Les pathologies du nœud sino-atrial provoquent un dysfonctionnement intrinsèque de l'automaticité de ce tissu. La maladie, l'âge ou une anomalie génétique peuvent être la cause d'un dérèglement de la fréquence cardiaque associé à la bradycardie ou la dysfonction atrio-ventriculire. Sans intervention médicale cette pathologie peut conduire à l'arrêt cardiaque. Les pathologies touchant le sinus sont fréquentes, avec une occurrence accrue dans la population âgée. Ainsi, avec le vieillissement des populations occidentales il devient primordial de mieux comprendre les mécanismes générant l'activité automatique du cœur. Les nombreuses études déjà réalisées dans ce domaine ont conduit à une forte controverse entre deux modèles explicatifs des mécanismes pacemaker. Dans ce contexte, j'ai étudié au cours de cette thèse le rôle joué par les canaux calciques Cav1.3 dans la génération de l'activité pacemaker. Afin de distinguer et expliquer le rôle des différents canaux ioniques impliqués dans le mécanisme pacemaker nous avons utilisé une combinaison d'outils pharmacologiques et plusieurs souches de souris transgéniques dont les gènes impliqués dans l'activité pacemaker étaient inactivés ou leur fonction modifiée. Dans le but de constituer un nouveau cadre d'interprétation du mécanisme pacemaker, plusieurs approches expérimentales ont été utilisées. L'activité pacemaker a été étudié dans 3 systèmes au niveau de complexité croissant: des cellules sino-atriales isolées, des tissus sino-atriales entiers et des animaux vivants. Ces différentes approches ont permis d'obtenir des résultats probants et ouvrent la voie à une meilleure compréhension de l'automaticité. En conclusion de cette thèse, nous proposons un cadre intégratif des modèles préexistants, dans lequel les canaux de la membrane cytoplasmique et les libérations de calcium interagissent pour générer un mécanisme pacemaker complexe. / The “sick sinus syndrome” has been defined as an intrinsic dysfunction of the heart Sino-atrial node to perform its pacemaking function. Disease, ageing, or gene defects may cause sinus dysfunctions, ranging from rhythm disturbance to bradycardia, sinus pauses, sinus arrest, and arrhythmias. Without medical intervention these dysfunctions can result in heart block. Sick sinus syndrome is a common pathology, with an increased penetration in the elder population. In the light of the actual increase of elderly in western population, a better comprehension of the mechanism generating spontaneous automaticity appears fundamental. Several investigations have been already carried out in the field of automaticity, leading to a heated controversy between two models of the pacemaker mechanism. In the light this controversy, we investigated the role of Ca2+ channels in generating pacemaker activity. In order to discern and explain the roles of different ion channel actors already implicated in the complex pacemaker machinery we used a combination of pharmacological tools and a variety of transgenic mice. These mice present genetic inactivation or modification in genes involved in pacemaker activity. Furthermore, to provide a new framework for interpreting the pacemaker mechanism, different experimental approaches have been employed. Pacemaker activity was studied in three systems with increasing complexity: isolated sino-atrial cells, intact sino-atrial tissues and in freely-moving animals. These systems led us to consistent conclusions and will pave the way to a better understanding of pacemaking. In particular, we propose an integrative framework for bridging current models in a common mechanism where both, membrane channels and Ca2+ release interact generating a complex pacemaker machinery.

Heart failure is responsible for one in twenty deaths in the UK, and as the average age of the general population increases that number is predicted to rise over the coming years. Hypertrophic growth is believed to be an adaptive response to a chronic increase in workload under circumstances such as hypertension, yet it is also known to contribute to the pathological progression into heart failure. Abnormal calcium handling is known to play a critical role in determining disease progression, not only through its function as the driving force behind myocardial contraction and relaxation but also through directing the signals which regulate hypertrophic growth. Both isoforms 1 and 4 of the diastolic calcium extrusion pump plasma membrane calcium ATPase (PMCA) are present in the heart, yet unlike in other cell types their contribution to overall calcium clearance is only small; however their role in the disease process is yet to be defined. A novel mouse line was generated in which both PMCA1 and 4 were deleted from the myocardium (PMCA1:4dcko mice). Through comparison with PMCA1 knockout mice (PMCA1cko) this thesis set out to identify the specific function of each pump under normal conditions and during the development of pathological hypertrophy induced by pressure overload through transverse aortic constriction (TAC).Under basal conditions each isoform functioned independently, PMCA1 to extrude calcium during diastole and PMCA4 to regulate calcium levels during systole; however the loss of neither isoform impacted significantly on cardiac function. In response to TAC, PMCA1cko mice progressed rapidly into decompensation and displayed signs of systolic failure after just 2 weeks, whilst cardiac function was preserved in TAC controls. Calcium handling analysis revealed that prior to the onset of failure PMCA1cko mice displayed a distinct lack of adaptive changes to calcium cycling which were present in controls. In stark contrast, the additional loss of PMCA4 led to an attenuated hypertrophic response to TAC in PMCA1:4dcko mice which remarkably preserved cardiac function despite the absence of PMCA1. This adds to accumulating evidence which suggests that the inhibition of PMCA4 may be protective during the development of pathological hypertrophy, whilst highlighting the possibility for a novel role for PMCA1 in coordinating essential adaptations required to enhance calcium cycling in response to the increased demands imposed on the left ventricle during pressure overload.

