Shcherbina, Serafima A

Romanova S.A., Berezhnoy A.K., Ruppel L.E., Aitova A.A., Bakumenko S.S., Semidetnov I.S., Naumov V.D., Slotvitsky M.M., Tsvelaya V.A., Agladze K.I.

Cardiac arrhythmias are a major cause of cardiovascular mortality worldwide. Functional heterogeneity of cardiac tissue is an inevitable arrhythmogenic condition that may create nonlinear wave turbulence or reentry with subsequent arrhythmia initiation. The relation between propagation heterogeneity and the onset of reentry is of great theoretical and practical importance. Here, we present a conceptual representation of heterogeneous tissue expressed through alternating local and global tissue anisotropy with discreteness of membrane conductance. To contrast the influence of distributed heterogeneity, we investigated the interaction of a high-frequency wavetrain at a sharp anisotropy-symmetric obstacle. The revealed tendency of a heterogeneous system to form reentry was formalized into the single concept of a vulnerable frequency corridor that can be estimated experimentally. Using the joint in vitro–in silico approach, we defined an anomalous stable growth of a unidirectional block in the vicinity of an obstacle, depending on the direction of the anisotropy vector. This effect explains the limited applicability of homogeneous models to predicting the occurrence of primary reentry. Furthermore, computer simulations showed the special role played by other possible mechanisms of excitation, as ephaptic intercellular coupling, in the formation of a unidirectional block of conduction and reentry onset, which could not be predicted by conduction velocity measurements.

Kalinin A., Naumov V., Kovalenko S., Berezhnoy A., Slotvitsky M., Scherbina S., Aitova A., Syrovnev V., Popov M., Kalemberg A., kizi Frolova S.R., Agladze K., Tsvelaya V.

The occurrence of atrial fibrillation (AF), one of the most socially significant arrhythmias, is associated with the presence of areas of fibrosis. Fibrosis introduces conduction heterogeneity into the cardiac tissue and, thus, may be a substrate for spiral wave reentry, which provokes the onset of AF and is often associated with its persistence. Despite results from computer and animal models of cardiac tissues, data on the conditions under which microreentries occur in human tissues are limited. In this work, we conducted a study of the new approach to modeling the fibrous atrial tissue, which takes into account the cellular structure and conduction in fibrosis areas. Using the Potts model, we created a realistic texture of atrial tissues remodeled by fibroblasts and showed the presence of pathways in such a system with a low proportion of fibroblasts. Our study revealed the relationship between the shape of the cells’ action potential, their location in the tissue, and the direction of the wave propagation. The wavefront obtained in the model creates a dynamic heterogeneity of the tissue, which affects the migration and pinning of spiral waves, and explains the formation of microreentries in the cardiac tissue. In the future, such a model can become a potential tool for predictive modeling of AF and the search for ablation target identification.

Aitova A., Scherbina S., Berezhnoy A., Slotvitsky M., Tsvelaya V., Sergeeva T., Turchaninova E., Rybkina E., Bakumenko S., Sidorov I., Popov M.A., Dontsov V., Agafonov E.G., Efimov A.E., Agapov I., et. al.

Myocardial remodeling is an inevitable risk factor for cardiac arrhythmias and can potentially be corrected with cell therapy. Although the generation of cardiac cells ex vivo is possible, specific approaches to cell replacement therapy remain unclear. On the one hand, adhesive myocyte cells must be viable and conjugated with the electromechanical syncytium of the recipient tissue, which is unattainable without an external scaffold substrate. On the other hand, the outer scaffold may hinder cell delivery, for example, making intramyocardial injection difficult. To resolve this contradiction, we developed molecular vehicles that combine a wrapped (rather than outer) polymer scaffold that is enveloped by the cell and provides excitability restoration (lost when cells were harvested) before engraftment. It also provides a coating with human fibronectin, which initiates the process of graft adhesion into the recipient tissue and can carry fluorescent markers for the external control of the non-invasive cell position. In this work, we used a type of scaffold that allowed us to use the advantages of a scaffold-free cell suspension for cell delivery. Fragmented nanofibers (0.85 µm ± 0.18 µm in diameter) with fluorescent labels were used, with solitary cells seeded on them. Cell implantation experiments were performed in vivo. The proposed molecular vehicles made it possible to establish rapid (30 min) electromechanical contact between excitable grafts and the recipient heart. Excitable grafts were visualized with optical mapping on a rat heart with Langendorff perfusion at a 0.72 ± 0.32 Hz heart rate. Thus, the pre-restored grafts’ excitability (with the help of a wrapped polymer scaffold) allowed rapid electromechanical coupling with the recipient tissue. This information could provide a basis for the reduction of engraftment arrhythmias in the first days after cell therapy.

Abrasheva V.O., Kovalenko S.G., Slotvitsky M., Scherbina S.A., Aitova A.A., Frolova S., Tsvelaya V., Syunyaev R.A.

