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

T-wave morphology restitution in chronic heart failure patient with atrial fibrillation

Chronic heart failure (CHF) represents one of the major public health problems that often end in sudden cardiac death (SCD). Atrial fibrillation (AF) is associated withan increased risk of SCD but nowadays there is no non-invasive method that accurately predicts that risk. The recently developed T-wave morphology restitution (TMR) index showed its specific association with SCD risk prediction in sinus rhythm subjects with CHF. The aim of this work was to investigate the SCD predictive value of this index in individuals with AF. TMR was computed from 171 24-hour ECG Holter recordings from CHF patients enrolled in the “MUerte Súbita en Insuficiencia Cardiaca”study with AF. There were 19 SCD victims after the 4 years’follow-up. The Mann–Whitney U test showed that TMR was not significantly different in SCD victims as compared to survivors (p=0.617). However, this might be due to the huge gap in sample size betweenbothpopulations. Assuming a balanced case-control scenario, the TMR value distribution mayapproach to a normal distribution. Under this hypothesis, the t-test was performed under the condition of unequal variances between both populations, showinga significant difference in TMR between bothgroups (p=0.023). In conclusion, the predictive power of TMR index in AF rhythm should not be excluded, but it needs a more in-depth studyPeer ReviewedPostprint (published version

Estimation of potassium levels in hemodialysis patients by T wave nonlinear dynamics and morphology markers

Noninvasive screening of hypo- and hyperkalemia can prevent fatal arrhythmia in end-stage renal disease (ESRD) patients, but current methods for monitoring of serum potassium (K+) have important limitations. We investigated changes in nonlinear dynamics and morphology of the T wave in the electrocardiogram (ECG) of ESRD patients during hemodialysis (HD), assessing their relationship with K+ and designing a K+ estimator. Methods: ECG recordings from twenty-nine ESRD patients undergoing HD were processed. T waves in 2-min windows were extracted at each hour during an HD session as well as at 48 h after HD start. T wave nonlinear dynamics were characterized by two indices related to the maximum Lyapunov exponent (¿t, ¿wt) and a divergence-related index (¿). Morphological variability in the T wave was evaluated by three time warping-based indices (dw, reflecting morphological variability in the time domain, and da and daNL, in the amplitude domain). K+was measured from blood samples extracted during and after HD. Stage-specific and patient-specific K+ estimators were built based on the quantified indices and leave-one-out cross-validation was performed separately for each of the estimators. Results: The analyzed indices showed high inter-individual variability in their relationship with K+. Nevertheless, all of them had higher values at the HD start and 48 h after it, corresponding to the highest K+. The indices ¿ and dw were the most strongly correlated with K+ (median Pearson correlation coefficient of 0.78 and 0.83, respectively) and were used in univariable and multivariable linear K+ estimators. Agreement between actual and estimated K+ was confirmed, with averaged errors over patients and time points being 0.000 ± 0.875 mM and 0.046 ± 0.690 mM for stage-specific and patient-specific multivariable K+ estimators, respectively.ariability allow noninvasive monitoring of [K+] in ESRD patients. Significance: ECG markers have the potential to be used for hypo- and hyperkalemia screening in ESRD patient

Characterization of t wave amplitude, duration and morphology changes during hemodialysis: Relationship with serum electrolyte levels and heart rate

Objective: Chronic kidney disease affects more than 10% of the world population. Changes in serum ion concentrations increase the risk for ventricular arrhythmias and sudden cardiac death, particularly in end stage renal disease (ESRD) patients. We characterized how T wave amplitude, duration and morphology descriptors change with variations in serum levels of potassium and calcium and in heart rate, both in ESRD patients and in simulated ventricular fibers. Methods: Electrocardiogram (ECG) recordings from twenty ESRD patients undergoing hemodialysis (HD) and pseudo-ECGs (pECGs) calculated from twenty-two simulated ventricular fibers at varying transmural heterogeneity levels were processed to quantify T wave width (Tw), T wave slope-to-amplitude ratio (TS/A) and four indices of T wave morphological variability based on time warping (dw, dNLw, da and dNLa). Serum potassium and calcium levels and heart rate were measured along HD. Results: dNL with serum potassium, dw with calcium and da with heart rate, after correction for covariates. Median values of partial correlation coefficients were 0.75,−0.74 and −0.90, respectively. For all analyzed T wave descriptors, high inter-patient variability was observed in the pattern of such relationships. This variability, accentuated during the first HD time points, was reproduced in the simulations and shown to be influenced by differences in transmural heterogeneity. Conclusion: Changes in serum potassium and calcium levels and in heart rate strongly affect T wave descriptors, particularly those quantifying morphological variability. Significance: ECG markers have the potential to be used for monitoring serum ion concentrations in ESRD patients

ECG-based monitoring of blood potassium concentration: Periodic versus principal component as lead transformation for biomarker robustness

