Search

Cardiac fibroblasts are interspersed within mammalian cardiac tissue. Fibroblasts are mechanically passive; however, they may communicate electrically with cardiomyocytes via gap junctions and thus affect the electrical and mechanical activity of myocytes. Several in-silico studies at both cellular (0D) and ventricular (3D) levels analysed the effects of fibroblasts on the myocardial electrical function. However, none of them addressed possible effects of fibroblast-myocyte electrical coupling to cardiomyocyte mechanical activity. In this paper, we propose a mathematical model for studying both electrical and mechanical responses of the human cardiomyocyte to its electrotonic interaction with cardiac fibroblasts. Our simulations have revealed that electrotonic interaction with fibroblasts affects not only the mechanical activity of the cardiomyocyte, comprising either moderate or significant reduction of contractility, but also the mechano-calcium and mechano-electric feedback loops, and all these effects are enhanced as the number of coupled fibroblasts is increased. Obtained results suggest that moderate values of the myocyte-fibroblast gap junction conductance (less than 1 nS) can be attributed to physiological conditions, contrasting to the higher values (2 nS and higher) proper rather for pathological situations (e.g. for infarct and/or border zones), since all mechanical indexes falls down dramatically in the case of such high conductance.

Antibiotic resistance of bacteria is a topical problem on a global scale. Sometimes vigorous human activity leads to an increase in the number of bacteria carrying resistance genes in the environment. Antimicrobial peptides (AMPs) and similar compounds are potential candidates for combating antibiotic-resistant bacteria. Previously, we proposed and successfully tested on Thermus thermophilus a new mechanism of AMP action. This mechanism of directed coaggregation is based on the interaction of a peptide capable of forming fibrils with a target protein. In this work, we discuss the criteria for choosing a target for the targeted action of AMP, describe the features of the "parental" S1 ribosomal proteins T. thermophilus and Escherichia coli and the studied peptides using bioinformatic analysis methods, assess the antimicrobial effect of the synthesized peptides on a model organism of E. coli and cytotoxicity on cells of human fibroblasts. The obtained results will be important for the creation of new AMPs for pathogenic organisms.Antibiotikorezistentnost' bakteriĭ iavliaetsia zlobodnevnoĭ problemoĭ mirovogo masshtaba. Podchas aktivnaia chelovecheskaia deiatel'nost' privodit k uvelicheniiu predstavlennosti v okruzhaiushcheĭ srede bakteriĭ, ustoĭchivykh k deĭstviiu antibiotikov. Antimikrobnye peptidy (AMP) iavliaiutsia potentsial'nymi lekarstvennymi kandidatami dlia bor'by s takimi mikroorganizmami. Ranee nami byl predlozhen i uspeshno aprobirovan na primere Thermus thermophilus novyĭ mekhanizm deĭstviia AMP, osnovannyĭ na napravlennoĭ koagregatsii (vzaimodeĭstvii peptida, sposobnogo formirovat' fibrilly s belkom-mishen'iu). V nastoiashcheĭ rabote rassmotreny kriterii vybora misheni dlia napravlennogo deĭstviia AMP, opisany osobennosti “roditel'skikh” S1 ribosomnykh belkov Thermus thermophilus i Escherichia coli i issleduemykh peptidov s primeneniem metodov bioinformaticheskogo analiza, provedena otsenka antimikrobnogo deĭstviia sintezirovannykh peptidov na model'nom organizme Escherichia coli i tsitotoksichnosti na kletkakh fibroblastov cheloveka.

Antibiotic-resistant bacteria are recognized as one of the leading causes of death in the world. We proposed and successfully tested peptides with a new mechanism of antimicrobial action “protein silencing” based on directed co-aggregation. The amyloidogenic antimicrobial peptide (AAMP) interacts with the target protein of model or pathogenic bacteria and forms aggregates, thereby knocking out the protein from its working condition. In this review, we consider antimicrobial effects of the designed peptides on two model organisms, E. coli and T. thermophilus, and two pathogenic organisms, P. aeruginosa and S. aureus. We compare the amino acid composition of proteomes and especially S1 ribosomal proteins. Since this protein is inherent only in bacterial cells, it is a good target for studying the process of co-aggregation. This review presents a bioinformatics analysis of these proteins. We sum up all the peptides predicted as amyloidogenic by several programs and synthesized by us. For the four organisms we studied, we show how amyloidogenicity correlates with antibacterial properties. Let us especially dwell on peptides that have demonstrated themselves as AMPs for two pathogenic organisms that cause dangerous hospital infections, and in which the minimal inhibitory concentration (MIC) turned out to be comparable to the MIC of gentamicin sulfate. All this makes our study encouraging for the further development of AAMP. The hybrid peptides may thus provide a starting point for the antibacterial application of amyloidogenic peptides.

