This thesis focuses on the analysis of the cardiac electrical and kinematic function for heart failure patients. An expected outcome is a set of computational tools that may help a clinician in understanding, diagnosing and treating patients suffering from cardiac motion asynchrony, a specific aspect of heart failure. Understanding the inverse electro-kinematic coupling relationship is the main task of this study. With this knowledge, the widely available cardiac image sequences acquired non-invasively at clinics could be used to estimate the cardiac electrophysiology (EP) without having to perform the invasive cardiac EP mapping procedures. To this end, we use real clinical cardiac sequence and a cardiac electromechanical model to create controlled synthetic sequence so as to produce a training set in an attempt to learn the cardiac electro-kinematic relationship. Creating patient-specific database of synthetic sequences allows us to study this relationship using a machine learning approach. A first contribution of this work is a non-linear registration method applied and evaluated on cardiac sequences to estimate the cardiac motion. Second, a new approach in the generation of the synthetic but virtually realistic cardiac sequence which combines a biophysical model and clinical images is developed. Finally, we present the cardiac electrophysiological activation time estimation from medical images using a patient-specific database of synthetic image sequences.

A leading cause of morbidity and mortality in the developed world is cardiovascular disease (CVD). Like many other disease processes the etiology of CVD has origins in both genetic and environmental factors. These factors affect the development of the heart and vasculature and how they respond to physiological and pathological stress. Abnormal heart development can lead to cardiac pathologies that manifest in a shift from normal cardiac geometry and physiology to what is called pathological cardiac remodeling. Often though, pathological remodeling can result from cardiovascular stress even when heart development is normal. Growth factors are essential mediators of cardiac development and physiology and a good number of clinical and experimental studies have implicated growth factors and their signaling effectors as potential therapeutic targets for pathological cardiac remodeling. Of those is Fibroblast Growth Factor 2 (FGF2) which is a potent inducer of fibroblast and cardiomyocyte proliferation in vitro. FGF2 is made in high molecular weight and low molecular weight isoforms (Hi FGF2 and Lo FGF2, respectively). It has already been demonstrated that, in the context of the heart, FGF2 modulates cardiac hypertrophy, cardiac fibrosis and mediates protection against cardiac injury. However, the isoform specific role of FGF2 in cardiac development, physiology and pathological remodeling has not been disclosed, and in this dissertation I address the hypothesis that FGF2 has isoform-specific function in cardiac physiology and remodeling. To test this hypothesis I used mice that are either deficient in Hi FGF2 (Hi KO) or Lo FGF2 (Lo KO) and subjected them to echocardiographic analysis and isoproterenol (Iso) treatment and compared them to wildtype (WT) cohorts. At baseline echocardiographic measurements, female Lo KO hearts are smaller and present with increased peak E-wave velocity, a diminutive A wave, and shortened mitral-flow deceleration time consistent with a restricted filling pattern and myocardial stiffness. Conversely, male Lo KO hearts present with a lower E wave and a higher A-wave velocity and a prolonged isovolumic-relaxation time consistent with impaired left ventricular (LV) relaxation. Female Hi KO hearts display no significant deviation from WT, while male Hi KO hearts exhibit increased systolic function. Hence, a deficiency in Lo FGF2 results in a shift from normal diastolic parameters and geometric measurements which is gender specific. Conversely, a deficiency in Hi FGF2 produces a phenotype in male hearts only. Histological and gravimetric analysis of Lo KO and Hi KO hearts post-Iso treatment reveals that female Lo KO hearts remain smaller even though their cardiomyocytes are hypertrophied while female Hi KO hearts present with a blunted hypertrophic response indicating a hypoplastic myocardium. Male Lo KO hearts present with an exacerbated fibrotic response and increased alpha-smooth muscle actin protein expression while Hi KO hearts exhibit a resistance to the fibrotic response and an induction of atrial natriuretic factor protein expression. Thus, in female hearts Hi FGF2 mediate cardiac hypertrophy while in male hearts Lo FGF2 and Hi FGF2 display an antithetical role in cardiac fibrosis where Lo FGF2 is protective while Hi FGF2 is damaging. Hence, cardiac remodeling following catecholamine overactivation is modulated by FGF2 in isoform- and gender-specific manners. In conclusion, the results presented here provide novel evidence on the interaction of gender and endogenous FGF2 isoforms as modulators of cardiac development, physiology and remodeling. Lo FGF2 signaling is necessary in the male heart for normal myocardial relaxation and for amelioration of the fibrotic response induced by beta-adrenergic stress, while in female hearts Lo FGF2 is necessary for normal cardiac growth and normal myocardial compliance. Hi FGF2 is necessary only in female hearts for mediating the hypertrophic response. Hence, I demonstrate that Lo FGF2 and Hi FGF2 have non-redundant roles in cardiac physiology and remodeling which are gender-specific.