AbstractVoltage-gated sodium channels are crucial to action potential propagation in excitable tissues. Voltage-clamp measurements of sodium current are very challenging and are usually performed at room temperature due to the high amplitude and fast activation of the current. In this study, we measured sodium current’s voltage dependence in stem-cell-derived cardiomyocytes at physiological temperature. Although apparent activation and inactivation curves measured as the sodium current amplitude dependence on voltage step is within the range reported in previous studies, we demonstrate a systematic error in our measurements that is due to deviation of membrane potential from the command potential of the amplifier. We show how this artifact can be accounted for by the computer simulation of the patch-clamp experiment. This patch-clamp model optimization technique yields a surprising result: −11.5 mV half-activation and −87 mV half-inactivation of the sodium current. Although the half-activation is strikingly different from what was previously believed to be typical for the cardiac sodium current, we show that this estimate explains conduction velocity dependence on extracellular potassium in hyperkalemic conditions.Key pointsVoltage gated sodium currents play a crucial role in excitable tissues including neurons, cardiac and skeletal muscles.Measurement of sodium current is challenging because of its high amplitude and rapid kinetics, especially at physiological temperature.We have used the patch-clamp technique to measure human sodium current voltage-dependence in human induced pluripotent stem cell-derived cardiomyocytes.The patch-clamp data was processed by optimization of the model accounting for voltage-clamp experiment artifacts, revealing a large difference between apparent parameters of sodium current and the results of the optimization.We conclude that actual sodium current activation is extremely depolarized in comparison to previous studies.The new sodium current model provides a better understanding of action potential propagation, we demonstrate that it explains propagation in hyperkalemic conditions.

Slotvitsky M., Berezhnoy A., Scherbina S., Rimskaya B., Tsvelaya V., Balashov V., Efimov A.E., Agapov I., Agladze K.

Induced pluripotent stem cells (iPSCs) constitute a potential source of patient-specific human cardiomyocytes for a cardiac cell replacement therapy via intramyocardial injections, providing a major benefit over other cell sources in terms of immune rejection. However, intramyocardial injection of the cardiomyocytes has substantial challenges related to cell survival and electrophysiological coupling with recipient tissue. Current methods of manipulating cell suspensions do not allow one to control the processes of adhesion of injected cells to the tissue and electrophysiological coupling with surrounding cells. In this article, we documented the possibility of influencing these processes using polymer kernels: biocompatible fiber fragments of subcellular size that can be adsorbed to a cell, thereby creating the minimum necessary adhesion foci to shape the cell and provide support for the organization of the cytoskeleton and the contractile apparatus prior to adhesion to the recipient tissue. Using optical excitation markers, the restoration of the excitability of cardiomyocytes in suspension upon adsorption of polymer kernels was shown. It increased the likelihood of the formation of a stable electrophysiological coupling in vitro. The obtained results may be considered as a proof of concept that the stochastic engraftment process of injected suspension cells can be controlled by smart biomaterials.

Shcherbina S.A., Shutko A.V., Nizamieva A.A., Nikitina A.V., Slotvitsky M.M., Tsvelaya V.A., Agladze K.I.

In the last decade, in vitro experiments have shown that mechanical properties of the bases could markedly influence the efficacy of differentiation of the induced pluripotent and embryonic stem cells and their development into the mature phenotype. By changing of mechanical, elastic and structural characteristics of the base, it is possible to increase the percentage of stem cells that differentiate to cardiomyocytes. The study was aimed at evaluation of the effects induced by changing physical characteristics of the base on the formation of phenotypic characteristics of cardiac cells. This included the comparison of structural properties of the cultured layer of heart tissue obtained by changing of elasticity and structure of polymeric bases. The results showed significant differences in calcium activity and structural characteristics of cardiomyocytes depending on the base properties, as well as significant variation in the excitation conduction. As long as conduction abnormalities in the heart tissues can often lead to occurrence of life-threatening cardiac arrhythmias, the results can be used to determine patient groups at increased risk of death from heart failure.

Nezhad Hajian D., Parastesh F., Rajagopal K., Jafari S., Perc M.

This study explores the interaction between two distinct sites, termed the source and the sink, to analyze the possibility of spiral wave formation. To this aim, a grid of memristive FitzHugh–Nagumo elements is designed to simulate biological excitable media, such as the myocardium. The source, characterized by high excitation levels with a gradual increase in the recovery variable, is primed to generate an excitatory wavefront. In contrast, the sink remains quiescent in excitation yet elevated in the recovery state, thus tending to absorb excitation as it is temporarily unexcitable but soon recoverable. Existing literature on spiral wave formation primarily focuses on rotor formation under source–sink adjacency. This work, on the other hand, examines the potential for re-entrant behavior under spatial separation between the source and the sink. Within the context of eight-nearest neighbor coupling, the results indicate that the time delay for the excitation wave to reach the refractory state of the sink, due to the increased distance, may still facilitate re-entry if the intensity of connections is sufficiently weak. However, beyond a certain threshold of the source–sink distance under weak connections, wave breakage may occur without resulting in re-entry. For the birth of a spiral wave rotor, the tip of the excitatory wavefront must converge with its refractory back, specifically at the outermost contour in the final stage of refractoriness, referred to as the wavetail. The formation of a spiral rotor cannot arise from a wavefront encountering any site earlier in the stage of refractoriness.

