Development of a Novel Dataset and Tools for Non-Invasive Fetal Electrocardiography Research

This PhD thesis presents the development of a novel open multi-modal dataset for advanced studies on fetal cardiological assessment, along with a set of signal processing tools for its exploitation. The Non-Invasive Fetal Electrocardiography (ECG) Analysis (NInFEA) dataset features multi-channel electrophysiological recordings characterized by high sampling frequency and digital resolution, maternal respiration signal, synchronized fetal trans-abdominal pulsed-wave Doppler (PWD) recordings and clinical annotations provided by expert clinicians at the time of the signal collection. To the best of our knowledge, there are no similar dataset available. The signal processing tools targeted both the PWD and the non-invasive fetal ECG, exploiting the recorded dataset. About the former, the study focuses on the processing aimed at the preparation of the signal for the automatic measurement of relevant morphological features, already adopted in the clinical practice for cardiac assessment. To this aim, a relevant step is the automatic identification of the complete and measurable cardiac cycles in the PWD videos: a rigorous methodology was deployed for the analysis of the different processing steps involved in the automatic delineation of the PWD envelope, then implementing different approaches for the supervised classification of the cardiac cycles, discriminating between complete and measurable vs. malformed or incomplete ones. Finally, preliminary measurement algorithms were also developed in order to extract clinically relevant parameters from the PWD. About the fetal ECG, this thesis concentrated on the systematic analysis of the adaptive filters performance for non-invasive fetal ECG extraction processing, identified as the reference tool throughout the thesis. Then, two studies are reported: one on the wavelet-based denoising of the extracted fetal ECG and another one on the fetal ECG quality assessment from the analysis of the raw abdominal recordings. Overall, the thesis represents an important milestone in the field, by promoting the open-data approach and introducing automated analysis tools that could be easily integrated in future medical devices

Haemodynamic changes during human pregnancy

MD ThesisThe aim of this work was to investigate the physiological adaptations that occur in the maternal cardiovascular system during singleton and twin pregnancy. The cardiovascular system has been shown to undergo major adaptations during human pregnancy. Most investigators agreed that cardiac output increased during pregnancy however there was no unanimity regarding the extent and timing of this increase nor about the physiological mechanisms underlying it. Even less was known about the haemodynamic readjustments following delivery and about the alterations in multiple pregnancy. Further study has been limited by the lack of an accurate noninvasive technique which is applicable and reproducible during pregnancy. Cross-sectional echocardiography combined with Doppler ultrasound measurement of blood velocity provides a noninvasive method for measuring cardiac output at a number of locations within the heart and great vessels. Preliminary investigations revealed that cardiac outputs determined by this method correlated closely with those measured by the direct Fick technique in non-pregnant subjects. In addition the method was highly reproducible in both pregnant and nonpregnant subjects. M-mode echocardiography allows accurate and noninvasive measurements of cardiac chamber size and ventricular function. These measurements were also found to be highly reproducible in pregnant and non-pregnant subjects. Using these techniques the aims of this thesis were to investigate the extent, timing and mechanisms of the changes in cardiac output during singleton and twin pregnancy. Echocardiographic investigations were performed prior to and during singleton pregnancy, during the first 6 months after singleton pregnancy, and during and 6 months after twin pregnancy. All subjects were studied in the left semi-lateral position. The results suggested that; (1) During singleton pregnancy cardiac output was increased early in the first trimester and continued to rise until 24 weeks gestation when values were 43-49% above pre-pregnant control values. Thereafter there was no further change. Heart rate and left ventricular function increased during the first trimester. Left atrial and left ventricular end-diastolic dimensions increased during the second trimester suggesting an increase in venous return. Cardiac valve cross-sectional areas and left ventricular wall thickness also increased during pregnancy. After delivery cardiac output had fallen to non-pregnant values by 2 weeks. This was associated with reductions in left ventricular performance and left atrial and left ventricular end-diastolic dimensions. The decrease in valve cross-sectional areas and left ventricular wall thickness was not evident until later in the puerperium. (2) During twin pregnancy cardiac output was increased by 20 weeks gestation and thereafter showed no further change. Maximum cardiac output was 59-62% above postnatal control values. This increase was greater than that recorded during singleton pregnancy due to a relatively greater increase in heart rate. Twin pregnancy was also associated with a greater increase in left atrial dimension. The results of these studies shed light on some of the the unanswered questions in the field of maternal haemodynamics. The noninvasive Doppler techniques used allowed accurate and reproducible measurements of cardiac output in pregnant subjects. This work has important implications for the future investigation of cardiac and hypertensive disorders during pregnancy.Newcastle Health Authority: Birthright

