Biology subjects

Sato, D.

Publications and source records attributed to Sato, D..

8 recordsLinked to original sources

bioRxiv2025

Role of Dynamical Instability in QT Interval Variability and Early Afterdepolarization Propensity

Beat-to-beat variability of the QT interval (QTV) is a well-established marker of cardiac health, with increased QTV (> 5 ms) often associated with a higher risk of arrhythmias. However, the underlying mechanisms contributing to this phenomenon remain poorly understood. Recently, we showed that cardiac instability is a major cause of QTV. Early afterdepolarizations (EADs) are abnormal electrical oscillations that occur during the plateau phase of the cardiac action potential (AP), often arising when the membrane potential becomes unstable. In this study, we use a physiologically detailed computational model of rabbit ventricular myocytes with stochastic ion channel gating to investigate the relationship between QTV and EAD propensity. We found that increased AP duration (APD) variability, which serves as a surrogate for QTV on the ECG at the single-cell level, can arise even in the absence of apparent EADs, driven by intrinsic dynamical instability. As the cellular state approaches the threshold for EAD generation, small perturbations in membrane voltage are amplified, leading to increased APD variability. The phase-plane analysis in the voltage-calcium channel inactivation space demonstrates that proximity to the EAD-generating basin of attraction strongly influences repolarization variability, establishing a mechanistic link between QTV and EAD propensity. Furthermore, we observed that QTV increases at longer pacing cycle lengths (PCLs), distinguishing it from alternans-associated APD variability, which increases at shorter PCLs. These findings suggest that increased QTV may serve as an early indicator of arrhythmic risk before the manifestation of EADs, potentially offering a critical window for preventive intervention. Our results provide novel insights into the fundamental mechanisms underlying QTV and its potential role in arrhythmia prediction. Significance statementThis study investigates the relationship between beat-to-beat variability of the QT interval (QTV) and the propensity for early afterdepolarizations (EADs), abnormal electrical oscillations linked to life-threatening arrhythmias. Using a computational model, we show that increased QTV can precede apparent EADs, driven by inherent dynamical instability of cardiac cells. As cells approach an arrhythmia-prone state, small membrane voltage fluctuations are amplified, increasing repolarization variability and thus QTV. Furthermore, QTV increases with slower heart rates, distinguishing it from alternans, another type of instability arising at faster rates. Thus, increased QTV may serve as an early warning signal for arrhythmia risk, potentially enabling preventative interventions. Our results provide novel insights into the fundamental mechanisms underlying QTV and its potential role in arrhythmia prediction.