Kiseleva D.G., Dzhabrailov V.D., Aitova A.A., Turchaninova E.A., Tsvelaya V.A., Kazakova M.A., Plyusnina T.Y., Markin A.M.

Myocardial edema is a common symptom of pathological processes in the heart, causing aggravation of cardiovascular diseases and leading to irreversible myocardial remodeling. Patient-based studies show that myocardial edema is associated with arrhythmias. Currently, there are no studies that have examined how edema may influence changes in calcium dynamics in the functional syncytium. We performed optical mapping of calcium dynamics on a monolayer of neonatal rat cardiomyocytes with Fluo-4. The osmolality of the solutions was adjusted using the NaCl content. The initial Tyrode solution contained 140 mM NaCl (1T) and the hypoosmotic solutions contained 105 (0.75T) and 70 mM NaCl (0.5T). This study demonstrated a sharp decrease in the calcium wave propagation speed with a decrease in the solution osmolality. The successive decrease in osmolality also showed a transition from a normal wavefront to spiral wave and multiple wavelets of excitation with wave break. Our study demonstrated that, in a cellular model, hypoosmolality and, as a consequence, myocardial edema, could potentially lead to fatal ventricular arrhythmias, which to our knowledge has not been studied before. At 0.75T spiral waves appeared, whereas multiple wavelets of excitation occurred in 0.5T, which had not been recorded previously in a two-dimensional monolayer under conditions of cell edema without changes in the pacing protocol.

Gizzi A., McCulloch A.D., Drapaca C.S.

Romanova S.A., Berezhnoy A.K., Ruppel L.E., Aitova A.A., Bakumenko S.S., Semidetnov I.S., Naumov V.D., Slotvitsky M.M., Tsvelaya V.A., Agladze K.I.

Cardiac arrhythmias are a major cause of cardiovascular mortality worldwide. Functional heterogeneity of cardiac tissue is an inevitable arrhythmogenic condition that may create nonlinear wave turbulence or reentry with subsequent arrhythmia initiation. The relation between propagation heterogeneity and the onset of reentry is of great theoretical and practical importance. Here, we present a conceptual representation of heterogeneous tissue expressed through alternating local and global tissue anisotropy with discreteness of membrane conductance. To contrast the influence of distributed heterogeneity, we investigated the interaction of a high-frequency wavetrain at a sharp anisotropy-symmetric obstacle. The revealed tendency of a heterogeneous system to form reentry was formalized into the single concept of a vulnerable frequency corridor that can be estimated experimentally. Using the joint in vitro–in silico approach, we defined an anomalous stable growth of a unidirectional block in the vicinity of an obstacle, depending on the direction of the anisotropy vector. This effect explains the limited applicability of homogeneous models to predicting the occurrence of primary reentry. Furthermore, computer simulations showed the special role played by other possible mechanisms of excitation, as ephaptic intercellular coupling, in the formation of a unidirectional block of conduction and reentry onset, which could not be predicted by conduction velocity measurements.

Abrasheva V.O., Kovalenko S.G., Slotvitsky M., Romanova S.А., Aitova A.A., Frolova S., Tsvelaya V., Syunyaev R.A.

AbstractVoltage‐gated Na+ channels are crucial to action potential propagation in excitable tissues. Because of the high amplitude and rapid activation of the Na+ current, voltage‐clamp measurements are very challenging and are usually performed at room temperature. In this study, we measured Na+ current voltage‐dependence in stem cell‐derived cardiomyocytes at physiological temperature. While the apparent activation and inactivation curves, measured as the dependence of current amplitude on voltage, fall within the range reported in previous studies, we identified a systematic error in our measurements. This error is caused by the deviation of the membrane potential from the command potential of the amplifier. We demonstrate that it is possible to account for this artifact using computer simulation of the patch‐clamp experiment. We obtained surprising results through patch‐clamp model optimization: a half‐activation of −11.5 mV and a half‐inactivation of −87 mV. Although the half‐activation deviates from previous research, we demonstrate that this estimate reproduces the conduction velocity dependence on extracellular potassium concentration. imageKey points Voltage‐gated Na+ currents play a crucial role in excitable tissues including neurons, cardiac and skeletal muscle. Measurement of Na+ current is challenging because of its high amplitude and rapid kinetics, especially at physiological temperature. We have used the patch‐clamp technique to measure human Na+ current voltage‐dependence in human induced pluripotent stem cell‐derived cardiomyocytes. The patch‐clamp data were processed by optimization of the model accounting for voltage‐clamp experiment artifacts, revealing a large difference between apparent parameters of Na+ current and the results of the optimization. We conclude that actual Na+ current activation is extremely depolarized in comparison to previous studies. The new Na+ current model provides a better understanding of action potential propagation; we demonstrate that it explains propagation in hyperkalaemic conditions.

Aitova A., Berezhnoy A., Tsvelaya V., Gusev O., Lyundup A., Efimov A.E., Agapov I., Agladze K.

