Analysis of myocardial contractility with magnetic resonance

Heart failure has considerable morbidity and poor prognosis. An understanding of the underlying mechanics governing myocardial contraction is a prerequisite for interpreting and predicting changes induced by heart disease. Gross changes in contractile behaviour of the myocardium are readily detected with existing techniques. For more subtle changes during early stages of cardiac dysfunction, however, it requires a sensitive method for measuring, as well as a precise criterion for quantifying, normal and impaired myocardial function. Cardiovascular Magnetic Resonance (CMR) imaging is emerging as an important clinical tool because of its safety, versatility, and the high quality images it produces that allow accurate and reproducible quantification of cardiac structure and function. Traditional CMR approaches for measuring contractility rely on tagging of the myocardium with fiducial markers and require a lengthy and often subjective dependant post-processing procedure. The aim of this research is to develop a new technique, which uses velocity as a marker for the visualisation and assessment of myocardial contractility. Two parallel approaches have been investigated for the assessment of myocardial velocity. The first of these is haimonic phase (HARP) imaging. HARP imaging allows direct derivation of myocardial velocity and strain without the need of further user interaction. We investigated the effect of respiration on the accuracy of the derived contractility, and assessed the clinical applicability and potential pitfalls of the technique by analysing results from a group of patients with hypertrophic cardiomyopathy. The second technique we have investigated is the direct measurement of myocardial velocity with phase contrast myocardial velocity mapping. The imaging sequence used employs effective blood saturation for reducing flow induced phase errors within the myocardium. View sharing was used to improve the temporal resolution, which permitted acquisition of 3D velocity information throughout the cardiac cycle in a single breath-hold, enabling a comprehensive assessment of strain rate of the left ventricle. One key factor that affects the derivation of myocardial contractility based on myocardial velocity is the practical inconsistency of the velocity data. A novel iterative optimisation scheme by incorporating the incompressibility constraint was developed for the restoration of myocardial velocity data. The method allowed accurate assessment of both in-plane and through-plan strain rates, as demonstrated with both synthetic and in vivo data acquired from normal subjects and ischaemic patients. To further enhance the clinical potential of the technique and facilitate the visual assessment of contractile abnormality with myocardial velocity mapping, a complementary analysis framework, named Virtual Tagging, has been developed. The method used velocity data in all directions combined with a finite element mesh incorporating geometrical and physical constraints. The Virtual Tagging framewoik allowed velocity measurements to be used for calculating strain distribution within the 3D volume. It also permitted easy visualisation of the displacement of the tissue, akin to traditional CMR tagging. Detailed validation of the technique is provided, which involves both numerical simulation and in vitro phantom experiments. The main contribution of this thesis is in the improvement of the effectiveness and quality of quantitative myocardial contractility analysis from both sequence design and medical image computing perspectives. It is aimed at providing a sensitive means of detecting subtle as well as gross changes in contractile behaviour of the myocardium. The study is expected to provide a clinically viable platform for functional correlation with other functional measures such as myocardial perfusion and diffusion, and to serve as an aid for further understanding of the links between intrinsicOpen acces

Translating computational modelling tools for clinical practice in congenital heart disease

Increasingly large numbers of medical centres worldwide are equipped with the means to acquire 3D images of patients by utilising magnetic resonance (MR) or computed tomography (CT) scanners. The interpretation of patient 3D image data has significant implications on clinical decision-making and treatment planning. In their raw form, MR and CT images have become critical in routine practice. However, in congenital heart disease (CHD), lesions are often anatomically and physiologically complex. In many cases, 3D imaging alone can fail to provide conclusive information for the clinical team. In the past 20-30 years, several image-derived modelling applications have shown major advancements. Tools such as computational fluid dynamics (CFD) and virtual reality (VR) have successfully demonstrated valuable uses in the management of CHD. However, due to current software limitations, these applications have remained largely isolated to research settings, and have yet to become part of clinical practice. The overall aim of this project was to explore new routes for making conventional computational modelling software more accessible for CHD clinics. The first objective was to create an automatic and fast pipeline for performing vascular CFD simulations. By leveraging machine learning, a solution was built using synthetically generated aortic anatomies, and was seen to be able to predict 3D aortic pressure and velocity flow fields with comparable accuracy to conventional CFD. The second objective was to design a virtual reality (VR) application tailored for supporting the surgical planning and teaching of CHD. The solution was a Unity-based application which included numerous specialised tools, such as mesh-editing features and online networking for group learning. Overall, the outcomes of this ongoing project showed strong indications that the integration of VR and CFD into clinical settings is possible, and has potential for extending 3D imaging and supporting the diagnosis, management and teaching of CHD