biophysics↗

bioRxiv2025

Fibroblast Density is a Risk Factor for Drug-induced Arrhythmias

A recent study by Kawatou et al. has shown that the local heterogeneity of ion channel conductance is a critical substrate for focal or reentrant arrhythmias. However, the role of fibroblasts with repolarization heterogeneity in the initiation and maintenance of arrhythmias remains unknown. In this study, we investigated how diffuse fibrosis contributes to the formation of focal and reentrant arrhythmias under drug-induced heterogeneity using physiologically detailed mathematical models of the human heart. To simulate drug-induced heterogeneity, we varied the maximum conductance of transmembrane potassium and calcium currents, leading to heterogeneity in action potential duration (APD). Then, we assessed the effects of different fibrosis densities (FD) on the occurrence of premature ventricular complexes (PVCs). Fibroblasts were randomly and evenly inserted into the tissue, and various FD levels ranging from 0 to 35% were examined. We found a biphasic relationship between FD and drug-induced PVCs. Within a certain range of FD, FD positively correlated with PVC susceptibility. However, excessively high fibrosis levels were associated with reduced susceptibility to PVCs. In addition, the self-sustainability of arrhythmias exhibited a positive correlation with FD. This study demonstrates the interplay between the diffuse fibrosis and the drug-induced heterogeneity of APD in the genesis of ventricular arrhythmias. Author summarySudden cardiac death remains a leading cause of death worldwide. Understanding the mechanisms underlying arrhythmia and its precursors is critical for the development of effective therapies and drugs. Repolarization heterogeneity plays a crucial role in both the initiation and maintenance of arrhythmias. Fibroblasts constitute a vital component of cardiac structure, originating from the remodeling of ventricular wall cells or the transformation of injured myocardial cells. Fibroblasts are known to couple with and alter the electrical properties of myocardial cells. However, our understanding of the role of fibroblasts in the development of arrhythmia remains limited. In this study, we employed a physiologically detailed mathematical model of cardiac tissue to investigate the roles of drug-induced heterogeneity and diffuse fibrosis in the initiation and maintenance of arrhythmias. We used 2D and 3D computational models to simulate various levels of drug-induced heterogeneity conditions with normal to pathological levels of fibroblast density (FD). We found that within a certain range of FD, fibroblasts promote PVCs under drug-induced heterogeneity. However, if FD exceeds 30%, the occurrence of PVCs decreases (biphasic relationship). On the other hand, the self-sustainability of VF (ventricular fibrillation) consistently increases with FD. This study implies that fibroblasts in cardiac tissue may play different roles in the initiation and maintenance of arrhythmia.

bioinformatics↗

bioRxiv2024

Exercising with virtual reality is potentially better for the working memory and positive mood than cycling alone

Although virtual reality (VR) exercise has attracted attention as a factor in exercise habituation due to its mood-enhancing effects, its impact on brain function remains unclear. This study, involving 23 healthy university students, used functional magnetic resonance imaging (fMRI) to explore how VR exercise affects working memory, a key executive function, and its underlying neural mechanisms. Our findings indicate that a 10-min VR exercise session improved mood (arousal and vitality level) and working memory task performance (3-back task) more effectively than exercise or rest alone. Furthermore, the results confirmed that increased vitality from exercise and VR exercise interventions was associated with improved 3-back task performance. However, specific brain regions contributing to this enhancement remain unidentified. These results highlight VR exercise as the optimal exercise program for enhancing working memory function by increasing vitality level. These insights underscore VRs potential as a novel exercise modality with benefits extending beyond exercise adherence to potentially preventing dementia and depression.

neuroscience↗

bioRxiv2023

The formation of KV2.1 macro-clusters is required for sex-specific differences in L-type CaV1.2 clustering and function in arterial myocytes

In arterial myocytes, the canonical function of voltage-gated CaV1.2 and KV2.1 channels is to induce myocyte contraction and relaxation through their responses to membrane depolarization, respectively. Paradoxically, KV2.1 also plays a sex-specific role by promoting the clustering and activity of CaV1.2 channels. However, the impact of KV2.1 protein organization on CaV1.2 function remains poorly understood. We discovered that KV2.1 forms micro-clusters, which can transform into large macro-clusters when a critical clustering site (S590) in the channel is phosphorylated in arterial myocytes. Notably, female myocytes exhibit greater phosphorylation of S590, and macro-cluster formation compared to males. Contrary to current models, the activity of KV2.1 channels seems unrelated to density or macro-clustering in arterial myocytes. Disrupting the KV2.1 clustering site (KV2.1S590A) eliminated KV2.1 macro-clustering and sex-specific differences in CaV1.2 cluster size and activity. We propose that the degree of KV2.1 clustering tunes CaV1.2 channel function in a sex-specific manner in arterial myocytes.

physiology↗

bioRxiv2022

Mechanisms of spontaneous Ca2+ release-mediated arrhythmia in a novel 3D human atrial myocyte model: I. Transverse-axial tubule variation