Cardiac arrhythmias are a major cause of cardiovascular mortality worldwide. Many arrhythmias are caused by reentry, a phenomenon where excitation waves circulate in the heart. Optical mapping techniques have revealed the role of reentry in arrhythmia initiation and fibrillation transition, but the underlying biophysical mechanisms are still difficult to investigate in intact hearts. Tissue engineering models of cardiac tissue can mimic the structure and function of native cardiac tissue and enable interactive observation of reentry formation and wave propagation. This review will present various approaches to constructing cardiac tissue models for reentry studies, using the authors’ work as examples. The review will highlight the evolution of tissue engineering designs based on different substrates, cell types, and structural parameters. A new approach using polymer materials and cellular reprogramming to create biomimetic cardiac tissues will be introduced. The review will also show how computational modeling of cardiac tissue can complement experimental data and how such models can be applied in the biomimetics of cardiac tissue.

Aitova A., Scherbina S., Berezhnoy A., Slotvitsky M., Tsvelaya V., Sergeeva T., Turchaninova E., Rybkina E., Bakumenko S., Sidorov I., Popov M.A., Dontsov V., Agafonov E.G., Efimov A.E., Agapov I., et. al.

Myocardial remodeling is an inevitable risk factor for cardiac arrhythmias and can potentially be corrected with cell therapy. Although the generation of cardiac cells ex vivo is possible, specific approaches to cell replacement therapy remain unclear. On the one hand, adhesive myocyte cells must be viable and conjugated with the electromechanical syncytium of the recipient tissue, which is unattainable without an external scaffold substrate. On the other hand, the outer scaffold may hinder cell delivery, for example, making intramyocardial injection difficult. To resolve this contradiction, we developed molecular vehicles that combine a wrapped (rather than outer) polymer scaffold that is enveloped by the cell and provides excitability restoration (lost when cells were harvested) before engraftment. It also provides a coating with human fibronectin, which initiates the process of graft adhesion into the recipient tissue and can carry fluorescent markers for the external control of the non-invasive cell position. In this work, we used a type of scaffold that allowed us to use the advantages of a scaffold-free cell suspension for cell delivery. Fragmented nanofibers (0.85 µm ± 0.18 µm in diameter) with fluorescent labels were used, with solitary cells seeded on them. Cell implantation experiments were performed in vivo. The proposed molecular vehicles made it possible to establish rapid (30 min) electromechanical contact between excitable grafts and the recipient heart. Excitable grafts were visualized with optical mapping on a rat heart with Langendorff perfusion at a 0.72 ± 0.32 Hz heart rate. Thus, the pre-restored grafts’ excitability (with the help of a wrapped polymer scaffold) allowed rapid electromechanical coupling with the recipient tissue. This information could provide a basis for the reduction of engraftment arrhythmias in the first days after cell therapy.

Abrasheva V.O., Kovalenko S.G., Slotvitsky M., Scherbina S.A., Aitova A.A., Frolova S., Tsvelaya V., Syunyaev R.A.

AbstractVoltage-gated sodium channels are crucial to action potential propagation in excitable tissues. Voltage-clamp measurements of sodium current are very challenging and are usually performed at room temperature due to the high amplitude and fast activation of the current. In this study, we measured sodium current’s voltage dependence in stem-cell-derived cardiomyocytes at physiological temperature. Although apparent activation and inactivation curves measured as the sodium current amplitude dependence on voltage step is within the range reported in previous studies, we demonstrate a systematic error in our measurements that is due to deviation of membrane potential from the command potential of the amplifier. We show how this artifact can be accounted for by the computer simulation of the patch-clamp experiment. This patch-clamp model optimization technique yields a surprising result: −11.5 mV half-activation and −87 mV half-inactivation of the sodium current. Although the half-activation is strikingly different from what was previously believed to be typical for the cardiac sodium current, we show that this estimate explains conduction velocity dependence on extracellular potassium in hyperkalemic conditions.Key pointsVoltage gated sodium currents play a crucial role in excitable tissues including neurons, cardiac and skeletal muscles.Measurement of sodium current is challenging because of its high amplitude and rapid kinetics, especially at physiological temperature.We have used the patch-clamp technique to measure human sodium current voltage-dependence in human induced pluripotent stem cell-derived cardiomyocytes.The patch-clamp data was processed by optimization of the model accounting for voltage-clamp experiment artifacts, revealing a large difference between apparent parameters of sodium current and the results of the optimization.We conclude that actual sodium current activation is extremely depolarized in comparison to previous studies.The new sodium current model provides a better understanding of action potential propagation, we demonstrate that it explains propagation in hyperkalemic conditions.

Nezhad Hajian D., Parastesh F., Jafari S., Perc M., Klemenčič E.