This study was designed to elicit women's perceptions of their illness experience with myocardial infarction for the purpose of exploring and describing the nature and meaning of this illness experience and its impact on everyday life. The phenomenological method, a type of qualitative research, was used to direct the study. The data were compiled through a series of semi-structured intensive interviews with eight women. The women were 36 to 71 years of age. Six of the women were married and living with their husbands. The women had been at home following discharge from hospital for 2 to 14 weeks. Data collection and data analysis proceeded simultaneously and data collection ceased once consistent themes were identified and validated and the data collected were sufficiently rich and in-depth. Women explain their illness experience with myocardial infarction as a loss phenomenon and the central and dominant loss within the heart attack experience for women is loss of predictability. Women's need for information following myocardial infarction is not met and lack of energy is a prominent feature in everyday life after a heart attack. Traditional sex role socialization sets the stage for potential problems in women's cardiac rehabilitation, especially in relation to support and role enactment. Physical rehabilitation is not a selected strategy to gain control over their loss experience for women with myocardial infarction. The findings and conclusions of this study suggest a number of implications for nursing practice. There is clear direction for family-centered nursing care in the rehabilitation of women with myocardial infarction to address potential problems in relation to support and role enactment. This study reinforces the value of using the concepts of loss and grief to care for patients with myocardial infarction. Also, this study indicates that, in planning nursing care for women with myocardial infarction, nurses should focus on Interventions to increase support, to meet patient and family educational needs, and to help women to anticipate normal physical and psychological responses to myocardial infarction. This study also has specific implications for the development of structured cardiac rehabilitation programmes addressing the special needs of women. In relation to nursing education, nurses must be prepared to assess, teach, and counsel patients with myocardial infarction and their families. Most importantly, this study directs nursing educators to provide course work in women's health issues to sensitize nurses to this field of study and to equip nurses with the understanding necessary to facilitate changes in women's health care. Implications for future research include further exploration of information needs, support, and strategies for control in relation to women with myocardial infarction. / Applied Science, Faculty of / Nursing, School of / Graduate

The survival data for two hundred patients who underwent coronary bypass surgery are subjected to quantitative analysis. The questions of interest are: (i) the long-term survival rates of these patients, (ii) the prognostic factors influencing survival, and (iii) the importance of types of grafting in long-term survival. Statistical methods used to ascertain the important prognostic variables include contingency table analysis and discriminant analysis. It is found that left ventricular function, age, risk classification, and extent of occlusion of the diseased artery are the most influential variables. The relationship of these variables to survival is analysed in detail using the proportional hazards model discussed by Cox (1972). / Science, Faculty of / Statistics, Department of / Graduate

