Advances in Electrocardiograms

Electrocardiograms have become one of the most important, and widely used medical tools for diagnosing diseases such as cardiac arrhythmias, conduction disorders, electrolyte imbalances, hypertension, coronary artery disease and myocardial infarction. This book reviews recent advancements in electrocardiography. The four sections of this volume, Cardiac Arrhythmias, Myocardial Infarction, Autonomic Dysregulation and Cardiotoxicology, provide comprehensive reviews of advancements in the clinical applications of electrocardiograms. This book is replete with diagrams, recordings, flow diagrams and algorithms which demonstrate the possible future direction for applying electrocardiography to evaluating the development and progression of cardiac diseases. The chapters in this book describe a number of unique features of electrocardiograms in adult and pediatric patient populations with predilections for cardiac arrhythmias and other electrical abnormalities associated with hypertension, coronary artery disease, myocardial infarction, sleep apnea syndromes, pericarditides, cardiomyopathies and cardiotoxicities, as well as innovative interpretations of electrocardiograms during exercise testing and electrical pacing

Multiscale Modeling of the Ventricles: From Cellular Electrophysiology to Body Surface Electrocardiograms

This work is focused on different aspects within the loop of multiscale modeling: On the cellular level, effects of adrenergic regulation and the Long-QT syndrome have been investigated. On the organ level, a model for the excitation conduction system was developed and the role of electrophysiological heterogeneities was analyzed. On the torso level a dynamic model of a deforming heart was created and the effects of tissue conductivities on the solution of the forward problem were evaluated

The Application of Computer Techniques to ECG Interpretation

This book presents some of the latest available information on automated ECG analysis written by many of the leading researchers in the field. It contains a historical introduction, an outline of the latest international standards for signal processing and communications and then an exciting variety of studies on electrophysiological modelling, ECG Imaging, artificial intelligence applied to resting and ambulatory ECGs, body surface mapping, big data in ECG based prediction, enhanced reliability of patient monitoring, and atrial abnormalities on the ECG. It provides an extremely valuable contribution to the field

Telomere Biology in Ischaemic Cardiomyopathy.

MPhil.Implantable cardioverter defibrillators (ICDs) reduce mortality in patients with ischaemic cardiomyopathy at high risk of ventricular arrhythmias (VA). However, the current indication for ICD prescription needs improvement. Telomere length and telomerase activity in leukocytes have been shown to correlate with biological aging and pathogenesis of cardiovascular diseases. Their role in arrhythmias, however, is unknown. I examined telomere biology in ischaemic cardiomyopathy patients and established its association with VA. This study stemmed from the primary hypothesis that telomere shortening at the time of the index event (myocardial infarction), results in poor myocardial repair process and predisposes patients to greater arrhythmic tendency. Hence there would be a correlation between leukocyte telomere length, load-of-short telomeres and telomerase activity with VA occurrence in these patients. I also investigated the effect of genetic variation on telomerase activity and VA. From a basic science perspective, different mechanisms of telomere shortening were studied by using a novel method for measuring critically short telomeres. 90 ischaemic cardiomyopathy patients with primary prevention ICDs were recruited. 35 had received appropriate therapy from the ICD for potentially-fatal VA while the remaining 55 patients had not. No significant differences in baseline demographic data were seen between the two groups. There was no significant difference in the age and sex adjusted mean telomere length analysed by qPCR between the groups (p=0.66). In contrast, the loadof- short telomeres assessed by Universal-STELA method and telomerase activity by TRAP assay were both higher in patients who had appropriate ICD therapy and were significantly associated with incidence of ICD therapy 3 (p=0.02, p= 0.02). Genetic variation in telomerase activity was observed with a significant correlation between telomerase and VA in C/C genotype only. These data collectively suggest that telomere biology is a promising area of exploration for further research in risk stratification for ICD prescription.Barts and the London Charity Project Grant and supported by the Barts Cardiovascular Biomedical Research Unit

Morphological Variability Analysis of Physiologic Waveform for Prediction and Detection of Diseases

For many years it has been known that variability of the morphology of high-resolution (∼30-1000 Hz) physiological time series data provides additional prognostic value over lower resolution (≤ 1Hz) derived averages such as heart rate (HR), breathing rate (BR) and blood pressure (BP). However, the field has remained rather ad hoc, based on hand-crafted features. Using a model-based approach we explore the nature of these features and their sensitivity to variabilities introduced by changes in both the sampling period (HR) and observational reference frame (through breathing). HR and BR are determined as having a statistically significant confounding effect on the morphological variability (MV) evaluated in high-resolution physiological time series data, thus an important gap is identified in previous studies that ignored the effects of HR and BR when measuring MV. We build a best-in-class open-source toolbox for exploring MV that accounts for the confounding factors of HR and BR. We demonstrate the toolbox’s utility in three domains on three different signals: arterial BP in sepsis; photoplethysmogram in coarctation of the aorta; and electrocardiogram (ECG) in post-traumatic stress disorder (PTSD). In each of the three case studies, incorporating features that capture MV while controlling for BR and/or HR improved disease classification performance compared to previously established methods that used features from lower resolution time series data. Using the PTSD example, we then introduce a deep learning approach that significantly improves our ability to identify the effects of PTSD on ECG morphology. In particular, we show that pre-training the algorithm on a database of over 70,000 ECGs containing a set of 25 rhythms, allowed us to boost performance from an area under the receiver operating characteristic curve (AUROC) of 0.61 to 0.85. This novel approach to identifying morphology indicates that there is much more to morphological variability during stressful PTSD-related events than the simple periodic modulation of the T-wave amplitude. This research indicates that future work should focus on identifying the etiology of the dynamic features in the ECG that provided such a large boost in performance, since this may reveal novel underlying mechanisms of the influence of PTSD on the myocardium.Ph.D