We study the spatiotemporal dynamics of spiral waves in a lattice of chemically coupled memristive FitzHugh–Nagumo neurons. We also introduce local and global functional inhomogeneities by means of variations in nodal action potentials that are distributed in different ways. We find that, in the presence of globally distributed random inhomogeneity, increasing the maximum threshold for excitability generates neurons with reduced depolarization capacity. Although such a setup makes the entire medium less excitable and thus challenges the robustness of emerging spiral waves, highly excitable neurons can compensate for the less excitable ones, thereby nonetheless preserving the spiral wave pattern. However, this compensatory mechanism has limitations, which can ultimately lead to the elimination of spiral waves under specific conditions. When inhomogeneities are local, two different scenarios are possible. If the distribution is random, the spiral tip cannot penetrate the inhomogeneous region but remains resilient against it. The tip is consistently anchored to the inhomogeneity, meandering around its boundary. As the inhomogeneity size increases, the curvature of the spiral tip and the propagation speed of the circular wavefronts decrease. If the distribution is uniform, inhomogeneities are analogous to semi-conducting barriers, thus permitting the spiral rotor to penetrate while sacrificing the strength of its wavefronts.

Hussaini S., Lädke S.L., Schröder-Schetelig J., Venkatesan V., Quiñonez Uribe R.A., Richter C., Majumder R., Luther S.

Rotating spiral waves in the heart are associated with life-threatening cardiac arrhythmias such as ventricular tachycardia and fibrillation. These arrhythmias are treated by a process called defibrillation, which forces electrical resynchronization of the heart tissue by delivering a single global high-voltage shock directly to the heart. This method leads to immediate termination of spiral waves. However, this may not be the only mechanism underlying successful defibrillation, as certain scenarios have also been reported, where the arrhythmia terminated slowly, over a finite period of time. Here, we investigate the slow termination dynamics of an arrhythmia in optogenetically modified murine cardiac tissue both in silico and ex vivo during global illumination at low light intensities. Optical imaging of an intact mouse heart during a ventricular arrhythmia shows slow termination of the arrhythmia, which is due to action potential prolongation observed during the last rotation of the wave. Our numerical studies show that when the core of a spiral is illuminated, it begins to expand, pushing the spiral arm towards the inexcitable boundary of the domain, leading to termination of the spiral wave. We believe that these fundamental findings lead to a better understanding of arrhythmia dynamics during slow termination, which in turn has implications for the improvement and development of new cardiac defibrillation techniques.

Peters M.M., Brister J.K., Tang E.M., Zhang F.W., Lucian V.M., Trackey P.D., Bone Z., Zimmerman J.F., Jin Q., Burpo F.J., Parker K.K.

In tissues and organs, the extracellular matrix (ECM) helps maintain inter- and intracellular architectures that sustain the structure–function relationships defining physiological homeostasis. Combining fiber scaffolds and cells to form engineered tissues is a means of replicating these relationships. Engineered tissues' fiber scaffolds are designed to mimic the topology and chemical composition of the ECM network. Here, we asked how cells found in the heart compare in their propensity to align their cytoskeleton and self-organize in response to topological cues in fibrous scaffolds. We studied cardiomyocytes, valvular interstitial cells, and vascular endothelial cells as they adapted their inter- and intracellular architectures to the extracellular space. We used focused rotary jet spinning to manufacture aligned fibrous scaffolds to mimic the length scale and three-dimensional (3D) nature of the native ECM in the muscular, valvular, and vascular tissues of the heart. The representative cardiovascular cell types were seeded onto fiber scaffolds and infiltrated the fibrous network. We measured different cell types' propensity for cytoskeletal alignment in response to fiber scaffolds with differing levels of anisotropy. The results indicated that valvular interstitial cells on moderately anisotropic substrates have a higher propensity for cytoskeletal alignment than cardiomyocytes and vascular endothelial cells. However, all cell types displayed similar levels of alignment on more extreme (isotropic and highly anisotropic) fiber scaffold organizations. These data suggest that in the hierarchy of signals that dictate the spatiotemporal organization of a tissue, geometric cues within the ECM and cellular networks may homogenize behaviors across cell populations and demographics.

Liu P., Leung E.M., Badshah M.A., Moore C.S., Gorodetsky A.A.

Wearable thermoregulatory technologies have attracted widespread attention because of their potential for impacting individual physiological comfort and for reducing building energy consumption. Within this context, the study of materials and systems that can merge the advantageous characteristics of both active and passive operating modes has proven particularly attractive. Accordingly, our laboratory has drawn inspiration from the appearance-changing skin of Loliginidae (inshore squids) for the introduction of a unique class of dynamic thermoregulatory composite materials with outstanding figures of merit. Herein, we demonstrate a straightforward approach for experimentally controlling and computationally predicting the adaptive infrared properties of such bioinspired composites, thereby enabling the development and validation of robust structure–function relationships for the composites. Our findings may help unlock the potential of not only the described materials but also comparable systems for applications as varied as thermoregulatory wearables, food packaging, infrared camouflage, soft robotics, and biomedical sensing.

Maciunas K., Snipas M., Kraujalis T., Kraujalienė L., Panfilov A.V.

