scholarly journals Self-organization of conducting pathways explains electrical wave propagation in cardiac tissues with high fibrosis

2018 ◽  
Author(s):  
Nina Kudryashova ◽  
Aygul Nizamieva ◽  
Valeriya Tsvelaya ◽  
Alexander Panfilov ◽  
Konstantin Agladze
Keyword(s):  
Wave Propagation ◽  
Computer Simulations ◽  
Cardiac Arrhythmias ◽  
Cardiac Fibrosis ◽  
Cardiac Tissue ◽  
Geometric Analysis ◽  
Cardiac Cells ◽  
High Density ◽  
Neonatal Rat ◽  
Electrical Signals

AbstractCardiac fibrosis occurs in many forms of heart disease and is considered to be one of the main arrhythmogenic factors. Regions with a high density of fibrosis are likely to cause blocks of wave propagation that give rise to dangerous cardiac arrhythmias. Therefore, studies of the wave propagation through these regions are very important, yet the precise mechanisms leading to arrhythmia formation in fibrotic cardiac tissue remain poorly understood. Particularly, it is not clear how wave propagation is organized at the cellular level, as experiments show that the regions with a high percentage of fibrosis (65-75%) are still conducting electrical signals, whereas geometric analysis of randomly distributed cells predicts connectivity loss at 40% at the most (percolation threshold). To address this question, we used a joint in vitro-in silico approach, which combined experiments in neonatal rat cardiac monolayers with morphological and electrophysiological computer simulations. We have shown that the main reason for sustainable wave propagation in highly fibrotic samples is the formation of a branching network of cardiomyocytes. We have successfully reproduced the morphology of conductive pathways in computer modelling, assuming that cardiomyocytes align their cytoskeletons to fuse into cardiac syncytium. The electrophysiological properties of the monolayers, such as conduction velocity, conduction blocks and wave fractionation, were reproduced as well. In a virtual cardiac tissue, we have also examined the wave propagation at the subcellular level, detected wavebreaks formation and its relation to the structure of fibrosis and, thus, analysed the processes leading to the onset of arrhythmias.Author summaryCardiac arrhythmias are one of the major causes of death in the industrialized world. The most dangerous ones are often caused by the blocks of propagation of electrical signals. One of the common factors that contribute to the likelihood of these blocks, is a condition called cardiac fibrosis. In fibrosis, excitable cardiac tissue is partially replaced with the inexcitable connective tissue. The precise mechanisms leading to arrhythmia formation in fibrotic cardiac tissue remain poorly understood. Therefore, it is important to study wave propagation in fibrosis from cellular to tissue level. In this paper, we study fibrosis of high density in experiments and computer simulations. We have observed a paradoxical ability of the tissue with extremely high fibrosis (up to 75% of fibroblasts) to conduct electrical signals and contract synchronously, whereas geometric analysis of randomly distributed cells predicted connectivity loss at 40% at the most. To explain this phenomenon, we have studied the patterns that cardiac cells form in the tissue and reproduced their self-organisation in a computer model. Our virtual model also took into account the polygonal shapes of the spreading cells and explained high arrhythmogenicity of fibrotic tissue.

Basic Mechanisms of Cardiac Impulse Propagation and Associated Arrhythmias

2004 ◽  
Vol 84 (2) ◽  
pp. 431-488 ◽  
Author(s):  
ANDRÉ G. KLÉBER ◽  
YORAM RUDY
Keyword(s):  
Computer Simulations ◽  
Cardiac Arrhythmias ◽  
Cardiac Tissue ◽  
Cell Communication ◽  
Cardiac Cells ◽  
Tissue Structure ◽  
Strong Interactions ◽  
Complex Interactions ◽  
Cardiac Impulse ◽  
Impulse Propagation

Kléber, André G., and Yoram Rudy. Basic Mechanisms of Cardiac Impulse Propagation and Associated Arrhythmias. Physiol Rev 84: 431–488, 2004; 10.1152/physrev.00025.2003.—Propagation of excitation in the heart involves action potential (AP) generation by cardiac cells and its propagation in the multicellular tissue. AP conduction is the outcome of complex interactions between cellular electrical activity, electrical cell-to-cell communication, and the cardiac tissue structure. As shown in this review, strong interactions occur among these determinants of electrical impulse propagation. A special form of conduction that underlies many cardiac arrhythmias involves circulating excitation. In this situation, the curvature of the propagating excitation wavefront and the interaction of the wavefront with the repolarization tail of the preceding wave are additional important determinants of impulse propagation. This review attempts to synthesize results from computer simulations and experimental preparations to define mechanisms and biophysical principles that govern normal and abnormal conduction in the heart.

scholarly journals Boron improves cardiac contractility and fibrotic remodeling following myocardial infarction injury

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Rihab Bouchareb ◽  
Michael Katz ◽  
Najla Saadallah ◽  
Yassine Sassi ◽  
Shakir Ali ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Cycle ◽  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Cardiac Tissue ◽  
Ventricular Remodeling ◽  
Cardiac Contractility ◽  
Neonatal Rat ◽  
Saline Control ◽  
Post Injury