Intracellular calcium (Ca2+) cycling is tightly regulated in the healthy heart ensuring effective contraction. This is achieved by transverse (t)-tubule membrane invaginations that facilitate close coupling of key Ca2+-handling proteins such as the L-type Ca2+ channel (LCC) and Na+-Ca2+ exchanger (NCX) on the cell surface with ryanodine receptors (RyRs) on the intracellular Ca2+ store. Though less abundant and regular than in the ventricle, t-tubules also exist in atrial myocytes as a network of transverse invaginations with axial extensions known as the transverse-axial tubule system (TATS). In heart failure and atrial fibrillation there is TATS remodeling that is associated with aberrant Ca2+-handling and Ca2+-induced arrhythmic activity, however the mechanism underlying this is not fully understood. To address this, we developed a novel 3D human atrial myocyte model that couples electrophysiology and Ca2+-handling with variable TATS organization and density. We extensively parameterized and validated our model against experimental data to build a robust tool examining TATS regulation of subcellular Ca2+ release. We found that varying TATS density and thus the localization of key Ca2+-handling proteins has profound effects on Ca2+ handling. Following TATS loss there is reduced NCX that results in increased cleft Ca2+ concentration through decreased Ca2+ extrusion. This elevated Ca2+ increases RyR open probability causing spontaneous Ca2+ releases and promotion of arrhythmogenic waves (especially in the cell interior) that leads to voltage instabilities through delayed afterdepolarizations. In summary, this study demonstrates a mechanistic link between TATS remodeling and Ca2+-driven proarrhythmic behavior that likely reflects the arrhythmogenic state observed in disease. Key PointsO_LITransverse-axial tubule systems (TATS) modulate Ca2+ handling and excitation-contraction coupling in atrial myocytes, with TATS remodeling in heart failure and atrial fibrillation associated with altered Ca2+ cycling and subsequent arrhythmogenesis. C_LIO_LITo investigate the poorly understood mechanisms linking TATS variation and spontaneous Ca2+ release, we built, parameterized and validated a 3D human atrial myocyte model coupling electrophysiology and spatially-detailed subcellular Ca2+ handling governed by the TATS. C_LIO_LISimulated TATS loss causes diastolic Ca2+ and voltage instabilities through reduced NCX-mediated Ca2+ removal, cleft Ca2+ accumulation and increased RyR open probability, resulting in spontaneous Ca2+ release and promotion of arrhythmogenic waves and delayed afterdepolarizations. C_LIO_LIAt fast electrical rates typical of atrial tachycardia/fibrillation, spontaneous Ca2+ releases are larger and more frequent in the cell interior than at the periphery. C_LIO_LIOur work provides mechanistic insight into how atrial TATS remodeling can lead to Ca2+- driven instabilities that may ultimately contribute to the arrhythmogenic state in disease. C_LI

physiology↗

bioRxiv2022

Mechanisms of spontaneous Ca2+ release-mediated arrhythmia in a novel 3D human atrial myocyte model: II. Ca2+-handling protein variation