AbstractGap junctions (GJs) formed of connexin (Cx) protein are the main conduits of electrical signals in the heart. Studies indicate that the transitional zone of the atrioventricular (AV) node contains heterotypic Cx43/Cx45 GJ channels which are highly sensitive to transjunctional voltage (Vj). To investigate the putative role of Vj gating of Cx43/Cx45 channels, we performed electrophysiological recordings in cell cultures and developed a novel mathematical/computational model which, for the first time, combines GJ channel Vj gating with a model of membrane excitability to simulate a spread of electrical pulses in 2D. Our simulation and electrophysiological data show that Vj transients during the spread of cardiac excitation can significantly affect the junctional conductance (gj) of Cx43/Cx45 GJs in a direction- and frequency-dependent manner. Subsequent simulation data indicate that such pulse-rate-dependent regulation of gj may have a physiological role in delaying impulse propagation through the AV node. We have also considered the putative role of the Cx43/Cx45 channel gating during pathological impulse propagation. Our simulation data show that Vj gating-induced changes in gj can cause the drift and subsequent termination of spiral waves of excitation. As a result, the development of fibrillation-like processes was significantly reduced in 2D clusters, which contained Vj-sensitive Cx43/Cx45 channels.

Kalinin A., Naumov V., Kovalenko S., Berezhnoy A., Slotvitsky M., Scherbina S., Aitova A., Syrovnev V., Popov M., Kalemberg A., kizi Frolova S.R., Agladze K., Tsvelaya V.

The occurrence of atrial fibrillation (AF), one of the most socially significant arrhythmias, is associated with the presence of areas of fibrosis. Fibrosis introduces conduction heterogeneity into the cardiac tissue and, thus, may be a substrate for spiral wave reentry, which provokes the onset of AF and is often associated with its persistence. Despite results from computer and animal models of cardiac tissues, data on the conditions under which microreentries occur in human tissues are limited. In this work, we conducted a study of the new approach to modeling the fibrous atrial tissue, which takes into account the cellular structure and conduction in fibrosis areas. Using the Potts model, we created a realistic texture of atrial tissues remodeled by fibroblasts and showed the presence of pathways in such a system with a low proportion of fibroblasts. Our study revealed the relationship between the shape of the cells’ action potential, their location in the tissue, and the direction of the wave propagation. The wavefront obtained in the model creates a dynamic heterogeneity of the tissue, which affects the migration and pinning of spiral waves, and explains the formation of microreentries in the cardiac tissue. In the future, such a model can become a potential tool for predictive modeling of AF and the search for ablation target identification.

Chandarana P., Hegade N.N., Montalban I., Solano E., Chen X.

The challenge of predicting protein folding---a pivotal task in biology, chemistry, and drug design---has yet to be fully surmounted, due to the complexity of finding the lowest-energy configuration of the constituent amino acids. The current study provides a hybrid classical-quantum digitized counterdiabatic approach that enhances the performance of existing quantum algorithms, producing remarkable results even in the NISQ era. This innovative solution opens up possibilities for tackling complex problems in biology and chemistry, pushing the boundaries of what is achievable with quantum computing.

Aitova A., Scherbina S., Berezhnoy A., Slotvitsky M., Tsvelaya V., Sergeeva T., Turchaninova E., Rybkina E., Bakumenko S., Sidorov I., Popov M.A., Dontsov V., Agafonov E.G., Efimov A.E., Agapov I., et. al.

Myocardial remodeling is an inevitable risk factor for cardiac arrhythmias and can potentially be corrected with cell therapy. Although the generation of cardiac cells ex vivo is possible, specific approaches to cell replacement therapy remain unclear. On the one hand, adhesive myocyte cells must be viable and conjugated with the electromechanical syncytium of the recipient tissue, which is unattainable without an external scaffold substrate. On the other hand, the outer scaffold may hinder cell delivery, for example, making intramyocardial injection difficult. To resolve this contradiction, we developed molecular vehicles that combine a wrapped (rather than outer) polymer scaffold that is enveloped by the cell and provides excitability restoration (lost when cells were harvested) before engraftment. It also provides a coating with human fibronectin, which initiates the process of graft adhesion into the recipient tissue and can carry fluorescent markers for the external control of the non-invasive cell position. In this work, we used a type of scaffold that allowed us to use the advantages of a scaffold-free cell suspension for cell delivery. Fragmented nanofibers (0.85 µm ± 0.18 µm in diameter) with fluorescent labels were used, with solitary cells seeded on them. Cell implantation experiments were performed in vivo. The proposed molecular vehicles made it possible to establish rapid (30 min) electromechanical contact between excitable grafts and the recipient heart. Excitable grafts were visualized with optical mapping on a rat heart with Langendorff perfusion at a 0.72 ± 0.32 Hz heart rate. Thus, the pre-restored grafts’ excitability (with the help of a wrapped polymer scaffold) allowed rapid electromechanical coupling with the recipient tissue. This information could provide a basis for the reduction of engraftment arrhythmias in the first days after cell therapy.

Ammarullah M.I., Hartono R., Supriyono T., Santoso G., Sugiharto S., Permana M.S.