The need to develop new antimicrobial peptides is due to the high resistance of pathogenic bacteria to traditional antibiotics now and in the future. The creation of synthetic peptide constructs is a common and successful approach to the development of new antimicrobial peptides. In this work, we use a simple, flexible, and scalable technique to create hybrid antimicrobial peptides containing amyloidogenic regions of the ribosomal S1 protein from Staphylococcus aureus. While the cell-penetrating peptide allows the peptide to enter the bacterial cell, the amyloidogenic site provides an antimicrobial effect by coaggregating with functional bacterial proteins. We have demonstrated the antimicrobial effects of the R23F, R23DI, and R23EI hybrid peptides against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa, Escherichia coli, and Bacillus cereus. R23F, R23DI, and R23EI can be used as antimicrobial peptides against Gram-positive and Gram-negative bacteria resistant to traditional antibiotics.

Spiral waves lead to dangerous arrhythmias in the cardiac system. In 2015 Burton et al. demonstrated the reversal of the spiral wave chirality through the rotating spiral-shaped illumination on the optogenetically modified cardiac monolayers. We show that this process entails the recreation of a spiral wave. We show how this methodology can be used to control and create the desired spatial excitation pattern. We found that the control is sensitive to the area of illuminated region but independent of the phase difference of the existing spiral wave and the applied spiral-shaped light. We also discovered that our methodology can temporarily resynchronize a turbulent system. The results offer numerical evidence for the control of spatial pattern in biological excitable systems with optogenetics.

Spiral waves occur in various types of excitable media and their dynamics determine the spatial excitation patterns. An important type of spiral wave dynamics is drift, as it can control the position of a spiral wave or eliminate a spiral wave by forcing it to the boundary. In theoretical and experimental studies of the Belousov-Zhabotinsky reaction, it was shown that the most direct way to induce the controlled drift of spiral waves is by application of an external electric field. Mathematically such drift occurs due to the onset of additional gradient terms in the Laplacian operator describing excitable media. However, this approach does not work for cardiac excitable tissue, where an external electric field does not result in gradient terms. In this paper, we propose a method of how to induce a directed linear drift of spiral waves in cardiac tissue, which can be realized as an optical feedback control in tissue where photosensitive ion channels are expressed. We illustrate our method by using the FitzHugh-Nagumo model for cardiac tissue and the generic model of photosensitive ion channels. We show that our method works for continuous and discrete light sources and can effectively move spiral waves in cardiac tissue, or eliminate them by collisions with the boundary or with another spiral wave. We finally implement our method by using a biophysically motivated photosensitive ion channel model included to the Luo-Rudy model for cardiac cells and show that the proposed feedback control also induces directed linear drift of spiral waves in a wide range of light intensities.

One of the important questions in cardiac electrophysiology is to characterise the arrhythmogenic substrate; for example, from the texture of the cardiac fibrosis, which is considered one of the major arrhythmogenic conditions. In this paper, we perform an extensive in silico study of the relationships between various local geometric characteristics of fibrosis on the onset of cardiac arrhythmias. In order to define which texture characteristics have better predictive value, we induce arrhythmias by external stimulation, selecting 4363 textures in which arrhythmia can be induced and also selecting 4363 non-arrhythmogenic textures. For each texture, we determine such characteristics as cluster area, solidity, mean distance, local density and zig-zag propagation path, and compare them in arrhythmogenic and non-arrhythmogenic cases. Our study shows that geometrical characteristics, such as cluster area or solidity, turn out to be the most important for prediction of the arrhythmogenic textures. Overall, we were able to achieve an accuracy of 67% for the arrhythmogenic texture-classification problem. However, the accuracy of predictions depends on the size of the region chosen for the analysis. The optimal size for the local areas of the tissue was of the order of 0.28 of the wavelength of the arrhythmia. We discuss further developments and possible applications of this method for characterising the substrate of arrhythmias in fibrotic textures. © 2021, The Author(s). Research was funded by the Russian Foundation for Basic Research (№ 18-29-13008) and BOF of Ghent University.

