Quantification and classification of potassium and calcium disorders with the electrocardiogram: What do clinical studies, modeling, and reconstruction tell us?

Diseases caused by alterations of ionic concentrations are frequently observed challenges and play an important role in clinical practice. The clinically established method for the diagnosis of electrolyte concentration imbalance is blood tests. A rapid and non-invasive point-of-care method is yet needed. The electrocardiogram (ECG) could meet this need and becomes an established diagnostic tool allowing home monitoring of the electrolyte concentration also by wearable devices. In this review, we present the current state of potassium and calcium concentration monitoring using the ECG and summarize results from previous work. Selected clinical studies are presented, supporting or questioning the use of the ECG for the monitoring of electrolyte concentration imbalances. Differences in the findings from automatic monitoring studies are discussed, and current studies utilizing machine learning are presented demonstrating the potential of the deep learning approach. Furthermore, we demonstrate the potential of computational modeling approaches to gain insight into the mechanisms of relevant clinical findings and as a tool to obtain synthetic data for methodical improvements in monitoring approaches

Sudden Cardiac Death in Dialysis: Arrhythmic Mechanisms and the Value of Non-invasive Electrophysiology

Sudden Cardiac Death (SCD) is the leading cause of cardiovascular death in dialysis patients. This review discusses potential underlying arrhythmic mechanisms of SCD in the dialysis population. It examines recent evidence from studies using implantable loop recorders and from electrophysiological studies in experimental animal models of chronic kidney disease. The review summarizes advances in the field of non-invasive electrophysiology for risk prediction in dialysis patients focusing on the predictive value of the QRS-T angle and of the assessments of autonomic imbalance by means of heart rate variability analysis. Future research directions in non-invasive electrophysiology are identified to advance the understanding of the arrhythmic mechanisms. A suggestion is made of incorporation of non-invasive electrophysiology procedures into clinical practice.Key Concepts:– Large prospective studies in dialysis patients with continuous ECG monitoring are required to clarify the underlying arrhythmic mechanisms of SCD in dialysis patients.– Obstructive sleep apnoea may be associated with brady-arrhythmias in dialysis patients. Studies are needed to elucidate the burden and impact of sleeping disorders on arrhythmic complications in dialysis patients.– The QRS-T angle has the potential to be used as a descriptor of uremic cardiomyopathy.– The QRS-T angle can be calculated from routine collected surface ECGs. Multicenter collaboration is required to establish best methodological approach and normal values.– Heart Rate Variability provides indirect assessment of cardiac modulation that may be relevant for cardiac risk prediction in dialysis patients. Short-term recordings with autonomic provocations are likely to overcome the limitations of out of hospital 24-h recordings and should be prospectively assessed

Monitoring of serum potassium and calcium levels in end-stage renal disease patients by ecg depolarization morphology analysis

Objective: Non-invasive estimation of serum potassium, [K+], and calcium, [Ca2+], can help to prevent life-threatening ventricular arrhythmias in patients with advanced renal disease, but current methods for estimation of electrolyte levels have limitations. We aimed to develop new markers based on the morphology of the QRS complex of the electrocardiogram (ECG). Methods: ECG recordings from 29 patients undergoing hemodialysis (HD) were processed. Mean warped QRS complexes were computed in two-minute windows at the start of an HD session, at the end of each HD hour and 48 h after it. We quantified QRS width, amplitude and the proposed QRS morphology-based markers that were computed by warping techniques. Reference [K+] and [Ca2+] were determined from blood samples acquired at the time points where the markers were estimated. Linear regression models were used to estimate electrolyte levels from the QRS markers individually and in combination with T wave morphology markers. Leave-one-out cross-validation was used to assess the performance of the estimators. Results: All markers, except for QRS width, strongly correlated with [K+] (median Pearson correlation coefficients, r, ranging from 0.81 to 0.87) and with [Ca2+] (r ranging from 0.61 to 0.76). QRS morphology markers showed very low sensitivity to heart rate (HR). Actual and estimated serum electrolyte levels differed, on average, by less than 0.035 mM (relative error of 0.018) for [K+] and 0.010 mM (relative error of 0.004) for [Ca2+] when patient-specific multivariable estimators combining QRS and T wave markers were used. Conclusion: QRS morphological markers allow non-invasive estimation of [K+] and [Ca2+] with low sensitivity to HR. The estimation performance is improved when multivariable models, including T wave markers, are considered. Significance: Markers based on the QRS complex of the ECG could contribute to non-invasive monitoring of serum electrolyte levels and arrhythmia risk prediction in patients with renal diseas