This descriptive study was designed to investigate the problem of inadequate emotional recovery from open heart surgery. This problem has been defined by a number of earlier researchers who have noted adverse emotional reactions to the experience of cardiac surgery in both the early postoperative and the post-discharge periods. This investigation had as its purpose the examination of the pre-discharge recovery of patients, and the investigator intended to note whether there existed a common pattern of recovery among the patients studied (hence, a pattern of emotional response to surgery). It was anticipated that the discovery of similarities of behaviour might give insight into the responses to open heart surgery and provide information important to the study of long-term rehabilitation. Twenty adult patients scheduled for open heart surgery were selected as the sample for study. The principal setting for the investigation was the Cardiac Surgery Unit of a large metropolitan hospital. Subjects were interviewed one to two days prior to surgery and then every two to three days postoperatively until the time of discharge. The investigator obtained qualitative data with the aid of a data collection tool, noting the physiological status of the subjects but focusing most directly on verbal and nonverbal behaviours exhibited. The latter observations included focus of conversation, patterns of communication, affect, orientation, level of anxiety, and activity. Following analysis of the data, it was noted that a common pattern of recovery was indeed evident. Three phases of recovery - Somatic, Transition and Resolution - could be described for each subject in the sample. The phases indicated the subjects' general responses to surgery and their progression toward increased activity and independence at the time of discharge. In effect, the phases served to define the hospital course of emotional recovery from open heart surgery. The length and onset of these three phases were similar for patients with an uncomplicated recovery but varied with patients who experienced major physiologic difficulties. The implications of a recovery pattern have been discussed relative to nursing care of the cardiac surgical patient and specific recommendations for nursing intervention have been made. Subject areas worthy of further investigation have been enumerated by the investigator in light of the conclusions of the present study. / Applied Science, Faculty of / Nursing, School of / Graduate

No description available.

Background: Research has shown that music performance anxiety (MPA) is experienced by individuals in all age groups and skill levels. Due to the need for effective treatment of performance anxiety in musicians, researchers have begun to investigate the viability of mindfulness, which has been proven as an effective treatment in populations with generalized anxiety. Although preliminary studies have been undertaken in examining the effects of mindfulness training on the experience of MPA, these efforts have been by a small group of researchers, and further replication and statistical significance is needed. Objective: This study aims to monitor the effects of a two-week mindfulness intervention on musicians using questionnaires and heart rate data. Methods: This experiment used a control group design, in which the first 13 participants collected were allocated to the experimental group, and the next 13 collected were allocated to the control group. All participants underwent the same baseline data collection involving completing the state side of the State-Trait Anxiety Inventory (STAI) directly before and after performing in front of a mock jury panel while wearing a hear rate monitor watch. After this session, only the experimental group partook in two weeks of mindfulness training consisting of 6-9 sessions, each an hour in duration. Once the two-week intervention was concluded, both experimental and control groups participated in a post-intervention data collection identical to the baseline session. Results: The experimental group experienced a decrease in anxiety between pre- and post-intervention while the control group experienced an increase of anxiety. A two-way mixed ANOVA analysis revealed that there was a significant relationship between the changes in anxiety when comparing the control and experimental groups. However, statistical analysis also revealed that the two groups exhibited statistically different levels of anxiety at baseline. Heart rate data revealed no significant differences between groups. Conclusion: Data from the STAI suggests that mindfulness has a significantly positive effect on the cognitive experience of music performance anxiety. Through this study no correlation was found between the physiological experience of music performance anxiety and mindfulness training.

Background: Smoking continues to be the leading cause of preventable disease, disability and death in the United States attributing to more than 480,000 deaths every year. An estimated 36.5 million US adults (15% of US population) currently smoke, and more than 16 million live with a smoking-related disease. Since recent years, there has been a surge of alternate tobacco products in the US markets, and one such product that has gained importance was electronic cigarettes. Studies have demonstrated a rapid increase in e-cigarette use among US adults. However, research is limited on the effects of e-cigarette on human health. Thus, using a nationally representative sample of US adults, we investigated the association of e-cigarette use with coronary heart disease (CHD) among adults aged ≥18-years in the US. Methods: Data from the 2016 Behavioral Risk Factor Surveillance System (BRFSS) were used to conduct this study. BRFSS is a cross-sectional survey administered to 486,303 adults in all 50 states to collect information about their health-related risk behaviors, chronic health conditions and the use of preventive services. Participants’ self-reported responses were used to define study outcome (CHD), exposure (current e-cigarette use) and covariates (demographics [sex and race], behaviors [cigarette smoking, alcohol consumption, marijuana use, physical activity], and physical conditions [overweight or obesity]). Multiple logistic regression analysis was conducted to determine the association between e-cigarette use and CHD. Adjusted odds ratio and corresponding 95% confidence intervals were presented. Results: Approximately 6.19% of US adults reported CHD events and 3.1% of US adults were current e-cigarette users. Approximately 5.42% of e-cigarette smoking US adults reported CHD outcomes in 2016. Overall, the odds of CHD events was 34.9% less among e-cigarette users than those who were not e-cigarette users (adjusted odds ratio (aOR): 0.65, 95% confidence interval (CI): 0.60-0.70, p Conclusion: The study found out that e-cigarette user was less likely associated with CHD outcomes in US adults. Given the limitations of cross-sectional study nature and self-reported bias of responses, longitudinal studies with objective measures are needed to further investigate the association between e-cigarette use and CHD.