Abstract Myocardial fibrosis is a major determinant of clinical outcomes in heart failure (HF) patients. It is characterized by the emergence of myofibroblasts and early activation of pro-fibrotic signaling pathways before adverse ventricular remodeling and progression of HF. Boron has been reported in recent years to augment the innate immune system and cell proliferation, which play an important role in the repair and regeneration of the injured tissue. Currently, the effect of boron on cardiac contractility and remodeling is unknown. In this study, we investigated, for the first time, the effect of boron supplementation on cardiac function, myocardial fibrosis, apoptosis and regeneration in a rat model myocardial infarction (MI)-induced HF. MI was induced in animals and borax, a sodium salt of boron, was administered for 7 days, p.o., 21 days post-injury at a dose level of 4 mg/kg body weight. Transthoracic echocardiographic analysis showed a significant improvement in systolic and diastolic functions with boron treatment compared to saline control. In addition, boron administration showed a marked reduction in myocardial fibrosis and apoptosis in the injured hearts, highlighting a protective effect of boron in the ischemic heart. Interestingly, we observed a tenfold increase of nuclei in thin myocardial sections stained positive for the cell cycle marker Ki67 in the MI boron-treated rats compared to saline, indicative of increased cardiomyocyte cell cycle activity in MI hearts, highlighting its potential role in regeneration post-injury. We similarly observed increased Ki67 and BrdU staining in cultured fresh neonatal rat ventricular cardiomyocytes. Collectively, the results show that boron positively impacted MI-induced HF and attenuated cardiac fibrosis and apoptosis, two prominent features of HF. Importantly, boron has the potential to induce cardiomyocyte cell cycle entry and potentially cardiac tissue regeneration after injury. Boron might be beneficial as a supplement in MI and may be a good candidate substance for anti-fibrosis approach.

Abstract 262: Depolarization Stimulates Neonatal Cardiomyocyte Proliferation In Vitro

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Corin Williams ◽  
Michael Levin ◽  
Lauren D Black
Keyword(s):  
Cardiac Tissue ◽  
Heart Defects ◽  
Cell Types ◽  
Cardiac Cells ◽  
Neonatal Rat ◽  
Resting Membrane Potential ◽  
Cardiomyocyte Proliferation ◽  
Potassium Gluconate ◽  
Hypertrophic Growth

Cardiac tissue engineering is a promising approach for treating children with congenital heart defects. However, as cardiomyocytes (CMs) undergo a rapid transition from hyperplastic to hypertrophic growth after birth, a major challenge to the development of engineered cardiac tissue is the limited proliferation of CMs. Mature CMs and other terminally differentiated cell types tend to have a highly negative resting membrane potential (Vmem) while stem cells and less mature cells tend to have Vmem closer to zero. Vmem has been shown to play an important role in cell differentiation and proliferation. We hypothesized that depolarization of cardiac cells would stimulate CM proliferation in vitro . To test our hypothesis, we isolated neonatal rat cardiac cells and cultured them for 24 hr under standard conditions. Cells were then subjected to depolarization treatment for 72 hr using potassium gluconate or ouabain at various concentrations. Samples were fixed and stained for cardiac α-actin (Fig 1A, red) and phospho-histone H3 (Fig 1A, green) to assess CM mitosis. We found that potassium gluconate had no significant effect while ouabain significantly increased CM mitosis, suggesting Vmem regulation via Na/K-ATPase. CM-specific proliferation was significantly higher with 10nM (p= 0.015) and 100nM (p=0.008) ouabain treatment compared to controls (n=3) (Fig 1B). Cell density was significantly higher with 100μM ouabain versus controls (2656 ± 50 vs. 2026 ± 117 cells/mm 2 ), indicating increased cardiac cell proliferation (Fig 1C). Our findings suggest that depolarization promotes CM proliferation and may be a novel approach to encourage growth of engineered cardiac tissue in vitro .

Engineered Membranes Improve Cardiac Function in Ischemic Rat Hearts

2010 ◽  
Author(s):  
Monica Sandri ◽  
Anna Tampieri ◽  
Joung H. Levialdi Ghiron ◽  
Gianluigi Condorelli
Keyword(s):  
Cardiac Function ◽  
Cardiac Tissue ◽  
Diglycidyl Ether ◽  
Beating Heart ◽  
Cardiac Cells ◽  
Neonatal Rat ◽  
Heart Cell ◽  
Collagen Membrane ◽  
Heart Cells ◽  
Type I

In the relatively young field of cardiac tissue engineering, different biomaterials, methods and techniques have been tested for cardiac repair. In this study we examined the validity of a series of new preformed membrane scaffolds, based on collagen type I, for the transplantation of cardiac cells. One type of membrane, cross-linked with 1,4-butanediol diglycidyl ether (BDDGE) and fibronectin-enriched, gave rise to spontaneously beating heart cell constructs 5–9 days after seeding with neonatal rat cardiac cells. This membrane was then grafted, with and without beating cardiac cells, onto the infarcted area of rat models of heart failure. Seriate echocardiography, performed on rats before transplantation and at 4 and 8 weeks after transplantation, showed that rats that received collagen membranes with beating cells showed an improvement in cardiac function after 8 weeks. These results suggest that this new type of collagen membrane can be used as vector for the transplantation of beating heart cells to the injured myocardium, hence representing an important potential tool for cardiac tissue repair technologies.