No description available.

Techniques described to date for the reproducible and noninvasive quantification of regional cardiac function have been largely relegated to research settings due to time-consuming and cumbersome image acquisition and analysis. In this thesis, feature tracking algorithms are developed for 2-D+Time cardiac magnetic resonance (CMR) and 3-D+Time cardiac computed tomography (CCT) image sequences that are easily acquired clinically, while emphasising reproducibility and automation in their design. First, a commercially-implemented CMR feature tracking algorithm for the analysis of steady state free precession (SSFP) cine series is evaluated in patients with hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC), which primarily affect the left ventricle (LV) and right ventricle (RV), respectively, and functional impairment compared with control populations is found in both cases. The limitations of this implementation are then used to guide development of an automated algorithm for the same purpose, making use of fully convolutional neural networks (CNN) for segmentation and spline registration across all frames simultaneously for tracking. This study is performed in the subjects with HCM, and functional impairment is again identified in disease subjects. Finally, as myocardial contraction is inherently a 3-D phenomenon, a technique is developed for quantification of regional function from 3-D+Time functional CCT studies using simultaneous registration of automatically generated Loop subdivision surface models for tracking. This study is performed in canine mongrels, and compared with the current state of the art technique for CCT functional analysis. This work demonstrates the feasibility of automated, reproducible cardiac functional analysis from CMR and CCT image sequences. While work remains to be done in extending the principles demonstrated and modular components described to fully automated whole-heart analysis, it is hoped that this thesis will accelerate the clinical adoption of regional functional analysis.

Background: Exercise-based cardiac rehabilitation (CR) is considered routine practice for patients following an acute cardiac event or surgical intervention. Although there is a seemingly strong evidence base supporting it for patients with chronic heart failure (CHF), provision in the UK remains poor for this patient group. In addition, data for CHF patients reported in key CR reviews and meta-analyses are not a true representation of the UKs CHF population. The transferability of current evidence into actual practice settings in the UK therefore remains incongruous. Rationale and aims: Study outcomes have typically included an increase in VO2 peak/ VO2 max, a decrease in natriuretic peptides, improved left ventricular function and improved health related quality of life (QoL). Access to facilities and equipment, such as cardiopulmonary exercise testing equipment is limited in the UK for the majority of CR services thus an alternative means of assessment and exercise prescription is required. The recommended alternative for testing CHF patients is the six-minute walk test (6MWT); this requires a given space and a full practice test, the latter which adds to valuable clinical and staff time available. Methods: The first set of studies of this thesis therefore investigated two adapted assessment procedures for use with CHF patients: i. the use of a shorter practice walk test of two minutes vs six minutes prior to a 6MWT and ii. the use of the space saving Chester step test with an adapted lower step height protocol to accommodate the anticipated lower fitness in CHF (4-inch vs 6-inch). Having determined a more practical and efficient means of assessing exercise capacity in CHF patients, this thesis then used the 6MWT to evaluate the efficacy of a typically recommended 12-week programme (for the UK) of exercise-based rehabilitation. It was the aim of this PhD to also combine the use of the Chester step test with cardiopulmonary measures as a corresponding physiological outcome in a sub-sample of participants; however due to resource problems, only validation of the low-step protocol was possible. In the main intervention study, the efficacy of a 12-week course of supervised moderate intensity exercise in CHF patients (ejection fraction <44%, NYHA class II to III) was then evaluated. For purposes of evaluating safety and recovery of any acute myocardial stress induced by exercise in CHF, a sub-group study was performed to evaluate the influence of an acute exercise session on two-day post-exercise levels of circulating NT-proBNP. Results: In this current suite of studies, participants were more representative of the UK CHF population than typically reported in the current evidence. Their profile involved a median age of 76 ± 16 years (mean: 67 years and range: 30 to 84 years). 98% of whom were prescribed beta-blockers, 66% were diagnosed with atrial fibrillation and 98% had two or more co-morbidities. Study 1 (Chapter 3a) verified the efficacy of a two-minute practice walk in comparison to the recommended six-minute practice walk prior to performing a baseline 6MWT in patients with CHF. Study 2 (Chapter 3b) demonstrated that a 4-inch Chester step test is a reliable assessment when space is an issue, but the criterion validity of the actual oxygen costs at each stage compared with those estimated in healthy populations were significantly lower than recommended estimations from healthy populations. Study 3 (Chapter 4) revealed individual variability in the acute response of NT-proBNP release to exercise that is worthy of further study. However the NT-proBNP data overall did not suggest a need for ‘rest days’ between exercise training sessions. The main intervention study (Study 4, Chapter 5) demonstrated a significant improvement in 6MWT performance responses, compared with control, where an increased walking distance of 25 m (p < .0001) was coupled with a reduction in heart-rate-walking speed index (T1 16.3 ± 7.3 vs T2 15.3 ± 8.7 beats per 10 walked; p < .0001). Perceptually, patients were walking faster for the same rating of perceived exertion (RPE 12 to 13). This improved aerobic functioning coincided with an improved NYHA class (T1 2.3 ± .5 vs T2 1.8 ± .6; p < .0001); however there was no change in resting NT-proBNP levels after 12 weeks. Patients in the “control group” who then went on to be offered the same 12-week intervention achieved similar outcomes, but delaying their commencement of an exercise programme by 12 weeks negatively impacted on participation uptake. Key findings and conclusions: These results have demonstrated that exercise training in CHF can lead to an improvement in both physical and perceived functioning (NYHA class). In light of some previous studies showing decreases in BNP following an exercise programme and others like this one showing no change, further questions are raised about the effect of different types and doses of activity being offered to CHF patients and the responsiveness to training of different types of patients (disease severity and demographics). The nature of the cross-over design of this study revealed that delayed commencement of exercise negatively affects participation uptake by patients, which supports current UK standards in aiming for early referral to CR.