End organ effects of paediatric cardiopulmonary bypass

Despite the scientific, technological and surgical improvements of the past 50 years organ dysfunction following elective paediatric cardiac surgery utilising cardiopulmonary bypass continues to account for increased complications, often leading to a protracted course in hospital with a longer stay in intensive care and the potential for irreversible organ damage long term. Furthermore, paediatric cardiac surgeons are routinely undertaking more complex operations with a shift from palliation to early correction. This has resulted in younger children being subjected to longer periods on the bypass machine with increased effects on vital organs. This thesis describes two clinical studies designed to further assess and characterise peri-operative cardiac, renal and pulmonary function in children undergoing elective cardiac repair at a tertiary referral centre in Scotland, UK. In the first instance a prospective, observational study was undertaken in forty-five children to examine the use of tissue Doppler imaging in the assessment of peri-operative cardiac function, its relationship to myocardial injury and clinical outcome. Tissue Doppler parameters were obtained using a Vivid 7 ultrasound scanner with a 7-MHz probe pre-operatively, on admission to paediatric intensive care and on day one. Myocardial injury was assessed using Troponin-I on the first post-operative day by a commercially available chemiluminescent immunoassay. In twenty children within this group peri-operative renal function was also investigated using standard estimates of glomerular filtration rate, namely creatinine clearance measured by the kinetic Jaffe method during the first and second twelve hour post-operative periods, in comparison to serum creatinine and the novel biomarker cystatin C. Routine plasma retained pre-operatively and on days 0, 1, 2 and 3 post-operatively was used to measure serum cystatin C and creatinine using a particle-enhanced nephelometric immunoassay and the Roche Creatinine Plus enzymatic assay respectively. The association between cystatin C and recorded perfusion parameters including bypass duration, pump flow, haematocrit, oxygen delivery and Troponin-I was investigated. Peri-operative pulmonary function was evaluated through a phase IV, randomised, double-blind, placebo controlled trial. In total, twenty four children were randomised to receive oral sildenafil or equivalent volume placebo four times the day before surgery. Blood samples were collected peri-operatively to measure serum cyclic guanosine monophosphate with a commercially available competitive enzyme immunoassay. Haemodynamic data and echocardiography were acquired at two and twenty four hours post-operatively including pulmonary vascular resistance index and bi-ventricular contractility. Post-operative oxygenation was also determined at the same time by oxygen delivery and oxygenation index. In Chapter 2, peri-operative cardiac function as assessed by tissue Doppler imaging was examined. The results of this study demonstrated that pre-operatively, bi-ventricular systolic function in the study group was reduced compared with normal controls, displaying a significant step-wise decrease with increasing complexity of lesion. This picture persisted post-operatively predominantly in the right ventricle and was significantly associated with the extent of myocardial injury. Impaired peri-operative left ventricular function correlated with clinical outcomes. In Chapter 3, peri-operative renal function as assessed by cystatin C and its association with parameters of perfusion was examined. The results of this study demonstrated that in comparison to serum creatinine, cystatin C had a superior correlation with glomerular filtration rate in the early post-operative period. An elevated level of this biomarker was significantly associated with bypass duration, minimum pump flow and post-operative myocardial injury. Haematocrit was not directly linked to renal dysfunction in this study although evidence of a critical dysoxic threshold within the kidney was suggested indirectly through oxygen delivery calculations. In Chapter 4, peri-operative pulmonary function and vascular reactivity in association with the pre-operative administration of oral sildenafil (0.5mg/kg, six hourly) was examined. The results of this trial demonstrated that compared to placebo, pre-operative sildenafil resulted in modest elevations of serum cyclic guanosine monophosphate, limited effects on pulmonary vascular resistance index, significant reductions in peri-operative bi-ventricular contractility, significant reductions in post-operative oxygen delivery and a trend for increasing ventilatory support. In summary, the current thesis has demonstrated that in children undergoing corrective cardiac surgery peri-operative bi-ventricular function can be accurately assessed by tissue Doppler imaging which to date has had limited use in this patient group. With regards to renal function, cystatin C was shown to be a better estimate of glomerular filtration rate and a more sensitive marker of early renal dysfunction in children after surgery. Furthermore, cystatin C identified a transient post-operative renal impairment, the magnitude of which was associated with duration of bypass, pump flow and myocardial injury. In relation to pulmonary function, this research identified that pre-operative administration of oral sildenafil to children undergoing cardiac surgery produced limited effects on pulmonary vascular resistance but was associated with reduced ventricular contractility and post-operative oxygenation raising significant concerns over its routine clinical use