Development and application of novel processing tools and methods for cardiac optical mapping

Cardiac optical mapping provides unparalleled spatio-temporal resolution information of cardiac electrophysiology. It has hence emerged as an important technology in understanding cardiac electrical behaviour in physiological and pathophysiological states. There is a requirement for effective data analysis tools that are high-throughput, robustly characterised and flexible with regards to a growing array of experimental models. In this thesis a MATLAB based software, ElectroMap, was developed for analysis of diverse optical mapping datasets. ElectroMap incorporates existing and novel methods to allow quantification and mapping of action potential and calcium transient morphology and activation/repolarisation times. Automated pacing cycle length detection and segmentation were implemented, realising high-throughput analysis of beat-to-beat responses and transient behaviour. Standalone modules dedicated to calculation of conduction velocity and alternans were introduced, allowing thorough integration of key factors in arrhythmogenesis. Semi-automated analysis of temporal variations in wave morphology were developed from previous methodologies for electrogram analysis. Algorithms to use fractional rate of change of fluorescence as a measure of conduction were also introduced to the software. Algorithms were tested in silico datasets, mouse and guinea pig optical mapping datasets and preliminary experiments also showed use for in vivo human electrogram mapping of atrial fibrillation

Regulation of cardiogenesis by putative WNT signalling pathways

PhD ThesisThe Wnt/ -catenin and the Wnt/planar cell polarity (Wnt/PCP) signalling pathways have been shown to play important roles in cardiogenesis and their disruption has been shown to cause severe disturbances in heart development. Spatially and temporally complex interplays between the two pathways have been described. One component of the PCP pathway is Jnk, a member of the highly conserved mitogenactivated protein kinase (MAPK) family. This stress responsive mitogen is known to control a variety of cellular behaviours such as proliferation, apoptosis and cell migratory behaviour and as such, is likely to be of pivotal importance in cardiac development. The aim of this study was to investigate the role played by Jnk in vertebrate heart formation and the relationships between Jnk signalling and canonical Wnt signalling, using in silico and in vivo approaches in zebrafish and an in vitro approach on a mouse embryonic stem (ES) cell model of cardiogenesis. Firstly, using a range of bioinformatic methods, an analysis of jnk genes, splice variants and proteins, and an investigation of their phylogenetic relation with other species was undertaken. This suggested conservation of Jnk family members, but suggested that there were additional orthologues of jnk1 present in the zebrafish transcriptome. The spatial and temporal expression profiles of these genes were then examined by semi-quantitative PCR and in situ hybridisation. The functional role of Jnk proteins during zebrafish development was subsequently investigated using a specific chemical inhibitor, SP600125. Inhibition of Jnk signalling during gastrulation and somitogenesis caused a convergence extension-like phenotype and severe cardiac defects, including looping anomalies and alterations in atrial versus ventricular cell numbers. ES cells have the capacity to differentiate in vitro and give rise to cells of many different lineages, including cardiomyocytes. Canonical Wnt and Jnk components were manipulated during specific windows of differentiation as ES cells formed beating embryoid bodies. Examination of the spontaneous contractile behaviour of differentiating ES cells as they entered the cardiogenic lineage, and analysis of their developmental gene expression profiles, showed the beating behaviour of ES cellderived cardiac cells was enhanced in a temporally specific manner after inhibition of the non-canonical Wnt/Jnk pathway, while there was marked alteration of canonical Wnt signalling. To investigate whether there were reciprocal interactions between the two pathways, analysis of the system after activation of the canonical pathway was also undertaken. These studies indicated that the beating behaviour of ES cell-derived cardiac cells was enhanced in a temporally specific manner after inhibition of Jnk, while after activation of canonical Wnt/ -catenin signalling, the cardiogenic potential of differentiating ES cells was severely suppressed. The findings of this study extend our understanding of the role played by canonical and non-canonical Wnt signalling pathways in heart morphogenesis and highlight the interacting effects of related signalling pathways activity in cardiogenesis

