D inertial accelerations and 3D angular velocities at 50 Hz. After signal analysis, the results can be used to parametrize sediment movement but they do not contain positional information. The two sensors (spherical and ellipsoidal) were tested in a series of entrainment experiments, similar to the evaluation of the 111 mm prototype, for a slope of 0.02. The spherical sensor entrained at discharges of 24.8 ± 1.8 l/s while the same threshold for the ellipsoidal sensor was 45.2 ± 2.2 l/s. Kinetic energy calculations were used to quantify the particle-bed energy exchange under fluvial (discharge at 30 l/s) and non-fluvial conditions. All the experiments suggest that the effect of the inertial characteristics of coarse sediments on their motion is comparable to the effect hydrodynamic forces. The coupling of IMU sensors with advanced telemetric systems can lead to the tracking of Lagrangian particle trajectories, at a frequency and accuracy that will permit the testing of diffusion/dispersion models across the range of particle diameters.