Serum potassium concentration monitoring by ECG time warping analysis on the T wave

This doctoral thesis was developed within the joint Ph.D. program in biomedical engineering at Universitat Politècnica de Catalunya (Barcelona, Spain) and University of Zaragoza (Zaragoza, Spain) in the framework of Doctorats Industrials program co-financed by Laboratorios Rubió S.A. (Castellbisbal, Spain) and Agència de Gestió d’Ajuts Universitaris i de Recerca, Generalitat de Catalunya (Spain). This thesis was performed in partnership with the Nephrology ward from Hospital Clínico Universitario Lozano Blesa (Zaragoza, Spain) and in collaboration with Dr J. Ramírez from the William Harvey Research Institute, Queen Mary University of London (London, UK).End-stage renal disease (ESRD) patients demonstrate an increased incidence of sudden cardiac death (SCD) with declining kidney functioning as a consequence of blood potassium ([K+]) homeostasis impairment, which is restored by hemodialysis (HD) therapy. The clinically established method for the diagnosis of [K+] imbalance is blood tests, an invasive and costly procedure that limits continuous monitoring of ESRD patients. A non-invasive ambulatory index, able to quantify changes in [K+] level is an open issue. In this context, the electrocardiogram (ECG) and in particular, the T wave (TW) morphology, has been shown to be strongly correlated with [K+] imbalance. Therefore, the aim of this dissertation is to investigate and to propose TW-derived markers able to monitor changes in [K+] levels in ESRD patients undergoing HD. For that purpose, the time warping analysis, a technique that allows the comparison and quantification of differences between two different TW shapes, was investigated. The application of TW time warping based markers in monitoring [K+ ] variations (Δ [K+]) and the derivation of a heart-rate corrected marker is proposed and compared with respect to two well-established Δ [K+]-related TW-based indexes. All the markers are evaluated in a single lead approach and after having emphasised the TW energy content through spatial transformation by Principal Component Analysis (PCA). Results demonstrate that the proposed biomarkers outperform the already proposed indexes, also proving that the use of PCA transformed lead generates markers with a higher correlation with Δ [K+] than the single lead approach. The possibility to improve markers robustness in the case of low signal-to-noise ratio ECGs, by spatially transforming the signal maximising the beat-to-beat TW periodicity criteria through the so-called Periodic Component Analysis (pCA), is then explored. pCA-based markers show superior performance during and after the HD than those obtained by PCA suggesting improved stability for continuous Δ [K+] tracking. The thesis studies also the application of regressions models to quantify Δ [K+] from pCA-based time warping markers. The accuracy of the regression models is evaluated by correlation and estimation error between the actual and the corresponding model-estimated Δ [K+] values, and the smallest estimation error is found for quadratic regression models. Being the time warping derived markers sensitive to TW boundary delineation errors, which may endanger their prognostic power, the advantages of using a weighting stage is investigated for their robust computation. The performance of two weighting functions (WF)s is tested and compared with respect to the control no weighting case, in simulated scenarios and in real scenarios (i.e. for [K+] monitoring and SCD risk stratification). No improvements in [K+] monitoring are found, probably due to the considerable marked [K+]-induced TW morphological changes. On the contrary, both simulation tests and SCD risk stratification analysis show that the proposed WFs can enhance the robustness of TW time warping analysis against TW delineation errors. In conclusion, this Doctoral Thesis confirms the hypothesis that enhanced perforce in Δ [K+] tracking and quantification can be achieved by analysing the overall TW morphology by time warping analysis. The simplicity of the technology, together with its low cost and ease of acquisition, should provide a new opportunity for TW analysis to reach standard clinical