Heart disease is the leading cause of death globally. Early diagnosis is the key to successful treatment. By providing noninvasive, non-ionizing, and real-time imaging, echocardiography plays a critical role in identifying heart disease. Compared to other imaging modalities, ultrasound has unparalleled temporal resolution. High frame-rate imaging has enabled the development of new metrics to characterize myocardial mechanics. Strain imaging measures the heart's deformation throughout the cardiac cycle, providing a quantitative assessment of cardiac health. The intention of this dissertation is to bring Myocardial Elastography (ME) closer to clinical realization. ME is a high frame-rate strain imaging technique for transthoracic and intracardiac echocardiography. This work consists of four Aims. There is a fundamental trade-off between spatial and temporal resolution in strain imaging. In Aim 1, the optimal transmit sequence that generates the most accurate and precise strain estimate was determined. Two common approaches to coherent compounding (full and partial aperture) were compared in simulation and in transthoracic imaging of healthy human subjects (n=5). The optimized subaperture compounding sequence (25-element subperture, 90° angular aperture, 10 virtual sources, 300 Hz frame rate) was compared to the optimized steered compounding sequence (60° angular aperture, 15° tilt, 10 virtual sources, 300 Hz frame rate) and was found to measure strain in healthy human subjects with equivalent precision. The optimal compounding configuration was then evaluated against two other high-frame rate transmit strategies, ECG-gated focused imaging, and wide-beam imaging, in simulation and in healthy subjects (n=7). Achieving the highest level of strain precision, ECG-gated focused imaging was determined to be the preferred imaging approach in patients capable of sustaining a breath hold, with compounding preferred in those unable to do so. Rapid diagnosis is essential to successful treatment of myocardial infarction. In Aim 2, ME's ability to track infarct formation and recovery, and localize infarct using regional strain measurments, was investigated in a large animal survival model (n=11). Infarcts were generated via ligation of the left anterior descending, imaging regularly for up to 28 days. A radial strain-based metric, percentage of healthy myocardium by strain (PHM_ε), was developed as a marker for healthy myocardial tissue. PHM_ε was strongly linearly correlated with actual infarct size as determined by gross pathology (R2 = 0.80). ME was capable of diagnosing individual myocardial segments as non-infarcted or infarcted with high sensitivity (82%), specificity (92%), and precision (85%) (ROC AUC = 0.90), and tracked infarct recovery from collateral reperfusion through time. Noninvasive strain imaging at rest can improve pre-test probability accuracy, and reduce unnecessary stress testing. In Aim 3, ME's potential to provide early diagnosis of coronary artery disease was investigated in an ongoing study. Patients undergoing myocardial perfusion imaging were recruited (n=126). Perfusion scores were used as the reference standard. Morphological transformations were integrated into the processing pipeline to reduce variability in the strain measurements. PHM_ε was reintroduced and used to differentiate between patients with and without coronary artery disease. ME was capable of distinguishing between normal patients and those with significant ischemia or infarct (subjects with perfusion defects at rest) with statistical significance (p < 0.05), although a greater sample size is needed to confirm the results. One of the most common treatments for arrhythmia, catheter ablation, can fail if the lesion line intended to terminate the abnormal rhythm is non-contiguous. In Aim 4, the gap resolution and clinical feasibility of Intracardiac Myocardial Elastography (IME) strain imaging, an ablation monitoring technique, was investigated. Lesion size estimation and gap resolution was evaluated in an open chest canine model (n=3), wherein lesion lines consisting of three lesions and two gaps were generated in each canine left ventricle via epicardial ablation. All gaps were resolvable. Average lesion and gap areas were measured with high agreement (33 ± 14 mm2 and 30 ± 15 mm2, respectively) when compared against gross pathology (34 ± 19 mm2 and 26 ± 11 mm2, respectively). Gaps as small as 11 mm2 (3.6 mm on epicardial surface) were identifiable. Patients undergoing ablation to treat typical cavotricuspid isthmus atrial flutter (n=5) were imaged throughout the procedure. In all patients, strain decreased in the cavotricuspid isthmus after ablation (mean paired difference of -17 ± 11 %, p < 0.05). Together, these Aims intend to translate a promising imaging method from research to clinical reality.