Non-invasive remote detection of cardiac and blood displacements is an important topic in cardiac telemedicine. Here we propose kinocardiography (KCG), a non-invasive technique based onmeasurement of body vibrations produced by myocardial contraction and blood flow through thecardiac chambers and major vessels. KCG is based on ballistocardiography and seismocardiographyand measures 12 degrees-of-freedom (DOF) of body motion. The integral of kinetic energy (iK)and maximum Power (Pmax) obtained from the linear and rotational SCG/BCG signals, was computedover the cardiac cycle, and used as a marker of cardiac mechanical function. We showedthat KCG metrics show high repeatability, can be computed on 50 Hz and 1 kHz SCG/BCG signalsindifferently, that most of the metrics were highly similar when computed on different sensors,and with less than 5% of error when computed on record length longer than 60 s. Finally, weshow that KCG metrics allow detecting dobutamine-induced haemodynamic changes with a highaccuracy and present a major improvement over single axis ballistocardiography or seismocardiography.These results suggest that KCG may be a robust and non-invasive method to monitorcardiac inotropic activity. / La détection à distance et non invasive des déplacements cardiaques et sanguins est un sujet important en télémédecine. Nous proposons ici la kinocardiographie (KCG), une technique non invasive basée sur mesure des vibrations corporelles produites par la contraction du myocarde et par le flux sanguin au travers des cavités cardiaques et des principaux vaisseaux sanguins. La KCG est basée sur la balistocardiographie et la seismocardiographie et mesure 12 degrés de liberté (DOF) de mouvement corporel. L'intégrale de l'énergie cinétique (iK) et la puissance maximale (Pmax) obtenue à partir des signaux SCG / BCG linéaire et rotationnel, a été calculée au cours du cycle cardiaque, et sont utilisées comme marqueur de la fonction mécanique cardiaque. Ce travail montre que les métriques KCG sont caractérisées par une répétabilité élevée, peuvent être calculées sur des signaux SCG / BCG à 50 Hz et à 1 kHz indifféremment, que la plupart des métriques étaient très similaires lorsqu'elles étaient calculées sur différents capteurs, et avec moins de 5% d'erreur lors du calcul sur une longueur d'enregistrement supérieure à 60 s. Enfin ce travail montre que les métriques KCG permettent de détecter les changements hémodynamiques induits par la dobutamine avec précision et présentent une amélioration majeure par rapport à la balistocardiographie à un seul axe ou à la seismocardiographie. Ces résultats suggèrent que la KCG peut être une méthode robuste et non invasive pour surveiller l'activité inotrope du coeur. / Doctorat en Sciences de l'ingénieur et technologie / La défense publique a eu lieu le 05/05/2021. Cet upload remplace l'upload pécédent et contient les derniers commentaires du jury après la défense publique. / info:eu-repo/semantics/nonPublished