Disruption of the transverse-axial tubule system (TATS) in diseases such as heart failure and atrial fibrillation occurs in combination with changes in the expression and distribution of key Ca2+- handling proteins. Together this ultrastructural and ionic remodeling is associated with aberrant Ca2+ cycling and electrophysiological instabilities that underly arrhythmic activity. However, due to the concurrent changes in TATs and Ca2+-handling protein expression and localization that occur in disease it is difficult to distinguish their individual contributions to the arrhythmogenic state. To investigate this, we applied our novel 3D human atrial myocyte model with spatially detailed Ca2+ diffusion and TATS to investigate the isolated and interactive effects of changes in expression and localization of key Ca2+-handling proteins and variable TATS density on Ca2+- handling abnormality driven membrane instabilities. We show that modulating the expression and distribution of the sodium-calcium exchanger, ryanodine receptors, and the sarcoplasmic reticulum (SR) Ca2+ buffer calsequestrin have varying pro and anti-arrhythmic effects depending on the balance of opposing influences on SR Ca2+ leak-load and Ca2+-voltage relationships. Interestingly, the impact of protein remodeling on Ca2+-driven proarrhythmic behavior varied dramatically depending on TATS density, with intermediately tubulated cells being more severely affected compared to detubulated and densely tubulated myocytes. This work provides novel mechanistic insight into the distinct and interactive consequences of TATS and Ca2+-handling protein remodeling that underlies dysfunctional Ca2+ cycling and electrophysiological instability in disease. Key PointsO_LIIn our companion paper we developed a 3D human atrial myocyte model, coupling electrophysiology and Ca2+ handling with subcellular spatial details governed by the transverse-axial tubule system (TATS). C_LIO_LIHere we utilize this model to mechanistically examine the impact of TATS loss and changes in the expression and distribution of key Ca2+-handling proteins known to be remodeled in disease on Ca2+ homeostasis and electrophysiological stability. C_LIO_LIWe demonstrate that varying the expression and localization of these proteins has variable pro- and anti-arrhythmic effects with outcomes displaying dependence on TATS density. C_LIO_LIWhereas detubulated myocytes typically appear unaffected and densely tubulated cells seem protected, the arrhythmogenic effects of Ca2+ handling protein remodeling are profound in intermediately tubulated cells. C_LIO_LIOur work shows the interaction between TATS and Ca2+-handling protein remodeling that underlies the Ca2+-driven proarrhythmic behavior observed in AF and may help to predict the effects of antiarrhythmic strategies at varying stages of ultrastructural remodeling. C_LI

physiology↗

bioRxiv2021

Neural basis for anxiety and anxiety-related physiological responses during simulated driving: An fMRI study

While the exteroceptive and interoceptive prediction of a negative event increases a persons anxiety in daily life situations, the relationship between the brain mechanism of anxiety and the anxiety-related autonomic response has not been fully understood. In this fMRI study, we examined the neural basis of anxiety and anxiety-related autonomic responses in a daily driving situation. Participants viewed a driving video clip in the first-person perspective. During the video clip, participants were presented with a cue to indicate whether a subsequent crash could occur (attention condition) or not (safe condition). Enhanced activities in the anterior insula, bed nucleus of the stria terminalis, thalamus, and periaqueductal gray, and higher sympathetic nerve responses (pupil dilation and peripheral arterial stiffness) were triggered by the attention condition but not with the safe condition. Autonomic response-related functional connectivity was detected in the visual cortex, cerebellum, brainstem, and MCC/PCC with the right anterior insula and its adjacent regions as seed regions. Thus, the right anterior insula and adjacent regions, in collaboration with other regions play a role in eliciting anxiety based on the prediction of negative events, by mediating anxiety-related autonomic responses according to interoceptive information.

neuroscience↗

bioRxiv2021

Effect of electrical hybrid-frequency water bath stunning on the spontaneous electroencephalogram (EEG) and electrocardiogram (ECG) of broilers

Concerns about animal welfare and meat quality have encouraged research on new methods for the stunning of broilers during animal slaughter. In this study, the electroencephalogram (EEG) and electrocardiogram (ECG) of broilers were acquired during stunning using an electrical hybrid instead of a single frequency. Considering a square-wave with a current of 220 mA and a frequency of 1100 Hz (duty-cycle 50%), the hybrid-frequency waveform is obtained generating pulses at 6600 Hertz in the pulse-width phase. Sixty broilers aged 42 days were randomly sampled; thirty were used for EEG measurement and thirty for ECG measurement. For EEG measurements, the birds scalps were anaesthetized, and EEG electrode needles were inserted on the subcutaneous part of the occipital scalp. For ECG, the non-invasive surface electrode was used. The electrodes were connected to a digital EEG/ECG system. The results showed that the hybrid-frequency waveform system generated epileptic forms in the birds EEGs. Therefore, a hybrid-frequency system may present better carcass quality results, while preserving the birds welfare, when compared with a single frequency system use.

neuroscience↗