Due to polymeric wear debris causing osteolysis from polymer, metal ions causing metallosis from metal, and brittle characteristic causing fracture failure from ceramic in the application on bearing of total hip prosthesis requires the availability of new material options as a solution to these problems. Polycrystalline diamond (PCD) has the potential to become the selected material for hard-on-hard bearing in view of its advantages in terms of mechanical properties and biocompatibility. The present study contributes to confirming the potential of PCD to replace metals and ceramics for hard-on-hard bearing through von Mises stress investigations. A computational simulation using a 2D axisymmetric finite element model of hard-on-hard bearing under gait loading has been performed. The percentage of maximum von Mises stress to respective yield strength from PCD-on-PCD is the lowest at 2.47%, with CoCrMo (cobalt chromium molybdenum)-on-CoCrMo at 10.79%, and Al2O3 (aluminium oxide)-on-Al2O3 at 13.49%. This confirms that the use of PCD as a hard-on-hard bearing material is the safest option compared to the investigated metal and ceramic hard-on-hard bearings from the mechanical perspective.

Shipunova V.O., Komedchikova E.N., Kotelnikova P.A., Nikitin M.P., Deyev S.M.

Therapy for aggressive metastatic breast cancer remains a great challenge for modern biomedicine. Biocompatible polymer nanoparticles have been successfully used in clinic and are seen as a potential solution. Specifically, researchers are exploring the development of chemotherapeutic nanoagents targeting the membrane-associated receptors of cancer cells, such as HER2. However, there are no targeting nanomedications that have been approved for human cancer therapy. Novel strategies are being developed to alter the architecture of agents and optimize their systemic administration. Here, we describe a combination of these approaches, namely, the design of a targeted polymer nanocarrier and a method for its systemic delivery to the tumor site. Namely, PLGA nanocapsules loaded with a diagnostic dye, Nile Blue, and a chemotherapeutic compound, doxorubicin, are used for two-step targeted delivery using the concept of tumor pre-targeting through the barnase/barstar protein “bacterial superglue”. The first pre-targeting component consists of an anti-HER2 scaffold protein, DARPin9_29 fused with barstar, Bs-DARPin9_29, and the second component comprises chemotherapeutic PLGA nanocapsules conjugated to barnase, PLGA-Bn. The efficacy of this system was evaluated in vivo. To this aim, we developed an immunocompetent BALB/c mouse tumor model with a stable expression of human HER2 oncomarkers to test the potential of two-step delivery of oncotheranostic nano-PLGA. In vitro and ex vivo studies confirmed HER2 receptor stable expression in the tumor, making it a feasible tool for HER2-targeted drug evaluation. We demonstrated that two-step delivery was more effective than one-step delivery for both imaging and tumor therapy: two-step delivery had higher imaging capabilities than one-step and a tumor growth inhibition of 94.9% in comparison to 68.4% for the one-step strategy. The barnase*barstar protein pair has been proven to possess excellent biocompatibility, as evidenced by the successful completion of biosafety tests assessing immunogenicity and hemotoxicity. This renders the protein pair a highly versatile tool for pre-targeting tumors with various molecular profiles, thereby enabling the development of personalized medicine.

Fassina D., M. Costa C., Bishop M., Plank G., Whitaker J., Harding S.E., Niederer S.A.

Post myocardial infarction (MI) ventricles contain fibrotic tissue and may have disrupted electrical properties, both of which predispose to an increased risk of life-threatening arrhythmias. Application of epicardial patches obtained from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a potential long-term therapy to treat heart failure resulting from post MI remodelling. However, whether the introduction of these patches is anti- or pro-arrhythmic has not been studied. We studied arrhythmic risk using in silico engineered heart tissue (EHT) patch engraftment on human post-MI ventricular models. Two patient models were studied, including one with a large dense scar and one with an apparent channel of preserved viability bordered on both sides by scar. In each heart model a virtual EHT patch was introduced as a layer of viable tissue overlying the scarred area, with hiPSC-CMs electrophysiological properties. The incidence of re-entrant and sustained activation in simulations with and without EHT patches was assessed and the arrhythmia inducibility compared in the context of different EHT patch properties (conduction velocity (CV) and action potential duration (APD)). The impact of the EHT patch on the likelihood of focal ectopic impulse propagation was estimated by assessing the minimum stimulus strength and duration required to generate a propagating impulse in the scar border zone (BZ) with and without patch. We uncovered two main mechanisms by which ventricular tachycardia (VT) risk could be either augmented or attenuated by the interaction of the patch with the tissue. In the case of isthmus-related VT, our simulations predict that EHT patches can prevent the induction of VT when the, generally longer, hiPSC-CMs APD is reduced towards more physiological values. In the case of large dense scar, we found that, an EHT patch with CV similar to the host myocardium does not promote VT, while EHT patches with lower CV increase the risk of VT, by promoting both non-sustained and sustained re-entry. Finally, our simulations indicate that electrically coupled EHT patches reduce the likelihood of propagation of focal ectopic impulses. The introduction of EHT patches as a treatment for heart failure has the potential to augment or attenuate the risk of ventricular arrhythmias, and variations in the anatomic configuration of the substrate, the functional properties of the BZ and the electrophysiologic properties of the patch itself will determine the overall impact. Planning for delivery of this therapy will need to consider the possible impact on arrhythmia.