practice. Moreover, the use of WFs to minimise the undesired effects of TW delineation errors on the computation of time warping markers revealed a noticeable improvement of the SCD risk stratification power of time warping derived indexes.Los pacientes con enfermedad renal en etapa terminal (ESRD) demuestran una mayor incidencia de muerte cardíaca súbita (SCD) tras el deterioro del funcionamiento renal como consecuencia del desequilibrio del potasio ([K+]) en sangre. Este último se restablece mediante la terapia de hemodiálisis (HD). El desequilibrio de [K+] se diagnostica a través del análisis de sangre, un procedimiento invasivo y costoso que limita la monitorización de los pacientes con ESRD. Se necesita un índice ambulatorio no invasivo, capaz de cuantificar los cambios en el nivel de [K+] (Δ [K+]). En este contexto, se ha demostrado que el electrocardiograma (ECG) y en particular la onda T (TW), están correlacionados con Δ [K+]. El objetivo de esta tesis es evaluar marcadores derivados de la TW capaces de monitorizar ¿[K+] en pacientes con ESRD sometidos a HD. Para ello, se aplicó el análisis time warping, una técnica que permite la comparación de dos formas diferentes de TW. En primer lugar, se evalúa la aplicación de marcadores basados en el time warping para el seguimiento de Δ [K+] así como la derivación de un marcador corregido por la frecuencia cardíaca, comparando los marcadores con respecto a dos índices basados en TW bien establecidos y relacionados con Δ [K+]. Todos los marcadores se evalúan en las derivaciones independientes y después de haber enfatizado el contenido de energía de TW a través del Análisis de Componentes Principales (PCA). Los resultados demuestran mejores prestaciones de los marcadores time warping respecto a los ya propuestos y que el uso de PCA genera marcadores con una correlación más alta con Δ [K+] respecto a las derivaciones independientes. A continuación, se explora la posibilidad de mejorar la robustez de los marcadores en el caso de ECG con una relación señal/ruido baja, maximizando la periodicidad de TW latido a latido mediante el Análisisde Componentes Periódicos (pCA). Los marcadores basados en pCA muestran un rendimiento superior durante y después de la HD que los obtenidos por PCA, lo que sugiere una estabilidad mejorada para el seguimiento continuo de Δ [K+]. Luego, se evalúan modelos de regresión para cuantificar [K+] a partir de marcadores basados en pCA. La precisión de los modelos de regresión se evalúa mediante el error de estimación entre valores reales de Δ [K+] y los correspondientes estimados por el modelo. Con el error de estimación más pequeño, el modelo cuadrático es el más adecuado para la cuantificación de [K+].Siendo el análisis time warping sensible a los errores de delineación de los límites de TW, lo que supone un riesgo para su poder pronóstico, se investigan las ventajas de usar una etapa de ponderación para el cálculo de marcadores time warping. El rendimiento de dos funciones de ponderación (WF) se prueba y se compara con respecto al caso de control sin ponderación, en escenarios simulados y en escenarios reales (para el seguimiento de [K+] y la estratificación del riesgo de SCD). No se encontraron mejoras en la monitorización de [K+] debido a los considerables cambios morfológicos de TW inducidos por Δ [K+]. Por otro lado, tanto las pruebas de simulación como el análisis de estratificación de riesgo de SCD muestran que los WF propuestos pueden mejorar la robustez del análisis time warping de TW contra los errores dedelineación de TW. En conclusión, esta tesis doctoral confirma la hipótesis de que se puede lograr un mejor seguimiento y cuantificación de Δ [K+] mediante el análisis de la morfología de TW mediante el análisis time warping. La simplicidad de la tecnología, junto con su bajo costo y facilidad de adquisición del ECG, debería brindar una nueva oportunidad para que el análisis de TW en la práctica clínica rutinaria. Además, el uso de WF para minimizar los efectos no deseados de errores de delineación de TW en el cálculo de los marcadores time warping reveló una mejora del poder de estratificación del riesgoPostprint (published version

Serum potassium concentration monitoring by ECG time warping analysis on the T wave