Cardiac conduction abnormalities can often lead to heart failure, stroke and sudden cardiac death. Heart disease stands as the leading cause of mortality and morbidity in the United States, accounting for 30% of all deaths. Early detection of malfunctions such as arrhythmias and systolic heart failure, the two heart conditions studied in this dissertation, would definitely help reduce the burden cardiovascular diseases have on public health and overcome the current clinical challenges. The imaging techniques currently available to doctors for cardiac activation sequence mapping are invasive, ionizing, time-consuming and costly. Thus, there is an undeniable urgent need for a non-invasive and reliable imaging tool, which could play a crucial role in the early diagnosis of conduction diseases and allow physicians to choose the best course of action. The 12-lead electrocardiogram (ECG) is the current non-invasive clinical tool routinely used to diagnose and localize cardiac arrhythmias prior to intracardiac catheter ablation. However, it has limited accuracy and can be subject to operator bias. Besides, QRS complex narrowing on the clinical ECG after pacing device implantation is also used for response assessment in patients undergoing Cardiac Resynchronization Therapy (CRT). The latter is an established treatment for systolic heart failure patients who have Left Bundle Branch Block as well as a reduced ejection fraction and prolonged QRS duration. Yet, it is still not well understood why 30 to 40 % of CRT recipients do not respond. Echocardiography, due to its portability and ease-of-use, is the most frequently used imaging modality in clinical cardiology. In this dissertation, we assess the clinical performance of Electromechanical Wave Imaging (EWI) as a high frame rate ultrasound-based functional modality that can non-invasively map the electromechanical activation of the heart, i.e., the transient deformations immediately following the electrical activation. The objective of this dissertation is to demonstrate the potential clinical value of EWI for both arrhythmia detection and CRT characterization applications. The first step in translating EWI to the clinic was ensuring that the technique could reli- ably and reproducibly measure the electromechanical activation sequence independently of the probe angle and imaging view in healthy human volunteers (n=7). This dissertation then demonstrated the accuracy of EWI for localizing a variety of ventricular and atrial arrhythmias (accessory pathways in Wolff-Parkinson-White (WPW) syndrome, premature ventricular contractions, focal atrial tachycardia and macro-reentrant atrial flutter) in pediatric (n=14) and adult (n=55) patients prior to catheter ablation more accurately than 12-lead ECG predictions, as validated against electroanatomical mapping. Additionally, 3D-rendered EWI isochrones were illustrated to be capable of significantly distinguishing different biventricular pacing conditions (p≤0.05) with the RWAT and LWAT metrics, assessing the ventricular dyssynchrony change in heart failure patients (n=16) undergoing CRT, and visualizing it in 3D. EWI also provided quantification of %𝘙𝘔𝘓𝘝 in CRT patients (n=38): the amount of left-ventricular resynchronized myocardium, which was found to be a reliable response predictor at 3-, 6-, or 9-month clinical follow-up through its post-CRT values by significantly identifying super-responders from non-responders within 24 hours of implantation (p≤0.05). Furthermore, 3D-rendered isochrones successfully characterized the ventricular activation resulting from His Bundle pacing for the first time (n=4), which was undistinguishable from true physiological activation in sinus rhythm healthy volunteers with the EWI-based activation time distribution dispersion metric. The dispersion was, however, reported to significantly discriminate novel His pacing from other more conventional biventricular pacing schemes (p≤0.01). Finally, we developed and optimized a fully automated zero-crossing algorithm towards a faster, more robust and less observer dependent EWI isochrone generation process. The support vector machine (SVM) and Random Forest machine learning models were both shown capable of successfully identifying the accessory pathway in WPW patients and the pacing electrode location in paced canines. Nevertheless, the best performing algorithm was hereby proven to be the Random Forest classifier with n=200 trees with a precision rising to 97%, and a predictivity that was not impacted by the type of testing dataset it was applied to (human or canine). Overall, in this dissertation, we established the clinical potential of EWI as a viable assisting visual feedback tool, that could not only be used for diagnosis and treatment planning prior to surgical procedures, but also for monitoring during, and assessing long-term resolution of arrhythmia after catheter ablation or heart failure after a CRT implant.