Na/K pump regulation of cardiac repolarization: Insights from a systems biology approach

The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the Systems Biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most\ud important ionic mechanisms in regulating key properties of cardiac repolarization and its rate-dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies

A dual adaptive explicit time integration algorithm for efficiently solving the cardiac monodomain equation

The monodomain model is widely used in in-silico cardiology to describe excitation propagation in the myocardium. Frequently, operator splitting is used to decouple the stiff reaction term and the diffusion term in the monodomain model so that they can be solved separately. Commonly, the diffusion term is solved implicitly with a large time step while the reaction term is solved by using an explicit method with adaptive time stepping. In this work, we propose a fully explicit method for the solution of the decoupled monodomain model. In contrast to semi-implicit methods, fully explicit methods present lower memory footprint and higher scalability. However, such methods are only conditionally stable. We overcome the conditional stability limitation by proposing a dual adaptive explicit method in which adaptive time integration is applied for the solution of both the reaction and diffusion terms. We perform a set of numerical examples where cardiac propagation is simulated under physiological and pathophysiological conditions. Results show that the proposed method presents preserved accuracy and improved computational efficiency as compared to standard operator splitting-based methods. © 2021 John Wiley & Sons Ltd

Melatonin to rescue the aged heart: antiarrhythmic and antioxidant benefits

Aging comes with gradual loss of functions that increase the vulnerability to disease, senescence, and death. The mechanisms underlying these processes are linked to a prolonged imbalance between damage and repair. Damaging mechanisms include oxidative stress, mitochondrial dysfunction, chronodisruption, inflammation, and telomere attrition, as well as genetic and epigenetic alterations. Several endogenous tissue repairing mechanisms also decrease. These alterations associated with aging affect the entire organism. The most devastating manifestations involve the cardiovascular system and may lead to lethal cardiac arrhythmias. Together with structural remodeling, electrophysiological and intercellular communication alterations during aging predispose to arrhythmic events. Despite the knowledge on repairing mechanisms in the cardiovascular system, effective antiaging strategies able to reduce the risk of arrhythmias are still missing. Melatonin is a promising therapeutic candidate due to its pleiotropic actions. This indoleamine regulates chronobiology and endocrine physiology. Of relevance, melatonin is an antiaging, antioxidant, antiapoptotic, antiarrhythmic, immunomodulatory, and antiproliferative molecule. This review focuses on the protective effects of melatonin on age-induced cardiac functional and structural alterations, potentially becoming a new fountain of youth for the heart

Sedimentology and paleontology of the lower member of the Nogueras Fm (Lower Devonian) at Santa Cruz de Nogueras (Teruel, NE Spain)

An integrated sedimentological and paleontological analysis has been canted out in the lower member (d2a) of the shallow-marine Nogueras Formation (Lower Devonian, Iberian Chains). This formation represents the first carbonate-dominated and fossil-rich sedimentary unit of the Devonian of the Iberian Chains. Nine sedimentary facies, including terrigenous-clastic, mixed and carbonate facies, which are complexly intercalated at bed scale, have been characterized. Based on their sedimentary features and their lateral relationships using Markov chain analysis, two sedimentary models for the lower and upper part of d2a member have been proposed, which represent deposition in a mixed elastic-carbonate shallow marine depositional system. They include terrigenous-clastic intertidal deposits and predominant skeletal, carbonate-dominated and grain-supported facies in the high-energy shallow subtidal zone, whith a clear zonation of the skeletal components (brachiopods, bryozoans and crinoids, from shallow to relatively deep areas). Phosphate nodules, phosphatized fossils, ferruginous crusts and iron ooids, which are frequently associated with the relatively shallower bioclastic brachiopod facies, were probably linked to mineral continental sources and to remobilization in the shallow water high-energy area. The paleontological analysis shows that some of those organisms lived in protected areas of the subtidal zone, including in particular high-diversity communities of brachiopods, adapted to turbid waters with fine terrigenous suspended sediments. Se ha realizado un análisis sedimentológico y paleontológico integrado del miembro inferior (d2a) de la Formación Nogueras, que representa la primera unidad marina somera predominantemente carbonatada del Devónico de las Cadenas Ibéricas. Se han definido nueve facies sedimentarias tcrrígeno-clás ticas, mixtas y carbonatadas, que están complejamente intercaladas a escala de capa, depositadas en un sistema mixto de- trítico-carbonatado de aguas someras. En Junción de sus rasgos sedimentarios y del análisis de sus relaciones laterales mediante cadenas de Markov, se proponen dos modelos sedimentarios para la parte inferior y superior del miembro estudiado. Los dos modelos incluyen depósitos terrígenos en la zona intermareal y facies carbonatadas bioclásticas en la zona submareal somera, con una clara zonación de sus componentes esqueléticos dominantes (braquiópodos, briozoos, crinoides, desde la zona somera a la relativamente profunda). Los nodulos de fosfato, fósiles fósfatizados, costras y ooides ferruginosas frecuentes en las facies bioclasticas de braquiópodos relativamente someras, se relacionaron probablemente con aportes minerales desde el continente y retrabajamiento en la zona marina de alta energía. El análisis paleontológico muestra que algunos de estos organismos vivían en áreas protegidas de la zona submareal, incluyendo particularmente comunidades con alta diversidad de braquiópodos, adaptadas a aguas turbias con elevado sedimento terrígeno fino en suspensión

A Time-Varying Non-Parametric Methodology for Assessing Changes in QT Variability Unrelated to Heart Rate Variability

OBJECTIVE: To propose and test a novel methodology to measure changes in QT interval variability (QTV) unrelated to RR interval variability (RRV) in non-stationary conditions. METHODS: Time-frequency coherent and residual spectra representing QTV related (QTVrRRV) and unrelated (QTVuRRV) to RRV, respectively, are estimated using time-frequency Cohen's class distributions. The proposed approach decomposes the non-stationary output spectrum of any two-input one-output model with uncorrelated inputs into two spectra representing the information related and unrelated to one of the two inputs, respectively. An algorithm to correct for the bias of the time-frequency coherence function between QTV and RRV is proposed to provide accurate estimates of both QTVuRRV and QTVrRRV. Two simulation studies were conducted to assess the methodology in challenging non-stationary conditions and data recorded during head-up tilt in 16 healthy volunteers were analyzed. RESULTS: In the simulation studies, QTVuRRV changes were tracked with only a minor delay due to the filtering necessary to estimate the non-stationary spectra. The correlation coefficient between theoretical and estimated patterns was >0.92 even for extremely noisy recordings (SNR in QTV =-10dB). During head-up tilt, QTVrRRV explained the largest proportion of QTV, whereas QTVuRRV showed higher relative increase than QTV or QTVrRRV in all spectral bands (P<0.05 for most pairwise comparisons). CONCLUSION: The proposed approach accurately tracks changes in QTVuRRV. Head-up tilt induced a slightly greater increase in QTVuRRV than in QTVrRRV. SIGNIFICANCE: The proposed index QTVuRRV may represent an indirect measure of intrinsic ventricular repolarization variability, a marker of cardiac instability associated with sympathetic ventricular modulation and sudden cardiac death

Comparison of ECG T-wave Duration and morphology restitution markers for sudden cardiac death prediction in chronic heart Failure