Background Recently it was demonstrated how the heart itself could be enabled to quickly restore its rhythm by realizing a biologically-integrated cardiac defibrillator (BioICD) through modification and subsequent expression of ion channels in cardiomyocytes [1]. By incorporating these frequency-dependent depolarizing ion channels, abnormal cardiac rhythm could be rapidly detected and terminated to restore sinus rhythm in a fully biological and shock-free manner. However, from a translational point of view, it remains unclear how such rhythm restoration can be realized via ion channel gene therapy. Purpose To explore and understand the importance of the distribution and number of BioICD-expressing cardiomyocytes in realizing fully biological restoration of cardiac rhythm. Methods To this purpose, two different realistic gene therapy configurations, i.e. those corresponding to systemic and local transgene delivery, were tested in human ventricular virtual cardiac monolayers. For the systemic delivery group, BioICD-expressing cells were homogeneously distributed (10 random variations) over the tissue with fixed total expression percentage (14 percentages). For the local delivery group, circular areas (7 radii) were given BioICD-expressing cells randomly patterned (10 variations) in a Gaussian distribution with 3 fixed total expression percentages. For both groups, spiral waves were initiated (9 locations) and studied for the following 10 seconds for each test condition, thereby equaling 1260 and 1890 conditions, respectively. Results For systemic delivery, normal rhythm was restored in all cases for >50% BioICD expressing cells, with time till termination being inversely related to the percentage, resulting in only 4.3s and 2.5s for 50% and 100%, respectively. Regarding termination, it was observed that conduction blocks appeared throughout the tissue and subsequently connected to force arrhythmic waves to terminate, while this process remained incomplete in the Conclusion This study reveals that wide-spread distribution of BioICD-expressing cardiomyocytes is required for the realization of fully biological self-restoration of cardiac rhythm, of which the efficiency is dosage-dependent. Local expression, however, results in stabilization of spiral wave activity. Further exploration of this emerging concept of biological cardioversion may not only expand our understanding of cardiac arrhythmias, but also pave the way to breakthrough advances in arrhythmia management. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Council (Starting grant 716509) to D.A. Pijnappels.

Many dangerous cardiac arrhythmias are driven by rotating spiral waves of electrical excitation. The dynamics of these rotating waves determine the properties of the arrhythmia. In this paper, we present a numerical study of the dynamics of scroll waves in generic axisymmetric models of the left ventricle, coupled with an ionic model for human cardiac cells. We find that the most frequent type of dynamic present is annihilation of the scroll waves at the basal boundary of the heart. However, in several cases, the scroll waves stabilised inside the myocardium and rotated around transmural filaments. This behaviour is affected by many parameters, including the thickness of the myocardial wall, the cardiac tissue anisotropy, that is the anisotropy ratio and the directions of the myofibres, the chirality of the scroll waves and the parameters of the cell model. There can be several attractors, and a scroll wave can persist or disappear depending on the initial conditions, for example, S1S2 protocol parameters. However, the exact dependencies are complex and not always monotonic. In this study, we discuss the possible mechanisms underlying these dynamics and the application of our results to cardiac arrhythmias.

Funding Acknowledgements Type of funding sources: None. Background Entrainment mapping (EM) is an important tool to determine the mechanism of complex reentrant atrial tachycardias (ATs), mostly to distinguish dominant from bystander reentrant loops. However, entrainment maneuvers are challenging, time consuming and risk to end the tachycardia. Purpose Recently, we developed a novel method Directed Graph Mapping (DGM), using concepts of network theory, allowing to automatically determine AT reentry loops from the local activation times (LAT) of any clinical mapping system. DGM showed good performance: it correctly finds ablation target (100 % success rate) on simple AT cases and could automatically determine reentry loops confirmed by the expert electrophysiologist with EM in complex AT cases. Out of 32 single loop cases, 62.5 % was identified correctly with automated DGM and out of 6 true double loop cases, 83.3 %. Lower performance for single reentry complex cases compared to EM was mainly because DGM could not distinguish the dominant loop from additional bystander loops found by DGM. Hence, the purpose of this work was to develop additional algorithms which in case of multiple found DGM loops could automatically find the dominant loop and compare it with the results of EM. Methods We performed multiple simulations of various types of double loop reentry on a patient specific model of the left atrium. Based on a clinical case, double loops were simulated around a scar at the anterior wall (localized reentry) and the mitral valve (MV). LAT maps were determined similar as in the clinic. By varying the size of the scar in multiple steps, we obtained a transition from a regime of a dominant loop around the scar (small scar), to a true double loop and further to a regime of a dominant loop around the MV (large scar). We developed a novel DGM algorithm to determine the dominant loop from the region of collision (ROC) found from the vector field of the wavefront graph. The developed method was also tested on 8 clinical cases of double loop ATs with EM measurements. Results Our algorithm found the location of the ROC and determined the correct dominant loop in 100% of the simulated data. We tested this on 8 clinical cases of AT, and accuracy of the method was 75 %. Conclusions Determining the ROC in case of multiple loops in AT could correctly determine the dominant versus bystander loop, leading to the correct ablation target, without the need for further EM.