EVALUATION OF LEFT VENTRICULAR AND ATRIAL-APPENDAGE FUNCTION IN NORMAL AND ISCHEMIC MOUSE MODELS BY CARDIAC IMAGING TECHNIQUES: A PHARMACOLOGICAL VALIDATION

Despite progress in diagnosis and treatment lead to a significant reduction of the rate of death attributable to cardiovascular disease (CVD), many efforts must to be done to modify the pathological process and enhance protection. Thus the development of new technologies for diagnosis and novel therapeutic agents is fundamental for clinicians and researcher. In the last decade, murine model had become a useful tool to study CVDs mechanism and to test new pharmacological treatments. Noninvasive imaging technique, specific for laboratory animals, provide the opportunity to image longitudinally the same animal, investigating the follow-up of pathologies and assessing the effect of pharmacological treatments. Aims of this work are to set up an animal model of myocardial infarction (MI) and cardiac imaging (cardiac magnetic resonance imaging and echocardiography) of left ventricle (LV), left atrium (LA) and appendage (LAA) in healthy mice, and then evaluate the global and regional functional-structural changes and remodeling occurring on LV, LA and LAA after MI, with or without pharmacological treatment. The in vivo imaging data were supported by morphological, histological and gene expression analysis. Results from this study described the regional area changes occurring on LV after MI with a progressive loss of contractility also in remote non-infarcted tissue; the presence of only three pulmonary veins entering LA and the presence of the large LAA which, working together with LA, plays an important role in LV filling. After MI not only LV but also LA and LAA remodel in order to maintain, with their enlargement, LV stroke volume. The pharmacological treatment with valsartan, a selective inhibitor of AT1 receptor of Ang II, influenced LV remodeling by reducing LV enlargement, infarct size, ECM gene expression (in particular collagen VIII, fibulin-2 involved in fibrosis and hypertrophy), preserving LV SV without affecting LAA and LA increase in dimension