This doctoral thesis was developed within the joint Ph.D. program in biomedical engineering at Universitat Politècnica de Catalunya (Barcelona, Spain) and University of Zaragoza (Zaragoza, Spain) in the framework of Doctorats Industrials program co-financed by Laboratorios Rubió S.A. (Castellbisbal, Spain) and Agència de Gestió d’Ajuts Universitaris i de Recerca, Generalitat de Catalunya (Spain). This thesis was performed in partnership with the Nephrology ward from Hospital Clínico Universitario Lozano Blesa (Zaragoza, Spain) and in collaboration with Dr J. Ramírez from the William Harvey Research Institute, Queen Mary University of London (London, UK).End-stage renal disease (ESRD) patients demonstrate an increased incidence of sudden cardiac death (SCD) with declining kidney functioning as a consequence of blood potassium ([K+]) homeostasis impairment, which is restored by hemodialysis (HD) therapy. The clinically established method for the diagnosis of [K+] imbalance is blood tests, an invasive and costly procedure that limits continuous monitoring of ESRD patients. A non-invasive ambulatory index, able to quantify changes in [K+] level is an open issue. In this context, the electrocardiogram (ECG) and in particular, the T wave (TW) morphology, has been shown to be strongly correlated with [K+] imbalance. Therefore, the aim of this dissertation is to investigate and to propose TW-derived markers able to monitor changes in [K+] levels in ESRD patients undergoing HD. For that purpose, the time warping analysis, a technique that allows the comparison and quantification of differences between two different TW shapes, was investigated. The application of TW time warping based markers in monitoring [K+ ] variations (Δ [K+]) and the derivation of a heart-rate corrected marker is proposed and compared with respect to two well-established Δ [K+]-related TW-based indexes. All the markers are evaluated in a single lead approach and after having emphasised the TW energy content through spatial transformation by Principal Component Analysis (PCA). Results demonstrate that the proposed biomarkers outperform the already proposed indexes, also proving that the use of PCA transformed lead generates markers with a higher correlation with Δ [K+] than the single lead approach. The possibility to improve markers robustness in the case of low signal-to-noise ratio ECGs, by spatially transforming the signal maximising the beat-to-beat TW periodicity criteria through the so-called Periodic Component Analysis (pCA), is then explored. pCA-based markers show superior performance during and after the HD than those obtained by PCA suggesting improved stability for continuous Δ [K+] tracking. The thesis studies also the application of regressions models to quantify Δ [K+] from pCA-based time warping markers. The accuracy of the regression models is evaluated by correlation and estimation error between the actual and the corresponding model-estimated Δ [K+] values, and the smallest estimation error is found for quadratic regression models. Being the time warping derived markers sensitive to TW boundary delineation errors, which may endanger their prognostic power, the advantages of using a weighting stage is investigated for their robust computation. The performance of two weighting functions (WF)s is tested and compared with respect to the control no weighting case, in simulated scenarios and in real scenarios (i.e. for [K+] monitoring and SCD risk stratification). No improvements in [K+] monitoring are found, probably due to the considerable marked [K+]-induced TW morphological changes. On the contrary, both simulation tests and SCD risk stratification analysis show that the proposed WFs can enhance the robustness of TW time warping analysis against TW delineation errors. In conclusion, this Doctoral Thesis confirms the hypothesis that enhanced perforce in Δ [K+] tracking and quantification can be achieved by analysing the overall TW morphology by time warping analysis. The simplicity of the technology, together with its low cost and ease of acquisition, should provide a new opportunity for TW analysis to reach standard clinical