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Supported in part by Dirección General de Polı́tica Cientı́fica de la Generalitat Valenciana PROMETEU 2020/043 Background In realistic in-silico studies (Figure1, top row) it was shown that phase mapping PM (Figure 1, A) can detect the correct rotor as well as phantom rotors as an artefact of interpolation or due to the far field (Figure 1, B). After interpretation of the LAT, the far field detections could not be distinguished from the true rotor driving the excitation pattern. This can contribute to failure in Atrial Fibrillation (AF) ablation procedures. Objective We tested if the recently developed tool Directed Graph mapping (DGM) is less prone to far-field effects and interpolation artefacts than PM on the same in-silico data. DGM represents the excitation pattern as a directed network, from which the rotational activity is detected as cycles in that network. Methods Starting from the electrograms (EGMs) of the 64 electrode basket catheter, we interpolated to 957 equidistant electrodes and calculated local activation times (LATs) of the interpolated EGMs (Figure 1, C). We varied the minimal allowed conduction velocity and calculated the corresponding networks for the complete simulation time. Detections were considered as correct if they were located in the same region of the true core of the phasemaps. The false detections were classified in multiple different regions (Figure 1, D). Results We find that by proper choice of CVs in the graphs it is possible to achieve a 80% detection of true rotors with 26% detection of false rotors. Reducing restrictions on the CVs increased the detection rate of the false rotors. False rotors due to artifacts were not detected by DGM (Figure 1, last row). Conclusion DGM is able to distinguish between true and far field rotors. False detections due to interpolation artifacts as seen in the PM protocol were not observed. The velocity limits in the graph construction play a keyrole in eliminating the far field effects. Abstract Figure 1

Nonlinear waves of electrical excitation initiate cardiac contraction. Abnormal wave propagation in the heart, e.g., spiral waves, can lead to sudden cardiac arrest. This study analyzed the dynamics of spiral waves under the influence of an instability called negative filament tension, and examined how the spiral waves can be eliminated through high-frequency pacing. A generic anatomical model of the left ventricle of the human heart and the Aliev-Panfilov model for cardiac tissue were used. The study showed that the source of such arrhythmia is elongated filaments with lengths that can be 10-20 times greater than the characteristic thickness of the heart wall. In anisotropic tissue, the filament elongated before it was annihilated at the base of the heart. The spiral waves were eliminated through overdrive pacing with stimulation periods from 0.8 to 0.95 relative to the spiral wave period. The minimum time for the expulsion was about 10 s. © 2021 American Physical Society. Russian Science Foundation, RSF: 17-71-20024 Our work involved simulations at the “Uran” cluster of IMM UB RAS (Ekaterinburg). Our research is supported by a Russian Science Foundation grant (Project 17-71-20024).

Life threatening cardiac arrhythmias result from abnormal propagation of nonlinear electrical excitation waves in the heart. Finding the locations of the sources of these waves remains a challenging problem. This is mainly due to the low spatial resolution of electrode recordings of these waves. Also, these recordings are subjected to noise. In this paper, we develop a different approach: the AFV-DT method based on an averaged flow velocity (AFV) technique adopted from the analysis of optical flows and the determinant-trace (DT) method used for vector field analysis of dynamical systems. This method can find the location and determine all important types of sources found in excitable media such as focal activity, spiral waves, and waves rotating around obstacles. We test this method on in silico data of various wave excitation patterns obtained using the Luo-Rudy model for cardiac tissue. We show that the method works well for data with low spatial resolutions (up to 8×8) and is stable against noise. Finally, we apply it to two clinical cases and show that it can correctly identify the arrhythmia type and location. We discuss further steps on the development and improvement of this approach. © 2021 American Physical Society. This work was supported by the National Natural Science Foundation of China under Grants No. 12075203 and No. 11975194, and research at Sechenov University was financed by the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers “Digital biodesign and personalized healthcare” (Grant No. 075-15-2020-926).