End organ effects of paediatric cardiopulmonary bypass

Despite the scientific, technological and surgical improvements of the past 50 years organ dysfunction following elective paediatric cardiac surgery utilising cardiopulmonary bypass continues to account for increased complications, often leading to a protracted course in hospital with a longer stay in intensive care and the potential for irreversible organ damage long term. Furthermore, paediatric cardiac surgeons are routinely undertaking more complex operations with a shift from palliation to early correction. This has resulted in younger children being subjected to longer periods on the bypass machine with increased effects on vital organs. This thesis describes two clinical studies designed to further assess and characterise peri-operative cardiac, renal and pulmonary function in children undergoing elective cardiac repair at a tertiary referral centre in Scotland, UK. In the first instance a prospective, observational study was undertaken in forty-five children to examine the use of tissue Doppler imaging in the assessment of peri-operative cardiac function, its relationship to myocardial injury and clinical outcome. Tissue Doppler parameters were obtained using a Vivid 7 ultrasound scanner with a 7-MHz probe pre-operatively, on admission to paediatric intensive care and on day one. Myocardial injury was assessed using Troponin-I on the first post-operative day by a commercially available chemiluminescent immunoassay. In twenty children within this group peri-operative renal function was also investigated using standard estimates of glomerular filtration rate, namely creatinine clearance measured by the kinetic Jaffe method during the first and second twelve hour post-operative periods, in comparison to serum creatinine and the novel biomarker cystatin C. Routine plasma retained pre-operatively and on days 0, 1, 2 and 3 post-operatively was used to measure serum cystatin C and creatinine using a particle-enhanced nephelometric immunoassay and the Roche Creatinine Plus enzymatic assay respectively. The association between cystatin C and recorded perfusion parameters including bypass duration, pump flow, haematocrit, oxygen delivery and Troponin-I was investigated. Peri-operative pulmonary function was evaluated through a phase IV, randomised, double-blind, placebo controlled trial. In total, twenty four children were randomised to receive oral sildenafil or equivalent volume placebo four times the day before surgery. Blood samples were collected peri-operatively to measure serum cyclic guanosine monophosphate with a commercially available competitive enzyme immunoassay. Haemodynamic data and echocardiography were acquired at two and twenty four hours post-operatively including pulmonary vascular resistance index and bi-ventricular contractility. Post-operative oxygenation was also determined at the same time by oxygen delivery and oxygenation index. In Chapter 2, peri-operative cardiac function as assessed by tissue Doppler imaging was examined. The results of this study demonstrated that pre-operatively, bi-ventricular systolic function in the study group was reduced compared with normal controls, displaying a significant step-wise decrease with increasing complexity of lesion. This picture persisted post-operatively predominantly in the right ventricle and was significantly associated with the extent of myocardial injury. Impaired peri-operative left ventricular function correlated with clinical outcomes. In Chapter 3, peri-operative renal function as assessed by cystatin C and its association with parameters of perfusion was examined. The results of this study demonstrated that in comparison to serum creatinine, cystatin C had a superior correlation with glomerular filtration rate in the early post-operative period. An elevated level of this biomarker was significantly associated with bypass duration, minimum pump flow and post-operative myocardial injury. Haematocrit was not directly linked to renal dysfunction in this study although evidence of a critical dysoxic threshold within the kidney was suggested indirectly through oxygen delivery calculations. In Chapter 4, peri-operative pulmonary function and vascular reactivity in association with the pre-operative administration of oral sildenafil (0.5mg/kg, six hourly) was examined. The results of this trial demonstrated that compared to placebo, pre-operative sildenafil resulted in modest elevations of serum cyclic guanosine monophosphate, limited effects on pulmonary vascular resistance index, significant reductions in peri-operative bi-ventricular contractility, significant reductions in post-operative oxygen delivery and a trend for increasing ventilatory support. In summary, the current thesis has demonstrated that in children undergoing corrective cardiac surgery peri-operative bi-ventricular function can be accurately assessed by tissue Doppler imaging which to date has had limited use in this patient group. With regards to renal function, cystatin C was shown to be a better estimate of glomerular filtration rate and a more sensitive marker of early renal dysfunction in children after surgery. Furthermore, cystatin C identified a transient post-operative renal impairment, the magnitude of which was associated with duration of bypass, pump flow and myocardial injury. In relation to pulmonary function, this research identified that pre-operative administration of oral sildenafil to children undergoing cardiac surgery produced limited effects on pulmonary vascular resistance but was associated with reduced ventricular contractility and post-operative oxygenation raising significant concerns over its routine clinical use.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Detection and measurement and of repolarisation features in atrial fibrillation and healthy subjects

Major cardiac organisations recommended U wave abnormalities should be reported during ECG interpretation. However, U waves cannot be measured in patients with atrial fibrillation (AF) due to the obscuring fibrillatory wave.The first aim of the research was to provide a validated algorithm to clean the ECGs of AF patients by removing the atrial fibrillatory waves so that the characteristics of ventricle repolarisation components, U and T waves, could be detected and measured accurately without fibrillatory wave contamination.Having established a validated algorithm to measure the waveform features, the second aim was to use this algorithm to investigate the effect of beat interval dependency on the repolarisation waves, especially U waves, during AF and to compare them to those in sinus rhythm (SR) of healthy subjects. The research could provide mechanistic insight into the origin of U waves since AF is unique in its rapidly changing ventricular beat intervals. The preceding beat interval has a direct impact on ventricular filling dynamics and hence also on mechano-electrical coupling, one of the leading hypotheses of U wave genesis.Algorithms were developed to remove the contaminating fibrillatory waves in AF recordings and to measure features of the ventricular repolarisation waves.The ventricular repolarisation features, U and T waves, are measurable and dependent on preceding beat interval in AF and SR. The beat interval dependency of repolarisation features, especially the U wave, supported the mechano-electrical hypothesis during AF and SR.The research provides tools to facilitate the detection and reporting of U waves and their abnormalities in AF patients and provides mechanistic insight into rate dependency of ventricular repolarisation features