Atrial fibrosis identification with unipolar electrogram eigenvalue distribution analysis in multi-electrode arrays

Atrial fbrosis plays a key role in the initiation and progression of atrial fbrillation (AF). Atrial fbrosis is typically identifed by a peak-to-peak amplitude of bipolar electrograms (b-EGMs) lower than 0.5 mV, which may be considered as ablation targets. Nevertheless, this approach disregards signal spatiotemporal information and b-EGM sensitivity to catheter orientation. To overcome these limitations, we propose the dominant-to-remaining eigenvalue dominance ratio (EIGDR) of unipolar electrograms (u-EGMs) within neighbor electrode cliques as a waveform dispersion measure, hypothesizing that it is correlated with the presence of fbrosis. A simulated 2D tissue with a fbrosis patch was used for validation. We computed EIGDR maps from both original and time-aligned u-EGMs, denoted as R and RA, respectively, also mapping the gain in eigenvalue concentration obtained by the alignment, ΔRA. The performance of each map in detecting fbrosis was evaluated in scenarios including noise and variable electrode-tissue distance. Best results were achieved by RA, reaching 94% detection accuracy, versus the 86% of b-EGMs voltage maps. The proposed strategy was also tested in real u-EGMs from fbrotic and non-fbrotic areas over 3D electroanatomical maps, supporting the ability of the EIGDRs as fbrosis markers, encouraging further studies to confrm their translation to clinical settings

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

Psychosomatic response to acute emotional stress in healthy students

The multidimensionality of the stress response has shown the complexity of this phenomenon and therefore the impossibility of finding a unique biomarker among the physiological variables related to stress. An experimental study was designed and performed to guarantee the correct synchronous and concurrent measure of psychometric tests, biochemical variables and physiological features related to acute emotional stress. The population studied corresponds to a group of 120 university students between 20 and 30 years of age, with healthy habits and without a diagnosis of chronic or psychiatric illnesses. Following the protocol of the experimental pilot, each participant reached a relaxing state and a stress state in two sessions of measurement for equivalent periods. Both states are correctly achieved evidenced by the psychometric test results and the biochemical variables. A Stress Reference Scale is proposed based on these two sets of variables. Then, aiming for a non-invasive and continuous approach, the Acute Stress Model correlated to the previous scale is also proposed, supported only by physiological signals. Preliminary results support the feasibility of measuring/quantifying the stress level. Although the results are limited to the population and stimulus type, the procedure and methodological analysis used for the assessment of acute stress in young people can be extrapolated to other populations and types of stress

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 /

In Silico Investigation into Cellular Mechanisms of Cardiac Alternans in Myocardial Ischemia

Myocardial ischemia is associated with pathophysiological conditions such as hyperkalemia, acidosis, and hypoxia. These physiological disorders may lead to changes on the functions of ionic channels, which in turn form the basis for cardiac alternans. In this paper, we investigated the roles of hyperkalemia and calcium handling components played in the genesis of alternans in ischemia at the cellular level by using computational simulations. The results show that hyperkalemic reduced cell excitability and delayed recovery from inactivation of depolarization currents. The inactivation time constant τf of L-type calcium current (ICaL) increased obviously in hyperkalemia. One cycle length was not enough for ICaL to recover completely. Alternans developed as a result of ICaL responding to stimulation every other beat. Sarcoplasmic reticulum calcium-ATPase (SERCA2a) function decreased in ischemia. This change resulted in intracellular Ca (Cai) alternans of small magnitude. A strong Na+-Ca2+ exchange current (INCX) increased the magnitude of Cai alternans, leading to APD alternans through excitation-contraction coupling. Some alternated repolarization currents contributed to this repolarization alternans

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

Cardiac cells stimulated with an axial current-like waveform reproduce electrophysiological properties of tissue fibers

Background and objective: In silico electrophysiological models are generally validated by comparing simulated results with experimental data. When dealing with single-cell and tissue scales simultaneously, as occurs frequently during model development and calibration, the effects of inter-cellular coupling should be considered to ensure the trustworthiness of model predictions. The hypothesis of this paper is that the cell-tissue mismatch can be reduced by incorporating the effects of conduction into the single-cell stimulation current. Methods: Five different stimulation waveforms were applied to the human ventricular O'Hara-Rudy cell model. The waveforms included the commonly used monophasic and biphasic (symmetric and asymmetric) pulses, a triangular waveform and a newly proposed asymmetric waveform (stimulation A) that resembles the transmembrane current associated with AP conduction in tissue. A comparison between single-cell and fiber simulated results was established by computing the relative difference between the values of AP-derived properties at different scales, and by evaluating the differences in the contributions of ionic conductances to each evaluated property. As a proof of the benefit, we investigated multi-scale differences in the simulation of the effects induced by dofetilide, a selective IKr blocker with high torsadogenic risk, on ventricular repolarization at different pacing rates. Results: Out of the five tested stimulation waveforms, stimulation A produced the closest correspondence between cell and tissue simulations in terms of AP properties at steady-state and under dynamic pacing and of ionic contributors to those AP properties. Also, stimulation A reproduced the effects of dofetilide better than the other alternative waveforms, mirroring the ’beat-skipping’ behavior observed at fast pacing rates in experiments with human tissue. Conclusions: The proposed stimulation current waveform accounts for inter-cellular coupling effects by mimicking cell excitation during AP conduction. The proposed waveform improves the correspondence between simulation scales, which could improve the trustworthiness of single-cell simulations without adding computational cost. © 202

Electro-mechanical whole-heart digital twins: A fully coupled multi-physics approach

Mathematical models of the human heart are evolving to become a cornerstone of precision medicine and support clinical decision making by providing a powerful tool to understand the mechanisms underlying pathophysiological conditions. In this study, we present a detailed mathematical description of a fully coupled multi-scale model of the human heart, including electrophysiology, mechanics, and a closed-loop model of circulation. State-of-the-art models based on human physiology are used to describe membrane kinetics, excitation-contraction coupling and active tension generation in the atria and the ventricles. Furthermore, we highlight ways to adapt this framework to patient specific measurements to build digital twins. The validity of the model is demonstrated through simulations on a personalized whole heart geometry based on magnetic resonance imaging data of a healthy volunteer. Additionally, the fully coupled model was employed to evaluate the effects of a typical atrial ablation scar on the cardiovascular system. With this work, we provide an adaptable multi-scale model that allows a comprehensive personalization from ion channels to the organ level enabling digital twin modeling