Objective: The aim of this study is to compare the performance of two electrocardiogram (ECG) lead-space reduction (LSR) techniques in generating a transformed ECG lead from which T-wave morphology markers can be reliably derived to non-invasively monitor blood potassium concentration ([K+]) in end-stage renal disease (ESRD) patients undergoing hemodialysis (HD). These LSR techniques are: (1) principal component analysis (PCA), learned on the T wave, and (2) periodic component analysis (πCA), either learned on the whole QRST complex (πCB) or on the T wave (πCT). We hypothesized πCA is less sensitive to non-periodic disturbances, like noise and body position changes (BPC), than PCA, thus leading to more reliable T wave morphology markers. Methods: We compared the ability of T wave morphology markers obtained from PCA, πCB and πCT in tracking [K+] in an ESRD-HD dataset, including 29 patients, during and after HD (evaluated by correlation and residual fitting error analysis). We also studied their robustness to BPC using an annotated database, including 20 healthy individuals, as well as to different levels of noise using a simulation set-up (assessed by means of Mann–Whitney U test and relative error, respectively). Results: The performance of both πCB and πCT-based markers in following [K+]-variations during HD was comparable, and superior to that from PCA-based markers. Moreover, πCT-based markers showed superior robustness against BPC and noise. Conclusion: Both πCB and πCT outperform PCA in terms of monitoring [K+] in ESRD-HD patients, as well as of robustness against BPC and low SNR, with πCT showing the highest stability for continuous post-HD monitoring. Significance: The usage of πCA (i) increases the accuracy in monitoring dynamic [K+] variations in ESRD-HD patients and (ii) reduces the sensitivity to BPC and noise in deriving T wave morphology markers. © 2021 The Author(s

Evaluation of Novel Guanidino-Containing Isonipecotamide Inhibitors of Blood Coagulation Factors against SARS-CoV-2 Virus Infection

Coagulation factor Xa (fXa) and thrombin (thr) are widely expressed in pulmonary tissues, where they may catalyze, together with the transmembrane serine protease 2 (TMPRSS2), the coronaviruses spike protein (SP) cleavage and activation, thus enhancing the SP binding to ACE2 and cell infection. In this study, we evaluate in vitro the ability of approved (i.e., dabigatran and rivaroxaban) and newly synthesized isonipecotamide-based reversible inhibitors of fXa/thr (cmpds 1-3) to hinder the SARS-CoV-2 infectivity of VERO cells. Nafamostat, which is a guanidine/amidine antithrombin and antiplasmin agent, disclosed as a covalent inhibitor of TMPRSS2, was also evaluated. While dabigatran and rivaroxaban at 100 mu M concentration did not show any effect on SARS-CoV-2 infection, the virus preincubation with new guanidino-containing fXa-selective inhibitors 1 and 3 did decrease viral infectivity of VERO cells at subtoxic doses. When the cells were pre-incubated with 3, a reversible nanomolar inhibitor of fXa (K-i = 15 nM) showing the best in silico docking score toward TMPRSS2 (pdb 7MEQ), the SARS-CoV-2 infectivity was completely inhibited at 100 mu M (p < 0.0001), where the cytopathic effect was just about 10%. The inhibitory effects of 3 on SARS-CoV-2 infection was evident (ca. 30%) at lower concentrations (3-50 mu M). The covalent TMPRSS2 and the selective inhibitor nafamostat mesylate, although showing some effect (15-20% inhibition), did not achieve statistically significant activity against SARS-CoV-2 infection in the whole range of test concentrations (3-100 mu M). These findings suggest that direct inhibitors of the main serine proteases of the blood coagulation cascade may have potential in SARS-CoV-2 drug discovery. Furthermore, they prove that basic amidino-containing fXa inhibitors with a higher docking score towards TMPRSS2 may be considered hits for optimizing novel small molecules protecting guest cells from SARS-CoV-2 infection

“Time-Warping” ponderado sobre la onda T para reducir el impacto de errores de delineación: implicaciones clínicas

La morfología de la onda T (TW) se ha investigado para desarrollar marcadores de predicción de riesgo arrítmico específicos como ¿¿¿¿, que cuantifica el nivel de “warping” necesario para alinear temporalmente una TW con respecto a otra de referencia a diferente ritmo cardiaco. Sin embargo, los errores de delineación de los límites de la TW pueden poner en peligro la capacidad de diagnóstico de ¿¿¿¿. Por lo tanto, se han propuesto dos funciones de ponderación (WF) a partir de (i) la TW de referencia (¿¿) y (ii) el valor absoluto de su primera derivada (¿¿). Se simularon errores de delineación desplazando los límites de dos TW diferentes. Se calculó el ratio de variación (R), comparando ¿¿¿¿ derivado, aplicando las dos WF con el obtenido en el caso sin ponderación (¿¿). Luego, se comparó la capacidad de ¿¿¿¿, con y sin WF, para monitorizar cambios en la concentración de potasio en sangre (¿[¿¿+]) mediante la correlación de Pearson (r) en 29 registros Holter de 48 horas de pacientes durante hemodiálisis (HD). Las simulaciones mostraron que los valores de R para las dos TW fueron, respectivamente, 0,17 y 0,19 para ¿¿, 0,05 y 0,08 para ¿¿ y 0,07 y 0,10 para ¿¿. Sin embargo, se encontraron valores similares de mediana r [rango intercuartílico] para ¿¿ (0.90 [0.27]), ¿¿ (0.90 [0.25]) y ¿¿ (0,90 [0,29]) en el caso de HD. En conclusión, el uso de WF puede disminuir los efectos de los errores de delineación de las TW, aunque no se hallaron mejoras significativas en la monitorización de ¿[¿¿+].Peer ReviewedPostprint (published version

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p < 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p < 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p < 0.0001) or urgent (20.4% vs. 38.5%; p < 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p < 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice