Frontiers in Physiology

Recently, our group published a new model of human ventricular cardiomyocyte named ToR-ORd (Tomek et al., 2019). Its development, calibration, and validation, were performed using a broad range of human experimental data and brought general insights into modelling of ionic channels. Model calibration ensured the reproduction of key physiological cellular features, with independent multiscale validation demonstrating a correct response to channel blocking drugs and pathophysiological remodelling. However, for very long simulations (several hours rather than minutes), the ToR-ORd simulations display a drift in its behaviour, caused by modelling chloride concentrations as constant values. This may be a limitation for simulations considering extremely long protocols, or for studies on model stability. To remedy this, we present here an updated version, termed ToR-ORd-dynCl, with dynamic representation of intracellular chloride. This model behaves very similarly to the original ToR-ORd, but with stable properties over long simulations and only a small increase in model complexity.

Changes of serum and extracellular ion concentrations occur regularly in patients with chronic kidney disease (CKD). Recently, hypocalcemia, i.e. a decrease of the extra-cellular calcium concentration [Ca2+]o, has been suggested as potential pathomechanism contributing to the unexplained high rate of sudden cardiac death (SCD) in CKD patients. In particular, there is a hypothesis that hypocalcaemia could slow down natural pacemaking in the human sinus node to fatal degrees. Here, we address the question whether there are inter-species differences in the response of cellular sinus node pacemaking to changes of [Ca2+]o. Towards this end, we employ computational models of mouse, rabbit and human sinus node cells. The Fabbri et al. human model was updated to consider changes of intracellular ion concentrations. We identified crucial inter-species differences in the response of cellular pacemaking in the sinus node to changes of [Ca2+]o with little changes of cycle length in mouse and rabbit models (<83 ms) in contrast to a pronounced bradycardic effect in the human model (up to > 1000 ms). Our results suggest that experiments with human sinus node cells are required to investigate the potential mechanism of hypocalcaemia-induced bradycardic SCD in CKD patients and small animal models are not well suited.

Volitional motor activity is associated with a feedforward cardiorespiratory response to actual or impending movements. We have previously shown in the CRC study that the expectation of physical exercise causes a decrease in cardiorespiratory coherence that scales with the anticipated load. The present work uses a modeling approach to investigate the mechanisms that can cause a fall in cardiorespiratory coherence (CRC). We devised a Hodgkin-Huxley model of a cardiac pacemaker cell using the NEURON module. We simulated the effect of autonomic tone, sympathetic & respiratory-vagal modulation, and respiratory irregularity on pacemaker cell output by injecting efflux/influx current to model the parasympathetic/sympathetic effects, respectively. The vago-sympathetic tone was modeled by altering the direct current bias of the injected current and the respiratory-vagal effect by the periodic modulation of the injected current at a frequency of 0.2 Hz, corresponding to a respiratory rate of 12 breaths/min. Sympathetic modulation was simulated by injecting a low-frequency current close to Mayer wave frequency (0.08 Hz). We computed the coherence between the instantaneous pacemaker rate and respiratory-vagal modulation current as a model analog to experimental CRC. We found that sympathetic modulation, low vagal tone/high sympathetic tone, and respiratory irregularity can cause a decrease in CRC. We corroborated the model results with the actual data from the CRC study. In conclusion, we employ a novel approach combining insights from the experimental study and a physiologically plausible modeling framework to understand the mechanisms underlying the fall of cardiorespiratory coherence induced by the expectation of exercise. NEW & NOTEWORTHY Cardiorespiratory coherence is diminished in response to respiratory irregularity, low vagal/high sympathetic tone, and prominent low-frequency sympathetic modulation. Expectation of physical activity induces respiratory irregularity and increased sigh frequency and that contributes to diminished cardiorespiratory coherence in expectation of exercise. There is a greater fall of coherence with the non-linear (logistic) transformation of injected current, indicating the non-linear nature of cardiorespiratory interactions preceding the onset of exercise.

The major membrane currents responsible for sinoatrial and idioventricular rhythm-generation were studied in isolated rat heart preparations, perfused in Langendorff mode. The rates of whole isolated hearts beating with sinoatrial rhythm decreased with cesium and ivabradine, both blockers of the funny current, and were not affected by nickel, at a dose which blocks T-type calcium current. The sinoatrial rhythm was completely abolished by reduction or removal of sodium from the perfusate (interventions that inhibit calcium-extrusive mode of the sodium/calcium exchanger), or by nifedipine, an L-type calcium channel blocker. Idioventricular rhythm, however, was arrested only by reduction of sodium in the perfusate. Ivabradine reduced the idioventricular rate, nickel did not cause any change, while nifedipine in some cases increased it. The inferences made based on these observations are that INCX and ICaL are obligatory rhythm-generating currents in the sinoatrial node, while INCX is the only obligatory mechanism for an idioventricular rhythm. The funny current is not an obligatory requirement for sinoatrial as well as idioventricular rhythm-generation. However, it enhances the frequency of LCRs. Our results in the isolated whole heart are in corroboration with results from isolated cells.

Human red blood cells (RBCs) have a circulatory lifespan of about four months. Under constant oxidative and mechanical stress, but devoid of organelles and deprived of biosynthetic capacity for protein renewal, RBCs undergo substantial homeostatic changes, progressive densification followed by late density reversal among others, changes assumed to have been harnessed by evolution to sustain the rheological competence of the RBCs for as long as possible. The unknown mechanisms by which this is achieved are the subject of this investigation. Each RBC traverses capillaries between 1000 and 2000 times per day, roughly one transit per minute, a total of about 2*105 transits during their lifespan. A dedicated Lifespan model of RBC homeostasis was developed as an extension of the RCM introduced in the first paper of this series to explore the cumulative patterns predicted for repetitive capillary transits over a standardized lifespan period of 120 days, using experimental data to constrain the parameter space. Capillary transits were simulated by periods of elevated cell/medium volume ratios and by transient deformation-induced permeability changes attributed to PIEZO1 channel mediation as outlined in the second paper of this series. The first unexpected finding was that quantal changes generated during single capillary transits cease accumulating after a few days and cannot account for the observed progressive densification of RBCs on their own, thus ruling out the quantal hypothesis. The second unexpected finding was that the documented patterns of RBC densification and late reversal could only be emulated by the implementation of a strict time-course of decay in the activities of the calcium and Na/K pumps, but only in addition to the quantal changes. These results showed that both quantal changes and pump-decay regimes were necessary to account for the documented lifespan pattern, neither sufficient on their own. They also suggested a strong selective component in the pump decay sequence. A third finding was that RBCs exposed to levels of calcium permeation above certain thresholds in the circulation could develop a pattern of late or early hyperdense collapse followed by delayed density reversal. When tested over much reduced lifespan periods the results emulated the known circulatory fate of irreversible sickle cells, the cell subpopulation responsible for vaso-occlusion and for most of the clinical manifestations of sickle cell disease. Analysis of the results provided an insightful new understanding of the mechanisms driving the changes in RBC homeostasis during circulatory aging in health and disease.

Brief cardiac cycles are required to achieve high heart rates as seen in endothermic animals. A main determinant of the cardiac cycle is the repolarization phase of the cardiac action potential, which is visible in the ECG as a T-wave. In mammals with high heart rates - such as rodents - the repolarization phase is short and the ECG is characterized by a positive deflection following the QRS-complex, the J-wave. It is unclear whether birds with high heart rates show similar ECG characteristics. Here we study cardiac repolarization and the ECG in the zebra finch which has high heart rates. In ex vivo hearts of zebra finch (N=5) and mouse (N=5), pseudo-ECGs and optical action potentials were measured. In both species, total ventricular activation was fast with QRS durations shorter than 10ms. Ventricular activation progressed from the left to the right ventricle in zebra finch whereas the activation pattern was apex-to-base in mouse. In both species, phase 1 early repolarization followed the activation front, causing a positive J-wave in the pseudo-ECG. In zebra finch, late repolarization was directed from the right ventricle to the left ventricle, whereas late repolarization was directed opposite in mouse. Accordingly, on the zebra finch ECG, the J-wave and the T-wave have the same direction, whereas in the mouse the J-wave and the T-wave are discordant. Our findings demonstrate early repolarization and the associated J-wave are not restricted to mammals and that they also occur within birds. Early repolarization may have evolved by convergence in association with high heart rates. Summary statementZebra finches are small birds with high heart rates. Similar to small rodents, the zebra finch ECG contains a J-wave, which is caused by early repolarization

IntroductionThermal adaptation in fish is accompanied by morphological and electrophysiological changes in the myocardium. Little is known regarding changes of spatiotemporal organization of ventricular excitation and repolarization processes with acclimatization. We aimed to evaluate transmural and apicobasal heterogeneity of depolarization and repolarization characteristics in the in-situ heart of rainbow trout in seasonal acclimatization. MethodsThe experiments were done in the summer-acclimatized (SA, 18{degrees}C, n=8) and winter-acclimatized (WA, 3{degrees}C, n=8) rainbow trout. 24 unipolar electrograms were recorded with plunge needle electrodes (eight lead terminals each) impaled into the ventricular wall. Activation time (AT), end of repolarization time (RT), and activation-repolarization interval (ARI, a surrogate for action potential duration) were determined as dV/dt min during QRS-complex, dV/dt max during T-wave, and RT-AT difference, respectively. ResultsThe SA fish demonstrated relatively flat apicobasal and transmural AT and especially ARI profiles. In the WA animals, ATs and ARIs were longer as compared to SA animals (p[&le;]0.001), ARIs were shorter in the compact layer than in the spongy layer (p[&le;]0.050), and within the compact layer, the apical region had shorter ATs and longer ARIs as compared to the basal region (p[&le;]0.050). In multiple linear regression analysis, ARI duration was associated with cardiac cycle duration and AT in SA and WA animals. The WA animals demonstrated additionally an independent association of ARIs with spatial localization across the ventricle. ConclusionAdaptation to cold conditions in rainbow trout was associated with a spatial ventricular remodeling leading to the development of repolarization gradients typically observed in mammalian myocardium. SUMMARY STATEMENTThe study gives an example of thermal adaptation in fish realized at the level of spatiotemporal organization of myocardial depolarization and repolarization.

Hypertrophic cardiomyopathy (HCM) is characterised by asymmetric left ventricular hypertrophy, ventricular arrhythmias and cardiomyocyte dysfunction that may cause sudden death. HCM is associated with mutations in sarcomeric proteins and is usually transmitted as an autosomal-dominant trait. The aim of this in silico study was to assess the mechanisms that underlie the altered electrophysiological activity, contractility, regulation of energy metabolism and crossbridge cycling in HCM at the single cell level. To investigate this, we developed a human ventricular cardiomyocyte model that incorporates electrophysiology, metabolism and force generation. The model was validated by its ability to reproduce the experimentally observed kinetic properties of human HCM induced by a) remodelling of several ion channels and Ca2+-handling proteins arising from altered Ca2+/calmodulin kinase II signalling pathways; and b) increased Ca2+ sensitivity of the myofilament proteins. Our simulation showed a decreased phosphocreatine to ATP ratio (-9%) suggesting a negative mismatch between energy expenditure and supply. Using a spatial myofilament half sarcomere model, we also compared the fraction of detached, weakly bound and strongly bound crossbridges in the control and HCM conditions. Our simulations showed that HCM has more crossbridges in force producing states than in the control condition. In conclusion, our model reveals that impaired crossbridge kinetics is accompanied by a negative mismatch between the ATP supply : demand ratio. This suggests that improving this ratio may reduce the incidence of sudden death in HCM.

1Endogenous circadian clocks control circadian rhythms in physiology and behavior. The predominant hypothesis of biological timing suggests that the responsible master clock for all endogenous circadian rhythms is constituted by an evolutionary conserved transcriptional-translational feedback loop (TTFL) clock consisting of positive feedforward and negative feedback elements. Unexpectedly, in contrast to the evolutionary derived insect Drosophila, RNAi-dependent knockdown of any of the negative feedback elements of the core TTFL clock in the basal Madeira cockroach Rhyparobia maderae does not delete circadian rhythms in locomotor activity. Shown here, neither RNAi-dependent triple knockdowns of all three negative feedback elements Period, Timeless 1, and Cryptochrome 2, nor single and double knockdown of the positive elements Clock and Cycle did directly delete circadian locomotor rhythms as mRNA levels declined. Thus, our experimental data do not support the predominant hierarchical hypothesis of circadian timing. To explore alternative mechanisms, we constructed a computational model of a neuronal circadian pacemaker network using planar switching affine systems (PSAS). The PSAS model comprises plasma membrane-associated posttranslational feedback loop (PTFL) clocks that are coupled to the TTFL nuclear clocks. Modeling results aligned with our experimental results. Therefore, both our experimental and modeling data support a systemic hypothesis of biological timing. 3 Significance statementBased mostly upon genetic studies in derived taxa like Drosophila it is hypothesized that circadian timing of behavior is strictly controlled by specific circadian clock neurons in the brain, realized through a transcriptional-translational feedback loop (TTFL) clock. In contrast to this common hierarchical model that requires transcription, we provide evidence in a basal taxon - the Madeira cockroach - for a systemic explanation of circadian timing of behavior that is based on coupled TTFL and posttranslational feedback loop (PTFL) clocks in adaptive neuronal networks.

AO_SCPLOWBSTRACTC_SCPLOWRespiration and swallowing are vital orofacial motor behaviours that require the coordination of the activity of two brainstem central pattern generators (r-CPG, sw-CPG). Here, we use computational modelling to further elucidate the neural substrate for breathing-swallowing coordination. We progressively construct several computational models of the breathing-swallowing circuit, starting from two interacting half-centre oscillators for each CPG. The models are based exclusively on neuronal nodes with spike-frequency adaptation, having a parsimonious description of intrinsic properties. These basic models undergo a stepwise integration of synaptic connectivity between central sensory relay, sw- and r-CPG neuron populations to match experimental data obtained in a perfused brainstem preparation. In the model, stimulation of the superior laryngeal nerve (SLN, 10s) reliably triggers sequential swallowing with concomitant glottal closure and suppression of inspiratory activity, consistent with the motor pattern in experimental data. Short SLN stimulation (100ms) evokes single swallows and respiratory phase resetting yielding similar experimental and computational phase response curves. Subsequent phase space analysis of model dynamics provides further understanding of SLN-mediated respiratory phase resetting. Consistent with experiments, numerical circuit-busting simulations show that deletion of ponto-medullary synaptic interactions triggers apneusis and eliminates glottal closure during sequential swallowing. Additionally, systematic variations of the synaptic strengths of distinct network connections predict vulnerable network connections that can mediate clinically relevant breathing-swallowing disorders observed in the elderly and patients with neurodegenerative disease. Thus, the present model provides novel insights that can guide future experiments and the development of efficient treatments for prevalent breathing-swallowing disorders. KO_SCPLOWEYC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWPOINTSC_SCPLOWO_LIThe coordination of breathing and swallowing depends on synaptic interactions between two functionally distinct central pattern generators (CPGs) in the dorsal and ventral brainstem. C_LIO_LIWe model both CPGs as half-centre oscillators with spike-frequency adaptation to identify the minimal connectivity sufficient to mediate physiologic breathing-swallowing interactions. C_LIO_LIThe resultant computational model(s) can generate sequential swallowing patterns including concomitant glottal closure during simulated 10s stimulation of the superior laryngeal nerve (SLN) consistent with experimental data. C_LIO_LIIn silico, short (100 ms) SLN stimulation triggers a single swallow which modulates the respiratory cycle duration consistent with experimental recordings. C_LIO_LIBy varying the synaptic connectivity strengths between the two CPGs and the sensory relay neurons, and by inhibiting specific nodes of the network, the model predicts vulnerable network connections that may mediate clinically relevant breathing-swallowing disorders. C_LI

Vasoconstriction in small arteries and arterioles is known to increase resistance to flow, while vasoconstriction in large arteries and aorta is known to decrease their compliance. Besides this general understanding, there is no systematic documentation on what happens to small artery compliance and large artery resistance during vasoconstriction and the corresponding alterations in vascular pressure. The aim of the study is to assess the effect of adrenaline on goat aortae and small arteries in terms of resistance and compliance. Isolated goat aortae and small arteries were perfused with a pulsatile pump and lumen pressure was recorded before and after addition of adrenaline. In the aortae, systolic pressure increased, diastolic pressure decreased, pulse pressure increased (p = 0.018, WSR); but the mean pressure remained the same (p = 0.357, WSR). Small artery vasoconstriction caused an increase in systolic, diastolic and mean pressures (p = 0.028, WSR). Using length, radius, and thickness data from the tissues and the tubes of the experimental set-up, electrical models were simulated to understand the biological data. The simulations allow us to infer that vasoconstriction in aorta leads to a reduction in compliance, but an increase in resistance if any, is not sufficient to change the mean aortic pressure. On the other hand, vasoconstriction in small arteries increases resistance, but a decrease in compliance if any, does not affect any of the four pressure parameters measured. Vasoconstriction in aorta decreases compliance and therefore increases pulse pressure but does not change resistance significantly enough to alter mean pressure. Key Points SummaryO_LIThe main aim of the study is to understand where exactly resistance (R) and compliance (C) components of the vasculature occur. There is no definitive evidence for the effect of large artery vasoconstriction on resistance and hence the mean arterial pressure. C_LIO_LIThe manuscript presents biological experiments studying the pressure response of goat aorta and small arteries to adrenaline (invitro) and the interpretations using equivalent electrical models. C_LIO_LIThe study shows that in aorta and large arteries, vasoconstriction does not lead to a reduction in lumen diameter sufficient to cause a rise in resistance and mean pressure as compared to small arteries. C_LIO_LIKnowledge of exact location of R and C in the arterial tree enables re-assessment of the differential action of vasoactive drugs on resistance versus compliance vessels once we resolve beat-to-beat R and C changes in response to a drug. This way antihypertensive therapy can be tailored to address the specific cause of the type of hypertension. C_LI

ObjectiveWhile there are numerous reports on heart rate and its variabilities, a detailed analysis of the component intervals for healthy adults in well controlled condition is lacking. This study analyzes the effect of age, sex, and Body Mass Index (BMI) on nine resting electrocardiogram (ECG) intervals and their intra-individual variabilities in healthy adults under the same testing environment. MethodsUsing the "Autonomic Aging" dataset, ECG recordings from 1,121 healthy volunteers (ages 18-92) were processed. The study employed a specialized segmentation algorithm to identify key ECG markers. We analyze statistically how age, BMI, and sex impact the durations and variabilities of nine ECG intervals. ResultsFifty years of age serves as a critical transition age for cardiac aging for all subjects as a whole. Above this age, the active interval, which is the combined atrial and ventricular conduction time, increases three times faster than at a younger age, primarily driven by lengthening of depolarization times. Compared to the opposite sex, older low-BMI males have a longer atrial conduction time, and older low-BMI females have a larger variability in the ventricular conduction time. High BMI increases the heart rate by reducing the length of the idle interval, i.e., the isoelectric segment at the end of a cardiac cycle. The rate increase is more pronounced among older subjects than younger ones. High BMI males start to exhibit an elevated heart rate and larger variability in the atrial conduction time in their 30s. High BMI females start to show a larger variability in the ventricular repolarization time around 50 years old. ConclusionAge, BMI, and sex all have major impacts on the ECG intervals and their variability. A resting heart behaves largely like a pulse width modulation system, with a stable active interval and an adjustable idle interval to meet the varying needs for cardiac output. The durations and variabilities of the active interval, more than those of the RR interval, are indicators of a hearts health condition. A young and healthy heart tends to have a shorter duration and smaller variability in the active interval.

Dispersion of repolarization results from a non-homogeneous recovery of excitability in cardiac tissue, and it is an important factor in arrhythmogenesis because it could lead to the initiation and maintenance of a variety of arrhythmias. Antiarrhythmic agents that prolong APD by selectively blocking specific ion channels (like IKr) often increase dispersion of repolarization, which could result in a pro-arrhythmic risk. In this report, using computer models of the action potential of human epicardial and mid-myocardial myocytes, we have identified two strategies to prolong APD while reducing transmural dispersion of repolarization. The first strategy, which involves blocking several depolarizing and repolarizing ion channels (INaL, ICaL, IKr and INaCa), can reduce the transmural APD dispersion by about 20%. The second strategy, which involves the use of a combination of ion channel blockers and activators, results in a stronger reduction in transmural dispersion of repolarization than using only ion channel blockers. Enhancing IKs and blocking IKr can reduce transmural APD dispersion by about 70%. Our results suggest that a multichannel pharmacology strategy (as opposed to a single channel strategy), possibly using ion channel blockers and activators, can be effective at increasing APD while minimizing dispersion of repolarization.

The renin-angiotensin system (RAS) plays a pivotal role in the maintenance of volume homeostasis and blood pressure. In addition to the well-studied systemic RAS, local RAS have been documented in various tissues, including the kidney. Given the role of the intrarenal RAS in the pathogenesis of hypertension, a role established via various pharmacologic and genetic studies, substantial efforts have been made to unravel the processes that govern intrarenal RAS activity. In particular, several mechanisms have been proposed to explain the rise in intrarenal angiotensin II (Ang II) that accompanies Ang II infusion, including increased angiotensin type 1 receptor (AT1R)-mediated uptake of Ang II and enhanced intrarenal Ang II production. However, experimentally isolating their contribution to the intrarenal accumulation of Ang II in Ang II-induced hypertension is challenging, given that they are fundamentally connected. Computational modelling is advantageous because the feedback underlying each mechanism can removed and the effect on intrarenal Ang II can be studied. In this work, the mechanisms governing the intrarenal accumulation of Ang II during Ang II infusion experiments are delineated and the role of the intrarenal RAS in Ang II-induced hypertension is studied. To accomplish this, a compartmental ODE model of the systemic and intrarenal RAS is developed and Ang II infusion experiments are simulated. Simulations indicate that AT1Rmediated uptake of Ang II is the primary mechanism by which Ang II accumulates in the kidney during Ang II infusion. Enhanced local Ang II production is unnecessary. The results demonstrate the role of the intrarenal RAS in the pathogenesis of Ang II-induced hypertension and consequently, clinical hypertension associated with an overactive RAS.

IntroductionOrthostatic intolerance is highly prevalent in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and is caused by an abnormal reduction in cerebral blood flow (CBF). In healthy controls (HC) regulation of CBF is complex and involves multiple mechanisms including cardiac output (CO), cerebral perfusion pressure, PO2 and PCO2, flow-metabolism coupling, and innervation of cerebral vessels. In ME/CFS multiple other mechanisms have also been identified. Aim of the studyWe previously found that both CBF and CO were reduced in ME/CFS patients during tilt testing, and we hypothesized that the relation between CBF and CO is abnormal and different from HC. In this retrospective study we analyzed this relation in a large group of patients. To compare the patient data with those of HC, we focused on patients with a normal heart rate (HR) and blood pressure (BP) response to upright tilt. Also, the influence of clinical data was analyzed. MethodsA total of 534 ME/CFS patients and 49 HC underwent tilt testing with measurements of HR, BP, CBF, and CO. In 46 (9%) patients CO and CBF changes were in the normal range of HC, and in 488 (91%) an abnormal CO and CBF reduction was found. Resultspatients with a CO and CBF reduction in the range of HC had less severe disease and were more likely to be male. In patients with an abnormal CO and CBF reduction the slope of the regression line of CO versus CBF reduction was almost 1. A multiple regression analysis of the latter group, including patients with PetCO2 measurements (440/488: 90%) showed that the CO reduction for the major part predicted the CBF reduction, with a limited role for the PetCO2 reduction and the tilt duration. Other data did not add to the model. ConclusionsTwo different patient groups with a normal HR and BP response during the tilt were identified: those with a CO and CBF in the normal range of HC and those with an abnormal CO and CBF reduction during the tilt (91% of patients). The former group had milder disease and included more men. In the largest group of patients there was an almost 1:1 relation between the CO and CBF reduction, suggesting absence of compensatory vasodilation in the cerebral vasculature. This may be an appropriate target for clinical and therapeutic interventions.

Human induced pluripotent stem cells-derived cardiomyocytes have revolutionized the field of regenerative medicine, offering unparalleled potential for in-vitro modeling of normal and pathological human cardiomyocytes. The ability to produce stem cardiac myocytes in abundance has opened new avenues for drug efficacy and safety testing, as well as the study of conditions such as atrial fibrillation, a familial cardiac disorder. The development of atrial fibrillation is influenced by ion channel mutations, genetic variants, and other risk factors. Stem cells derived cardiomyocytes hold promise in personalized medicine, as they share the genetic heritage of the donor. While mathematical models have focused on immature stem cardiomyocytes phenotypes, they have primarily relied on a system of stiff ordinary differential equations. Computational modeling of diseased tissue presents an opportunity to evaluate drugs in a patient-specific manner, thereby improving therapeutic targets and ablation techniques. Previous studies categorized cell phenotypes based on action potential morphology, yet classification criteria remains ambiguous. This work introduces the first atrial-specific in-silico model of stem cells ionic currents, leveraging experimental data provided by Altomare et al. It begins by summarizing the baseline electrophysiological model and mathematical descriptions of atrial-specific additional currents. Model parameter tuning was performed through automatic optimization techniques to ensure realistic action potential shape and expedite the parameter adjustment process. The resulting model was validated against rate dependence and atrial-specific ion current blocking data. In summary, the development of an atrial-specific in-silico model represents a significant step forward in understanding cardiac electrophysiology and the potential for personalized medicine in treating conditions like atrial fibrillation. This model offers new tools for drug evaluation, therapeutic improvement, and a deeper comprehension of cardiac phenotypes. Author summaryHuman induced pluripotent stem cells have revolutionized regenerative medicine since their discovery in 2006, leading to a Nobel Prize in 2012. This kind of pluripotent cells can give rise to different types of specific tissue cells, such as derived cardiomyocytes. Differentiated cardiac cells offer an unlimited supply for studying human heart cells in normal and disease conditions, aiding a patient-specific drug testing and helping to explore pathogenic mechanisms behind different cardiomyopathies, including atrial fibrillation. Atrial fibrillation is a common heart condition, and stem cells with the same genetic heritage as the donor, are ideal for patient-specific treatments. Recent advances have produced mathematical models for the ionic currents in cardiomyocytes derived from stem cells, focusing on immature forms and enabling virtual drug testing. However, previous models did not capture the atrial-specific characteristics. We decided to create and introduce by this study the first atrial-like in-silico model for these cells, using novel experimental data. Thus, we describe the baseline model and additional atrial-specific currents, we tune the model parameters using automatic optimization technique, and we validate the models accuracy in simulating atrial action potentials and ion current blockage. This research paves the way for better understanding and treating atrial fibrillation and other heart conditions.

Cervical spinal cord injuries (cSCI) induce profound denervation in respiratory muscles leading to hypoventilation that compromises quality of life. Respiratory neuromuscular electrical stimulation of extra-diaphragmatic muscles (rNMES) could be a non-invasive approach to improve respiratory function following cSCI. However, it is critical to first synchronize rNMES with spontaneous breathing. An Ordinary Differential Equation (ODE) was solved and fitted to experimental breathing signals obtained via plethysmography in ten mice. Optimal stimulation ODE-based parameters were identified for intercostal and abdominal muscle stimulation for breathing-synchronized rNMES training. Feasibility was tested on tolerance to repetitive anesthesia and stimulation for ten training sessions in six mice. The ODE-based breathing signals matched the experimental ones with an average coefficient of determination (R{superscript 2}) of 81%. The developed algorithm, Algostim, provided average theoretical optimal times of 0.12 s for intercostal and 0.32 s for abdominal muscles contraction. Feasibility and tolerance to rNMES were favorable after ten sessions. This innovative mathematical approach to rNMES allows optimal stimulation of respiratory muscles while accounting for spontaneous breathing rate. Algostim established a framework for personalized rNMES therapies, enabling the delivery of standardized stimulation parameters and allowing detailed investigation into the underlying mechanisms of rNMES.