QT Variability and Other Electrocardiographic Predictors of Sudden Cardiac Death

This thesis investigates sudden cardiac death, focusing of QT variability, heart-rate variability and other electrocardiographic markers. Topics include: - Normal values for heart-rate variability - Normal values for QT variability - The association of QT variability with sudden cardiac death - The association of QT variability with Heart Failure - The association of thyroid function and Sudden cardiac death - The association of thyroid function with QT variability - The association of COPD with sudden cardiac deat

Cardiac Arrhythmias

The most intimate mechanisms of cardiac arrhythmias are still quite unknown to scientists. Genetic studies on ionic alterations, the electrocardiographic features of cardiac rhythm and an arsenal of diagnostic tests have done more in the last five years than in all the history of cardiology. Similarly, therapy to prevent or cure such diseases is growing rapidly day by day. In this book the reader will be able to see with brighter light some of these intimate mechanisms of production, as well as cutting-edge therapies to date. Genetic studies, electrophysiological and electrocardiographyc features, ion channel alterations, heart diseases still unknown , and even the relationship between the psychic sphere and the heart have been exposed in this book. It deserves to be read

Investigation of arrhythmogenesis in the desmoplakin knockout mouse: A model of arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM), in contrast with other cardiomyopathies, often presents with lethal ventricular arrhythmias with athletes affected more severely. It has the characteristic feature of fibrofatty replacement of the right ventricular myocardium, although left ventricular variants have been reported. It has been associated with desmosomal protein mutations – structural proteins involved in cell-cell adhesion at the intercalated disk between cardiomyocytes. Arrhythmias are often noted to occur in a ‘concealed phase’ with minimal or no evidence of structural change. There is a need for better understanding of the mechanisms promoting arrhythmogenesis in order to improve arrhythmic risk prediction. A cardiac restricted heterozygous desmoplakin (DSP) knockout mouse was developed using the Cre-lox system with the cardiac restricted αMHC promoter (αMHC-Cre DSP flox/+) as a model of ‘concealed phase’ ACM and was studied with ECG, electrophysiology study and histology. This model recapitulated the ventricular arrhythmias seen in patients with evidence of conduction delay at electrophysiology study. This was no evidence of fibrofatty replacement of the myocardium on histology. Immunohistochemistry, however, revealed connexin 43 (Cx43) mislocalization away from the intercalated disk and a reduction in mRNA expression. Cx43 is a protein that makes up gap junctions which are involved in allowing rapid electrical conduction in the heart. The sodium channel is also located at the intercalated disk, but no change in its distribution, mRNA expression or change in the sodium current was noted. This suggests that interactions between Cx43 and desmosomal proteins are a key driver of arrhythmogenesis in ACM. In order to assess the effect of exercise on the arrhythmic phenotype, the mice were allowed to exercise freely before electrophysiology study. One group had slow release β blocker pellets implanted prior to exercise. Exercise made the mice more prone to arrhythmia, consistent with human studies. β blockers significantly reduced the numbers of mice developing ventricular arrhythmia as well as reducing the conduction delay observed at electrophysiology study. Cx43 showed less mislocalization in the β blocker treated mice, suggesting a role in slowing disease progression. Using the CreER promoter, which knocks DSP out in the adult mouse, the effect of DSP loss in adulthood was investigated. Mice with a complete knockout of DSP in adulthood became rapidly unwell and died, with bradycardia the only notable arrhythmia. However, heterozygous CreER knockout mice did not develop arrhythmia. The αMHC promoter is maximally expressed in early postnatal life. This suggests that this period, when desmosomes and adherens junctions are forming the mixed cell-cell junctions called the area composita, is significant in forming functional gap junctions to allow normal conduction. This mechanism may be relevant to arrhythmogenesis in other inherited cardiomyopathies. HL-1 cells were used as a cellular cardiomyocyte model to express DSP mutations identified in our ACM patient cohort. These two mutations (R1113X and T586fsX594) were both nonsense mutations at the N terminus. Cx43 was also found to be mislocalised in this model and shows similarity between the heterozygous knockout murine model and a cellular m0del of disease causing mutations. Sodium channel localisation was variable and showed less membrane localisation with the R1113X mutation. This may account for differences in the arrhythmia burden amongst ACM patients and shows the complex nature of the interactions at the intercalated disk. Plakoglobin was found to be localised at the nucleus with mutant DSP. This shows it is a key binding partner for desmoplakin at the intercalated disk and may also promote arrhythmogenesis by alterations in nuclear signalling. In conclusion, this work has established the heterozygous DSP knockout mouse and HL-1 cells as useful models for investigating the mechanisms of arrhythmogenesis in ACM. The key mechanism is interaction of desmoplakin and Cx43 at the intercalated disk. Restriction on exercise and treatment with β blockers for ACM patients is supported by this model. Further investigation of the mechanisms of interaction of DSP with other desmosomal proteins, the sodium channel and Cx43 may allow better prediction of arrhythmic risk and targeted therapies for ACM patients