practice. Moreover, the use of WFs to minimise the undesired effects of TW delineation errors on the computation of time warping markers revealed a noticeable improvement of the SCD risk stratification power of time warping derived indexes.Los pacientes con enfermedad renal en etapa terminal (ESRD) demuestran una mayor incidencia de muerte cardíaca súbita (SCD) tras el deterioro del funcionamiento renal como consecuencia del desequilibrio del potasio ([K+]) en sangre. Este último se restablece mediante la terapia de hemodiálisis (HD). El desequilibrio de [K+] se diagnostica a través del análisis de sangre, un procedimiento invasivo y costoso que limita la monitorización de los pacientes con ESRD. Se necesita un índice ambulatorio no invasivo, capaz de cuantificar los cambios en el nivel de [K+] (Δ [K+]). En este contexto, se ha demostrado que el electrocardiograma (ECG) y en particular la onda T (TW), están correlacionados con Δ [K+]. El objetivo de esta tesis es evaluar marcadores derivados de la TW capaces de monitorizar ¿[K+] en pacientes con ESRD sometidos a HD. Para ello, se aplicó el análisis time warping, una técnica que permite la comparación de dos formas diferentes de TW. En primer lugar, se evalúa la aplicación de marcadores basados en el time warping para el seguimiento de Δ [K+] así como la derivación de un marcador corregido por la frecuencia cardíaca, comparando los marcadores con respecto a dos índices basados en TW bien establecidos y relacionados con Δ [K+]. Todos los marcadores se evalúan en las derivaciones independientes y después de haber enfatizado el contenido de energía de TW a través del Análisis de Componentes Principales (PCA). Los resultados demuestran mejores prestaciones de los marcadores time warping respecto a los ya propuestos y que el uso de PCA genera marcadores con una correlación más alta con Δ [K+] respecto a las derivaciones independientes. A continuación, se explora la posibilidad de mejorar la robustez de los marcadores en el caso de ECG con una relación señal/ruido baja, maximizando la periodicidad de TW latido a latido mediante el Análisisde Componentes Periódicos (pCA). Los marcadores basados en pCA muestran un rendimiento superior durante y después de la HD que los obtenidos por PCA, lo que sugiere una estabilidad mejorada para el seguimiento continuo de Δ [K+]. Luego, se evalúan modelos de regresión para cuantificar [K+] a partir de marcadores basados en pCA. La precisión de los modelos de regresión se evalúa mediante el error de estimación entre valores reales de Δ [K+] y los correspondientes estimados por el modelo. Con el error de estimación más pequeño, el modelo cuadrático es el más adecuado para la cuantificación de [K+].Siendo el análisis time warping sensible a los errores de delineación de los límites de TW, lo que supone un riesgo para su poder pronóstico, se investigan las ventajas de usar una etapa de ponderación para el cálculo de marcadores time warping. El rendimiento de dos funciones de ponderación (WF) se prueba y se compara con respecto al caso de control sin ponderación, en escenarios simulados y en escenarios reales (para el seguimiento de [K+] y la estratificación del riesgo de SCD). No se encontraron mejoras en la monitorización de [K+] debido a los considerables cambios morfológicos de TW inducidos por Δ [K+]. Por otro lado, tanto las pruebas de simulación como el análisis de estratificación de riesgo de SCD muestran que los WF propuestos pueden mejorar la robustez del análisis time warping de TW contra los errores dedelineación de TW. En conclusión, esta tesis doctoral confirma la hipótesis de que se puede lograr un mejor seguimiento y cuantificación de Δ [K+] mediante el análisis de la morfología de TW mediante el análisis time warping. La simplicidad de la tecnología, junto con su bajo costo y facilidad de adquisición del ECG, debería brindar una nueva oportunidad para que el análisis de TW en la práctica clínica rutinaria. Además, el uso de WF para minimizar los efectos no deseados de errores de delineación de TW en el cálculo de los marcadores time warping reveló una mejora del poder de estratificación del riesgoEnginyeria biomèdic