An index ofT-wave morphology restitution, TMR, has previously shown to be a sudden cardiac death (SCD) predictor in a population of chronic heart failure (CHF) patients. The aim of this study is to compare the predictive value of TMR, T-wave width restitution (TWR), T-peak-to-end (Tpe) morphology restitution (TpeMR) and Tpe duration restitution (TpeR) indices in the same CHF population. Holter ECG recordings from 651 CHF patients of the MUSIC study, including SCD victims and survivors, were analyzed. TMR was significantly correlated with TWR (ρ=0.66), TpeMR (ρ=0.70) and TpeR (ρ=0.42). SCD victims showed significantly higher values of TMR, TWR and TpeMR than the rest of patients, with TMR being the index most strongly associated with SCD (p=0.002, p=0.006 and p=0.011, respectively). TpeR values were only borderline significantly higher in SCD victims (p=0.061). Univariate Cox analysis showed that TMR was the restitution index with the strongest predictive value (hazard ratio (HR) of 1.466, p < 0.001), followed by TWR (HR of 1.295, p=0.005), TpeR (HR of 1.297, p=0.004) and TpeMR (HR of 1.164, p=0.020). In conclusion, considering the predictive value of the four T-wave restitution indices, TMR is the preferred index for SCD risk stratification, followed by TpeMR. However, the marker TWR could also be used for SCD prediction when computational efficiency is an issue

Interactive effect of beta-adrenergic stimulation and mechanical stretch on low-frequency oscillations of ventricular action potential duration in humans

Ventricular repolarization dynamics are crucial to arrhythmogenesis. Low-frequency oscillations of repolarization have recently been reported in humans and the magnitude of these oscillations proposed to be a strong predictor of sudden cardiac death. Available evidence suggests a role of the sympathetic nervous system. We have used biophysically detailed models integrating ventricular electrophysiology, calcium dynamics, mechanics and β-adrenergic signaling to investigate the underlying mechanisms. The main results were: (1) Phasic beta-adrenergic stimulation (β-AS) at a Mayer wave frequency between 0.03 and 0.15Hz resulted in a gradual decrease of action potential (AP) duration (APD) with concomitant small APD oscillations. (2) After 3-4minutes of phasic β-AS, the mean APD adapted and oscillations of APD became apparent. (3) Phasic changes in haemodynamic loading at the same Mayer wave frequency (a known accompaniment of enhanced sympathetic nerve activity), simulated as variations in the sarcomere length, also induced APD oscillations. (4) The effect of phasic β-AS and haemodynamic loading on the magnitude of APD oscillations was synergistic. (5) The presence of calcium overload and reduced repolarization reserve further enhanced the magnitude of APD oscillations and was accompanied by afterdepolarizations and/or spontaneous APs. In conclusion, low-frequency oscillations of repolarization recently reported in humans were induced by phasic β-AS and phasic mechanical loading, which acted synergistically, and were greatly enhanced by disease-associated conditions, leading to arrhythmogenic events

Response of Ventricular Repolarization to Simulated Microgravity Measured by Periodic Repolarization Dynamics Using Phase-Rectified Signal Averaging

Head-Down Bed Rest (HDBR) microgravity simulation induces cardiovascular deconditioning, including effects on ventricular repolarization. The index of Periodic Repolarization Dynamics (PRD) was developed to quantify low-frequency oscillations of cardiac repolarization. In this study, PRD was quantified by Phase Rectified Signal Averaging (PRDPRSA) and Continuous Wavelet Transform (PRDCWT) methods. PRD was analyzed in ECGs from 22 volunteers at rest and during orthostatic Tilt-Table Test (TTT) performed before and after -6° 60-days HDBR. Significant correlation was found between PRD measured by PRSA and CWT (Pearson''s ¿ = 0.93, p &lt; 10-54 and Kendall''s t = 0.79 p &lt; 10-38). A highly significant increase was found when PRDPRSA values were measured at POST-HDBR with respect to PRE-HDBR in the tilt phase: 1.40 [1.10] deg and 0.97 [0.90] deg (median [IQR]), p = 0.008, respectively. PRDPRSA also increased significantly in the tilt phase with respect to baseline, both at POST-HDBR (0.90 [0.57] deg, p = 0.003) and at PRE-HDBR (0.75 [0.45] deg, p = 0.011). PRD, either measured with PRSA or with CWT, is able to measure changes in ventricular repolarization induced by microgravity simulation as well as following sympathetic provocation