Cardiac output, the volume of blood pumped by the heart over time, is a powerful clinical metric used by physicians to assess overall cardiac health and patient well-being. However, current cardiac output estimation methods are typically invasive, time-consuming, expensive, or some combination of all three. Patients that receive artificial cardiac pacemaker devices are particularly susceptible to cardiac dysfunction and often require long-term cardiac monitoring support. This thesis proposes a novel cardiac output monitoring solution which leverages an implantable intracardiac medical device. The principles of traditional impedance cardiography, an established cardiac output monitoring technique in practice for over fifty years, have been adapted to incorporate a leadless artificial cardiac pacemaker, an implantable medical device contained entirely within the heart. This novel method, colloquially referred to as Z-Cardio, monitors time-varying intracardiac impedance modulation to assess changes in cardiac output. In this study, technologies both old and new are synthesized to produce a novel and effective method of monitoring a critical metric of cardiac health.

No description available.

Out-of-hospital cardiac arrest (OHCA) is a significant public health problem in most westernized industrialized nations. In spite of national and international guidelines for cardiopulmonary resuscitation and emergency cardiac care, the overall survival of patients with OHCA was essentially unchanged for 30 years--from 1978 to 2008 at 7.6%. Perhaps a better indicator of Emergency Medical System (EMS) effectiveness in treating patients with OHCA is to focus on the subgroup that has a reasonable chance of survival, e.g., patients found to be in ventricular fibrillation (VF). But even in this subgroup, the average survival rate was 17.7% in the United States, unchanged between 1980 and 2003, and 21% in Europe, unchanged between 1980 and 2004. Prior to 2003, the survival of patients with OHCA, in VF in Tucson, Arizona was less than 9% in spite of incorporating previous guideline recommendations. An alternative (non-guidelines) approach to the therapy of patients with OHCA and a shockable rhythm, called Cardiocerebral Resuscitation, based on our extensive physiologic laboratory studies, was introduced in Tucson in 2003, in rural Wisconsin in 2004, and in selected EMS areas in the metropolitan Phoenix area in 2005. Survival of patients with OHCA due to VF treated with Cardiocerebral Resuscitation in rural Wisconsin increased to 38% and in 60 EMS systems in Arizona to 39%. In 2004, we began a statewide program to advocate chest compression-only CPR for bystanders of witnessed primary OHCA. Over the next five years, we found that survival of patients with a shockable rhythm was 17.7% in those treated with standard bystander CPR (mouth-to-mouth ventilations plus chest compression) compared to 33.7% for those who received bystander chest-compression-only CPR. This article on Cardiocerebral Resuscitation, by invitation following a presentation at the 2011 Danish Society Emergency Medical Conference, summarizes the results of therapy of patients with primary OHCA treated with Cardiocerebral Resuscitation, with requested emphasis on the EMS protocol.

Cardiac motion is a highly complex and integrated process of vital importance as it sustains the primary function of the heart, that is pumping blood. Cardiac tissue microstructure, in particular the alignment of myocytes (also referred to as fibre direction) and their lateral organisation into laminae (or sheets), has been shown by both experimental and computational research to play an important role in the determination of cardiac motion patterns. However, current models of cardiac electromechanics, although already embedding structural information in the models equations, are not yet able to fully reproduce the connection between structural dynamics and cardiac deformation. The aim of this thesis was to develop an electromechanical modelling framework to investigate the impact of tissue structure on cardiac motion, focussing on left ventricular contraction in rat. The computational studies carried out were complemented with a preliminary validation study based on experimental data of tissue structure rearrangement during contraction from diffusion tensor MRI.