Chronic kidney disease and arrhythmias: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Patients with chronic kidney disease (CKD) are predisposed to heart rhythm disorders, including atrial fibrillation (AF)/atrial flutter, supraventricular tachycardias, ventricular arrhythmias, and sudden cardiac death (SCD). While treatment options, including drug, device, and procedural therapies, are available, their use in the setting of CKD is complex and limited. Patients with CKD and end-stage kidney disease (ESKD) have historically been under-represented or excluded from randomized trials of arrhythmia treatment strategies,1 although this situation is changing.2 Cardiovascular society consensus documents have recently identified evidence gaps for treating patients with CKD and heart rhythm disorders [...

Monitoring of Serum Potassium and Calcium Levels in End-Stage Renal Disease Patients by ECG Depolarization Morphology Analysis

International audienceObjective: Non-invasive estimation of serum potassium, [K + ], and calcium, [Ca 2+ ], can help to prevent life-threatening ventricular arrhythmias in patients with advanced renal disease, but current methods for estimation of electrolyte levels have limitations. We aimed to develop new markers based on the morphology of the QRS complex of the electrocardiogram (ECG). Methods: ECG recordings from 29 patients undergoing hemodialysis (HD) were processed. Mean warped QRS complexes were computed in two-minute windows at the start of an HD session, at the end of each HD hour and 48 h after it. We quantified QRS width, amplitude and the proposed QRS morphology-based markers that were computed by warping techniques. Reference [K + ] and [Ca 2+ ] were determined from blood samples acquired at the time points where the markers were estimated. Linear regression models were used to estimate electrolyte levels from the QRS markers individually and in combination with T wave morphology markers. Leave-one-out cross-validation was used to assess the performance of the estimators. Results: All markers, except for QRS width, strongly correlated with [K + ] (median Pearson correlation coefficients, r, ranging from 0.81 to 0.87) and with [Ca 2+ ] (r ranging from 0.61 to 0.76). QRS morphology markers showed very low sensitivity to heart rate (HR). Actual and estimated serum electrolyte levels differed, on average, by less than 0.035 mM (relative error of 0.018) for [K + ] and 0.010 mM (relative error of 0.004) for [Ca 2+ ] when patient-specific multivariable estimators combining QRS and T wave markers were used. Conclusion: QRS morphological markers allow non-invasive estimation of [K + ] and [Ca 2+ ] with low sensitivity to HR. The estimation performance is improved when multivariable models, including T wave markers, are considered. Significance: Markers based on the QRS complex of the ECG could contribute to non-invasive monitoring of serum electrolyte levels and arrhythmia risk prediction in patients with renal disease

Clinical Management of Hyperkalemia

© 2020 Mayo Foundation for Medical Education and Research Hyperkalemia is an electrolyte abnormality with potentially life-threatening consequences. Despite various guidelines, no universally accepted consensus exists on best practices for hyperkalemia monitoring, with variations in precise potassium (K+) concentration thresholds or for the management of acute or chronic hyperkalemia. Based on the available evidence, this review identifies several critical issues and unmet needs with regard to the management of hyperkalemia. Real-world studies are needed for a better understanding of the prevalence of hyperkalemia outside the clinical trial setting. There is a need to improve effective management of hyperkalemia, including classification and K+ monitoring, when to reinitiate previously discontinued renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, and when to use oral K+-binding agents. Monitoring serum K+ should be individualized; however, increased frequency of monitoring should be considered for patients with chronic kidney disease, diabetes, heart failure, or a history of hyperkalemia and for those receiving RAASi therapy. Recent clinical studies suggest that the newer K+ binders (patiromer sorbitex calcium and sodium zirconium cyclosilicate) may facilitate optimization of RAASi therapy. Enhancing the knowledge of primary care physicians and internists with respect to the safety profiles of these newer K+ binders may increase confidence in managing patients with hyperkalemia. Lastly, the availability of newer K+-binding agents requires further study to establish whether stringent dietary K+ restrictions are needed in patients receiving K+-binder therapy. Individualized monitoring of serum K+ among patients with an increased risk of hyperkalemia and the use of newer K+-binding agents may allow for optimization of RAASi therapy and more effective management of hyperkalemia

Estimation of Serum Potassium and Calcium Concentrations from Electrocardiographic Depolarization and Repolarization Waveforms