Takahashi F., Patel P., Kitsuka T., Arai K.

Induced pluripotent stem cells (iPSCs) have become a prevalent topic after their discovery, advertised as an ethical alternative to embryonic stem cells (ESCs). Due to their ability to differentiate into several kinds of cells, including cardiomyocytes, researchers quickly realized the potential for differentiated cardiomyocytes to be used in the treatment of heart failure, a research area with few alternatives. This paper discusses the differentiation process for human iPSC-derived cardiomyocytes and the possible applications of said cells while answering some questions regarding ethical issues.

Prakoso A.T., Basri H., Adanta D., Yani I., Ammarullah M.I., Akbar I., Ghazali F.A., Syahrom A., Kamarul T.

In designing porous scaffolds, permeability is essential to consider as a function of cell migration and bone tissue regeneration. Good permeability has been achieved by mimicking the complexity of natural cancellous bone. In this study, a porous scaffold was developed according to the morphological indices of cancellous bone (porosity, specific surface area, thickness, and tortuosity). The computational fluid dynamics method analyzes the fluid flow through the scaffold. The permeability values of natural cancellous bone and three types of scaffolds (cubic, octahedron pillar, and Schoen’s gyroid) were compared. The results showed that the permeability of the Negative Schwarz Primitive (NSP) scaffold model was similar to that of natural cancellous bone, which was in the range of 2.0 × 10−11 m2 to 4.0 × 10−10 m2. In addition, it was observed that the tortuosity parameter significantly affected the scaffold’s permeability and shear stress values. The tortuosity value of the NSP scaffold was in the range of 1.5–2.8. Therefore, tortuosity can be manipulated by changing the curvature of the surface scaffold radius to obtain a superior bone tissue engineering construction supporting cell migration and tissue regeneration. This parameter should be considered when making new scaffolds, such as our NSP. Such efforts will produce a scaffold architecturally and functionally close to the natural cancellous bone, as demonstrated in this study.

Nizamieva A.A., Kalita I.Y., Slotvitsky M.M., Berezhnoy A.K., Shubina N.S., Frolova S.R., Tsvelaya V.A., Agladze K.I.

The development of new approaches to suppressing cardiac arrhythmias requires a deep understanding of spiral wave dynamics. The study of spiral waves is possible in model systems, for example, in a monolayer of cardiomyocytes. A promising way to control cardiac excitability in vitro is the noninvasive photocontrol of cell excitability mediated by light-sensitive azobenzene derivatives, such as azobenzene trimethylammonium bromide (AzoTAB). The trans-isomer of AzoTAB suppresses spontaneous activity and excitation propagation speed, whereas the cis isomer has no detectable effect on the electrical properties of cardiomyocyte monolayers; cis isomerization occurs under the action of near ultraviolet (UV) light, and reverse isomerization occurs when exposed to blue light. Thus, AzoTAB makes it possible to create patterns of excitability in conductive tissue. Here, we investigate the effect of a simulated excitability gradient in cardiac cell culture on the behavior and termination of reentry waves. Experimental data indicate a displacement of the reentry wave, predominantly in the direction of lower excitability. However, both shifts in the direction of higher excitability and shift absence were also observed. To explain this effect, we reproduced these experiments in a computer model. Computer simulations showed that the explanation of the mechanism of observed drift to a lower excitability area requires not only a change in excitability coefficients (ion currents) but also a change in the diffusion coefficient; this may be the effect of the substance on intercellular connections. In addition, it was found that the drift direction depended on the observation time due to the meandering of the spiral wave. Thus, we experimentally proved the possibility of noninvasive photocontrol and termination of spiral waves with a mechanistic explanation in computer models.

Putra R.U., Basri H., Prakoso A.T., Chandra H., Ammarullah M.I., Akbar I., Syahrom A., Kamarul T.

In the present study, the effects of human physiological activity levels on the fatigue life of a porous magnesium scaffold have been investigated. First, the dynamic immersion and biomechanical testing are carried out on a porous magnesium scaffold to simulate the physiological conditions. Then, a numerical data analysis and computer simulations predict the implant failure values. A 3D CAD bone scaffold model was used to predict the implant fatigue, based on the micro-tomographic images. This study uses a simulation of solid mechanics and fatigue, based on daily physiological activities, which include walking, running, and climbing stairs, with strains reaching 1000–3500 µm/mm. The porous magnesium scaffold with a porosity of 41% was put through immersion tests for 24, 48, and 72 h in a typical simulated body fluid. Longer immersion times resulted in increased fatigue, with cycles of failure (Nf) observed to decrease from 4.508 × 1022 to 2.286 × 1011 (1.9 × 1011 fold decrease) after 72 hours of immersion with a loading rate of 1000 µm/mm. Activities played an essential role in the rate of implant fatigue, such as demonstrated by the 1.1 × 105 fold increase in the Nf of walking versus stair climbing at 7.603 × 1011 versus 6.858 × 105, respectively. The dynamic immersion tests could establish data on activity levels when an implant fails over time. This information could provide a basis for more robust future implant designs.