Video Kinematic Evaluation: new insights on the cardiac mechanical function

The cardiac mechanical function plays a critical role in governing and regulating its performance under both normal and pathological conditions. The left ventricle has historically received more attention in both congenital and acquired heart diseases and was considered as the mainstay of normal hemodynamics. However, over the past few decades, there has been increasing recognition of the pivotal role of the right ventricle in determining functional performance status and prognosis in multiple conditions. Nonetheless, the ventricles should not be considered separately as they share the septum, are encircled with common myocardial fibers and are surrounded by the pericardium. Thus, changes in the filling of one ventricle may alter the mechanical function of its counterpart. This ventricular interdependence remains even after the removal of the pericardium because of constrictive pericarditis or during open chest surgery. Interestingly, during open chest surgery, only the right ventricle mechanical activity is visually checked by the surgeon and cardiologist due to the absence of an intraoperative imaging technique able to evaluate its complex function. Noteworthy, most of the imaging techniques available to clinicians are established for the assessment of the left ventricle, with the ejection fraction being the most used parameter. However, this value is a measure of global systolic function which comes short in identifying regional myocardial impairment and the mechanical contraction. Therefore, new approaches are needed to deeply investigate the mechanics of both ventricles and correctly assess the cardiac mechanical performance. In this thesis, I studied the mechanical function of the left ventricle through different modalities of cardiac magnetic resonance and employed an innovative imaging technique for the assessment of the right ventricle mechanical function during open chest surgery

Pacing with restoration of respiratory sinus arrhythmia improved cardiac contractility and the left ventricular output: a translational study

Introduction: Respiratory sinus arrhythmia (RSA) is a prognostic value for patients with heart failure and is defined as a beat-to-beat variation of the timing between the heart beats. Patients with heart failure or patients with permanent cardiac pacing might benefit from restoration of RSA. The aim of this translational, proof-of-principle study was to evaluate the effect of pacing with or without restored RSAon parameters of LV cardiac contractility and the cardiac output

Characterisation and correction of respiratory-motion artefacts in cardiac PET-CT

Respiratory motion during cardiac Positron Emission Tomography (PET) Computed Tomography (CT) imaging results in blurring of the PET data and can induce mismatches between the PET and CT datasets, leading to attenuation-correction artefacts. The aim of this project was to develop a method of motion-correction to overcome both of these problems. The approach implemented was to transform a single CT to match the frames of a gated PET study, to facilitate respiratory-matched attenuation-correction, without the need for a gated CT. This is benecial for lowering the radiation dose to the patient and in reducing PETCT mismatches, which can arise even in gated studies. The heart and diaphragm were identied through phantom studies as the structures responsible for generating attenuation-correction artefacts in the heart and their motions therefore needed to be considered in transforming the CT. Estimating heart motion was straight-forward, due to its high contrast in PET, however the poor diaphragm contrast meant that additional information was required to track its position. Therefore a diaphragm shape model was constructed using segmented diaphragm surfaces, enabling complete diaphragm surfaces to be produced from incomplete and noisy initial estimates. These complete surfaces, in combination with the estimated heart motions were used to transform the CT. The PET frames were then attenuation-corrected with the transformed CT, reconstructed, aligned and summed, to produce motion-free images. It was found that motion-blurring was reduced through alignment, although benets were marginal in the presence of small respiratory motions. Quantitative accuracy was improved from use of the transformed CT for attenuation-correction (compared with no CT transformation), which was attributed to both the heart and the diaphragm transformations. In comparison to a gated CT, a substantial dose saving and a reduced dependence on gating techniques were achieved, indicating the potential value of the technique in routine clinical procedures

Doctor of Philosophy

dissertationAtrial fibrillation (AF) is the leading cause of ischemic stroke and is the most commonly observed arrhythmia in clinical cardiology. Catheter ablation of AF, in which specific regions of cardiac anatomy associated with AF are intenionally injured to create scar tissue, has been honed over the last 15 years to become a relatively common and safe treatment option. However, the success of these anatomically driven ablation strategies, particularly in hearts that have been exposed to AF for extended periods, remains poor. AF induces changes in the electrical and structural properties of the cardiac tissue that further promotes the permanence of AF. In a process known as electroanatomical (EAM) mapping, clinicians record time signals known as electrograms (EGMs) from the heart and the locations of the recording sites to create geometric representations, or maps, of the electrophysiological properties of the heart. Analysis of the maps and the individual EGM morphologies can indicate regions of abnormal tissue, or substrates that facilitate arrhythmogenesis and AF perpetuation. Despite this progress, limitations in the control of devices currently used for EAM acquisition and reliance on suboptimal metrics of tissue viability appear to be hindering the potential of treatment guided by substrate mapping. In this research, we used computational models of cardiac excitation to evaluate param- eters of EAM that affect the performance of substrate mapping. These models, which have been validated with experimental and clinical studies, have yielded new insights into the limitations of current mapping systems, but more importantly, they guided us to develop new systems and metrics for robust substrate mapping. We report here on the progress in these simulation studies and on novel measurement approaches that have the potential to improve the robustness and precision of EAM in patients with arrhythmias. Appropriate detection of proarrhythmic substrates promises to improve ablation of AF beyond rudimentary destruction of anatomical targets to directed targeting of complicit tissues. Targeted treatment of AF sustaining tissues, based on the substrate mapping approaches described in this dissertation, has the potential to improve upon the efficacy of current AF treatment options