Chronic kidney disease (CKD), a condition defined by a gradual decline in kidney function over time, has become a global health concern affecting between 11 and 13% of the world population [1]. As renal function declines, CKD patients gradually lose their ability to maintain normal values of potassium concentration ([K+]) in their blood. Elevated serum [K+], known as hyperkalemia, increases the risk for life-threatening arrhythmias and sudden cardiac death [2].An increase in serum [K+] outside the physiological range is commonly silent and is only detected when hyperkalemia is already very severe or when a blood test is performed. Maintenance and monitoring of [K+] in the blood is an important component in the treatment of CKD patients because therapies for hyperkalemia management in CKD patients are designed to prevent arrhythmias and to immediately lower serum [K+] to safe ranges. However, this is currently only possible by taking a blood sample and is associated with a long analysis time. Therefore it is useful to have a simple, noninvasive method to estimate serum [K+], particularly using the electrocardiogram (ECG). Indeed, variations in serum electrolyte levels have been shown to alter the electrical behavior of the heart and to induce changes in the ECG [3¿6]. However, large inter-individual variability existsin the relationship between ion concentrations and ECG features. Previous attempts to estimate serum [K+] from the ECG have therefore shown limitations [7¿9], such as not being applicable to some common types of ECG waveforms or relying on specific ECG characteristics that may present large variations not necessarily associated with hyperkalemia.The aim of this thesis is to develop novel estimates of serum [K+] that are robust enough to detect hypokalemia (reduced [K+]) or hyperkalemia in a timely manner to provide life-saving treatment. Additionally, the effect of changes in other electrolyte levels, like calcium concentration ([Ca2+]), and in heart rate are investigated. These aims are achieved by combining novel ECG signal processing techniques with in silico modeling and simulation of cardiac electrophysiology.The specific objectives are:1. Characterization of hypokalemia or hyperkalemia and hypocalcemia (reduced [Ca2+]) or hypercalcemia (elevated [Ca2+])-induced changes in ventricular repolarization from ECGs (T wave) of CKD patients. This is addressed in chapter 3 and chapter 4. In these chapters, we describe how T waves are extracted from ECGs and how we characterize changes in T waves at varying potassium, calcium and heart rate using analyses based on time warping and Lyapunov exponents. Next, univariable and multivariable regression models including markers of T wave nonlinear dynamics in combination with warping-based markers of T wave morphology are built and their performance for [K+] estimation is assessed.2. Characterization of hypo- or hyperkalemia and hypo- or hypercalcemia-induced changes in ventricular depolarization from the QRS complex of CKD patients. This is reported in chapter 5. In this chapter, we present how QRS complexes from ECGs of CKD patients are processed and how we measure changes at varying [K+], [Ca2+] and heart rate. Univariate and multivariate regression analyses including novel QRS morphological markers in combination with T wave morphological markers are performed to assess the contribution of depolarization and repolarization features for electrolyte monitoring in CKD patients.3. Identification of potential sources underlying inter-individual variability in ECG markers in response to changes in [K+] and [Ca2+]. In silico investigations of cardiac electrophysiology are conducted and ECG features are computed. Simulation results are compared with patient data. This is explained in chapter 3 using one-dimensional (1D) fibers and in chapter 6 using three-dimensional (3D) human heart-torso models. Chapter 6 includes the development of a population of realistic computational models of human ventricular electrophysiology, based on human anatomy and electrophysiology, to better understand how changes in individual characteristics influence the ECG (QRS and T wave) markers that we introduced in previous chapters. ECG waveforms are characterized by their amplitude, duration and morphology. Simulations are performed with the most realistic available techniques to model the electrophysiology of the heart and the resulting ECG. We establish mechanisms that contribute to inter-individual differences in the characterized ECG features.In conclusion, we identify several markers of ECG morphology, including depolarization and repolarization features, that are highly correlated with serum electrolyte (potassium and calcium) concentrations. ECG morphological variability markers vary significantly with [K+] and [Ca2+] in both simulated and measured ECGs, with a wide range of patterns observed for such relationships. The proportions of endocardial, midmyocardial and epicardial cells have a large impact on ECG markers, particularly for serum electrolyte concentrations out of their physiological levels. This suggests that transmural heterogeneities can modulate ECG responses to changes in electrolyte concentrations in CKD patients. Agreement between actual potassium and calcium levels and their estimates derived from the ECG is promising, with lower average errors than previously proposed markers in the literature. These findings can have major relevance for noninvasive monitoring of serum electrolyte levels and prediction of arrhythmic events in these patients.<br /