Objectives: Directed graph-mapping (DGM) is a novel operator-independent automatic tool that can be applied to the identification of the atrial tachycardia (AT) mechanism. In the present study, for the first time, DGM was applied in complex AT cases, and diagnostic accuracy was evaluated. Background: Catheter ablation of ATs still represents a challenge, as the identification of the correct mechanism can be difficult. New algorithms for high-density activation mapping (HDAM) render an easier acquisition of more detailed maps; however, understanding of the mechanism and, thus, identification of the ablation targets, especially in complex cases, remains strongly operator-dependent. Methods: HDAMs acquired with the latest algorithm (COHERENT version 7, Biosense Webster, Irvine, California) were interpreted offline by 4 expert electrophysiologists, and the acquired electrode recordings with corresponding local activation times (LATs) were analyzed by DGM (also offline). Entrainment maneuvers (EM) were performed to understand the correct mechanism, which was then confirmed by successful ablation (13 cases were centrifugal, 10 cases were localized re-entry, 22 cases were macro–re-entry, and 6 were double-loops). In total, 51 ATs were retrospectively analyzed. We compared the diagnoses made by DGM were compared with those of the experts and with additional EM results. Results: In total, 51 ATs were retrospectively analyzed. Experts diagnosed the correct AT mechanism and location in 33 cases versus DGM in 38 cases. Diagnostic accuracy varied according to different AT mechanisms. The 13 centrifugal activation patterns were always correctly identified by both methods; 2 of 10 localized reentries were identified by the experts, whereas DGM diagnosed 7 of 10. For the macro–re-entries, 12 of 22 were correctly identified using HDAM versus 13 of 22 for DGM. Finally, 6 of 6 double-loops were correctly identified by the experts, versus 5 of 6 for DGM. Conclusions: Even in complex cases, DGM provides an automatic, fast, and operator-independent tool to identify the AT mechanism and location and could be a valuable addition to current mapping technologies. © 2021 The Authors. Dr. Lorenzo is an employee of Biosense Webster. Dr. Goedgebeur is funded with a research grant of the Research Foundation Flanders/Fonds voor Wetenschappelijk Onderzoek (FWO). Dr. Strisciuglio is supported by a research grant from the Cardiopath PhD program. Dr. el Haddad is a consultant for Biosense Webster. Dr. Duytschaever is a consultant for Biosense Webster. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Vortices in excitable media underlie dangerous cardiac arrhythmias. One way to eliminate them is by stimulating the excitable medium with a period smaller than the period of the vortex. So far, this phenomenon has been studied mostly for two-dimensional vortices known as spiral waves. Here we present a first study of this phenomenon for three-dimensional vortices, or scroll waves, in a slab. We consider two main types of scroll waves dynamics: with positive filament tension and with negative filament tension and show that such elimination is possible for some values of the period in all cases. However, in the case of negative filament tension for relatively long stimulation periods, three-dimensional instabilities occur and make elimination impossible. We derive equations of motion for the drift of paced filaments and identify a bifurcation parameter that determines whether the filaments orient themselves perpendicular to the impeding wave train or not. © 2021 American Physical Society. Ministry of Education and Science of the Russian Federation, Minobrnauka: 075-15-2020-926 Our simulations used the Uran cluster of IMM UrB RAS (Ekaterinburg). Research at Sechenov University was financed by the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers, “Digital Biodesign and Personalized Healthcare,” No. 075-15-2020-926.

Ambient temperature has a profound influence on cellular electrophysiology through direct control over the gating mechanisms of different ion channels. In the heart, low temperature is known to favor prolongation of the action potential. However, not much is known about the influence of temperature on other important characterization parameters such as the resting membrane potential (RMP), excitability, morphology and characteristics of the action potential (AP), restitution properties, conduction velocity (CV) of signal propagation, etc. Here we present the first, detailed, systematic in silico study of the electrophysiological characterization of cardiomyocytes from different regions of the normal human atria, based on the effects of ambient temperature (5−50°C). We observe that RMP decreases with increasing temperature. At ~ 48°C, the cells lose their excitability. Our studies show that different parts of the atria react differently to the same changes in temperature. In tissue simulations a drop in temperature correlated positively with a decrease in CV, but the decrease was region-dependent, as expected. In this article we show how this heterogeneous response can provide an explanation for the development of a proarrhythmic substrate during mild hypothermia. We use the above concept to propose a treatment strategy for atrial fibrillation that involves severe hypothermia in specific regions of the heart for a duration of only ~ 200 ms. © Copyright © 2021 Majumder, Mohamed Nazer, Panfilov, Bodenschatz and Wang. This work was supported by the Max Planck Society and the German Center for Cardiovascular Research. Research at Sechenov University was financed by the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers Digital biodesign and personalized healthcare No. 075-15-2020-926.