The renin-angiotensin system (RAS) is a primary regulator of volume homeostasis and blood pressure, whose over-activation is commonly associated with hypertension. Indeed, medications that target the RAS are generally effective in reducing blood pressure. However, more can be learned about how these medications influence the intrarenal RAS. Angiotensin-receptor blockers (ARBs) in particular have been shown to exert different effects on the intrarenal and systemic RASs in various experimental models of hypertension. In rats chronically infused with angiotensin II (Ang II), ARBs consistently prevent intrarenal, but not systemic Ang II levels from rising. The former effect is sufficient in preventing the development of hypertension. The regulation of intrarenal RAS, independently of the systemic RAS, by ARBs has been hypothesized to be mediated by the inhibition of all positive feedback loops inherent to the intrarenal RAS, also known as the "key point breakdown effect." To investigate the validity of this hypothesis, we developed a PK/PD model of the ARB Losartan that considers the kidney, and applied the model to study how this class of medication influences intrarenal RAS activity and consequently blood pressure regulation in male rats. Simulations indicate that ARBs more effectively inhibit the activation of the intrarenal RAS because, unlike in the plasma, this process relies on the accumulation of cell-associated Ang II. We hypothesize that it is by blocking this intracellular uptake pathway, and restricting Ang II to extracellular regions of the kidney where the peptide cannot initiate downstream signalling, that Losartan normalizes blood pressure. While the key point break down effect assists in this response, it alone is not sufficient. Our results highlight the intrarenal RAS as the key pharmacological target of ARB treatment and emphasize the importance of this local tissue RAS in the development of hypertension.

The response of hemodynamic parameters in healthy volunteers to changes in alveolar pressure and lung volume was studied by noninvasive methods during respiratory maneuvers similar to Valsalva and Muller maneuvers (in a sitting position and lying on the back horizontally). The following lung volumes and values of pressure (relative to atmospheric pressure) were considered in various combinations: total lung capacity, functional residual capacity, residual volume, -30, -15, 0, +15, +30 mmHg. Changes in hemodynamic parameters averaged over the duration of a maneuver were studied (the duration of a maneuver was 30 s). Changes in alveolar and, accordingly, intrathoracic pressure influenced hemodynamic more strongly than changes in lung volume or body position. Stroke volume decreased with increasing alveolar pressure and increased with decreasing pressure regardless of lung volume and body position; changes ranged from -35 to +15 ml. The effect of changes in alveolar pressure was more pronounced in a sitting position. Heart rate increased with increasing alveolar pressure (up to +20 bpm) but changed little with decrease in pressure. Mean arterial pressure decreased with decreasing alveolar pressure regardless of lung volume and body position; with increasing alveolar pressure, the result depended on lung volume. When performing maneuvers at total lung capacity, mean arterial pressure remained below baseline values, in other cases it increased. Changes in mean arterial pressure were within {+/-}20 mmHg. Regardless of lung volume and body position, total peripheral resistance decreased with decreasing alveolar pressure and increased with increasing alveolar pressure; the range of changes in total peripheral resistance was -0.3 to +0.7 mmHg{middle dot}s/ml.

BackgroundDespite continuous progress in medical treatment, heart failure (HF) is the leading cause of hospitalizations with a high all-cause mortality in patients. Patients with a left ventricular ejection fraction (LVEF) below 50% are characterized by the highest risk of cardiovascular complications. The objective of this study was to examine how LVEF below 50% and aging impact cardiovascular physiology. MethodsSixteen males with physician diagnosed coronary artery disease and LVEF = 42 {+/-} 6% (age 62 {+/-} 6 years, BMI 29.1 {+/-} 3.8kg/m2) and 10 healthy controls (9 male and 1 female, age 28.5 {+/-} 9.1 years, BMI = 24.1 {+/-} 1.2kg/m2) were recruited in our study. Finger photoplethysmography for blood pressure (BP) and electrocardiogram (ECG) were recorded while participants rested in a supine position. Wavelet transformations were used to analyze the amplitudes, phase coherence and phase difference of BP and ECG. The frequency intervals were separated as follows: I (0.6-2Hz), II (0.145- 0.6Hz), III (0.052-0.145Hz), and IV (0.021-0.052Hz). ResultsHF patients showed a decrease (p<0.05) in BP wavelet amplitude intervals III and IV in comparison to controls, and interval I for ECG. A decrease in phase coherence (p<0.01) at interval I is also found in HF patients compared to controls. ConclusionsA decrease in smooth muscle cell activity and smooth muscle autonomic innervation (intervals III and IV) contributions to BP, along with a decrease in cardiac activity as shown by the wavelet amplitude in ECG, suggests altered BP and ECG function in aging HF patients. Furthermore, a decrease in the cardiac interval represents an impairment in the BP and ECG relationship in HF patients. The wavelet transform has the potential to expand our understanding of LVEF and improve diagnostic procedures and patient prognosis.