Endothelin-1 amplifies ventricular repolarization heterogeneities in chronic myocardial infarction pigs

Introduction: Endothelin-1 (ET-1) is a vasoconstrictor peptide secreted by endothelial cells and cardiac myocytes and fibroblasts. It is involved in oxidative stress, apoptosis regulation and ventricular remodeling processes associated with heart failure and ischemic cardiomyopathy, including myocardial hypertrophy, fibrosis and impaired conduction. ET-1 has been shown to influence cardiac electrophysiology by modulation of calcium and potassium currents and to contribute to arrhythmogenesis and sudden cardiac death. Purpose: We aim to characterize the functional role of ET-1 in the electrophysiology of healed myocardial infarction (MI) by analysis of porcine ventricular slices as a highly representative model of ventricular tissue with preserved cellular cross-talks and architecture. Methods: Domestic pigs (60–80 kg, n = 3) were infarcted by temporal occlusion of the left anterior descending coronary artery. 8-12 weeks after infarct induction, animals were cardioplegically arrested under deep anesthesia and sacrificed. All animal procedures conformed to the guidelines from Directive 2010/63/EU and were approved by local authorities. 350 µm-thick ventricular slices were produced from transmural tissue blocks of healed MI ventricles. Tissue blocks were taken from remote, adjacent and border zones of the infarct area. Slices were optically mapped within 8 hours after tissue collection to record transmembrane potential and intracellular calcium. Action Potential Duration (APD) and Calcium Transient Duration (CaTD) were measured at 80% repolarization for 0.5, 1 and 2 Hz pacing frequencies in the presence and absence of 100 nM ET-1. The notation n/N is used to denote n tissue slices from N pigs. Results: ET-1 prolonged the APD at all frequencies in remote zones, with mean prolongation percentages of 30.5%, 32%, 26.2% at 0.5, 1 and 2 Hz, respectively, n/N=7/3. However, only minor effects were observed in adjacent (mean APD prolongation of 3.3%, 4.9% and 10.7%, n/N=5/3) and border zones (7%, 4% and 3.6%, n/N=5/3). ET-1 caused an increase in CaTD at 1 Hz in the three zones, with no significant regional differences in the amount of CaTD increase: mean prolongation of 14.1% (n/N=7/3) in the remote zone, 12.4 % (n/N=5/3) in the adjacent zone and 20.9% (n/N=4/3) in the border zone. Conclusions: In chronic MI pigs, ET-1 induces strong APD and moderate CaTD prolongation of remote normal myocardium at low (0.5 Hz) to high (2 Hz) frequencies. The ET-1-induced effects on the AP of normal tissue, but not on CaT, are disrupted in the border zones of the infarct area and in its proximity. Our results point to ET-1 acting to enhance ventricular repolarization dispersion in chronic MI pigs, which might contribute to increased arrhythmia vulnerability

Quantification of T-wave Morphological Variability Using Time-warping Methods

The aim of this study is to quantify the variation of the T-wave morphology during a 24-hour electrocardiogram (ECG) recording. Two ECG-derived markers are presented to quantify T-wave morphological variability in the temporal, dw, and amplitude, da, domains. Two additional markers, dNLw and dNLa, that only capture the non-linear component of dw and da are also proposed. The proposed markers are used to quantify T-wave time and amplitude variations in 500 24-hour ECG recordings from chronic heart failure patients. Additionally, two mean warped T-waves, used in the calculation of those markers, are proposed to compensate for the rate dependence of the T-wave morphology. Statistical analysis is used to evaluate the correlation between dw, dNLw, da and dNLa and the maximum intra-subject RR range, ΔRR. Results show that the mean warped T-wave is able to compensate for the morphological differences due to RR dynamics. Moreover, the metrics dw and dNLw are correlated with ΔRR, but da and dNLa are not. The proposed dw and dNLw quantify variations in the temporal domain of the T-wave that are correlated with the RR range and, thus, could possibly reflect the variations of dispersion of repolarization due to changes in heart rate