scholarly journals Stilbene derivative as a photosensitive compound to control the excitability of neonatal rat cardiomyocytes

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Sheida R. Frolova ◽  
Vasili S. Gorbunov ◽  
Natalia S. Shubina ◽  
Alexander M. Perepukhov ◽  
Sandaara G. Romanova ◽  
...  
Keyword(s):  
Cardiac Tissue ◽  
Structural Analog ◽  
Cardiac Cells ◽  
Neonatal Rat ◽  
Light Illumination ◽  
Neural Cells ◽  
Trans Form ◽  
Rat Cardiomyocytes ◽  
Stilbene Derivative ◽  
Voltage Gated Ion Channels

Abstract Substances that can be used as photosensitizers for cardiac tissue are very helpful in modeling various excitation patterns in a cardiac tissue culture and may have prospective use in the temporary and permanent ablation of unwanted excitation sources in the heart. The aim of the present work is to study the effect of stilbene derivative c-TAB (2- {4- [(E) -2- (4-ethoxyphenyl) vinyl] phenoxy} ethyl) trimethylammonium bromide) on the cardiomyocyte layers and voltage-gated ion channels in cardiac cells. C-TAB is a structural analog to AzoTAB, reported previously as a photoswitch for cardiac and neural cells, in which the azobenzene moiety is replaced by a stilbene grouping. Such a replacement makes c-TAB less toxic to living cells. c-TAB has been shown to successfully inhibit excitation in cardiac cells in both trans- and cis- forms. The excitation inhibition of cardiac cells under c-TAB is reversible and can be overturned easily by washing out the c-TAB; however, not by light illumination. The irradiation of cardiac cells with near-UV, when the trans- form of c-TAB is applied, changes reversible inhibition to a permanent one that cannot be overturned by a washout.

scholarly journals Multiscale Characterization of Engineered Cardiac Tissue Architecture

2016 ◽  
Vol 138 (11) ◽  
Author(s):  
Nancy K. Drew ◽  
Nicholas E. Johnsen ◽  
Jason Q. Core ◽  
Anna Grosberg
Keyword(s):  
Self Assembly ◽  
Cardiac Tissue ◽  
Multiple Scales ◽  
Ventricular Myocytes ◽  
Orientational Order ◽  
Cardiac Cells ◽  
Neonatal Rat ◽  
Length Scales ◽  
Cardiac Tissues ◽  
The Relationship

In a properly contracting cardiac muscle, many different subcellular structures are organized into an intricate architecture. While it has been observed that this organization is altered in pathological conditions, the relationship between length-scales and architecture has not been properly explored. In this work, we utilize a variety of architecture metrics to quantify organization and consistency of single structures over multiple scales, from subcellular to tissue scale as well as correlation of organization of multiple structures. Specifically, as the best way to characterize cardiac tissues, we chose the orientational and co-orientational order parameters (COOPs). Similarly, neonatal rat ventricular myocytes were selected for their consistent architectural behavior. The engineered cells and tissues were stained for four architectural structures: actin, tubulin, sarcomeric z-lines, and nuclei. We applied the orientational metrics to cardiac cells of various shapes, isotropic cardiac tissues, and anisotropic globally aligned tissues. With these novel tools, we discovered: (1) the relationship between cellular shape and consistency of self-assembly; (2) the length-scales at which unguided tissues self-organize; and (3) the correlation or lack thereof between organization of actin fibrils, sarcomeric z-lines, tubulin fibrils, and nuclei. All of these together elucidate some of the current mysteries in the relationship between force production and architecture, while raising more questions about the effect of guidance cues on self-assembly function. These types of metrics are the future of quantitative tissue engineering in cardiovascular biomechanics.

Confocal imaging of calcium in intact ventricular muscle provides a new view of excitation-contraction coupling

1996 ◽  
Vol 54 ◽  
pp. 738-739
Author(s):  
W.G. Wier
Keyword(s):  
Local Control ◽  
Cardiac Tissue ◽  
Cell Function ◽  
Isolated Heart ◽  
Cardiac Cells ◽  
Confocal Imaging ◽  
Ion Concentration ◽  
Heart Cell ◽  
Free Calcium ◽  
Heart Cells

A fundamentally new understanding of cardiac excitation-contraction (E-C) coupling is being developed from recent experimental work using confocal microscopy of single isolated heart cells. In particular, the transient change in intracellular free calcium ion concentration ([Ca2+]i transient) that activates muscle contraction is now viewed as resulting from the spatial and temporal summation of small (∼ 8 μm3), subcellular, stereotyped ‘local [Ca2+]i-transients' or, as they have been called, ‘calcium sparks'. This new understanding may be called ‘local control of E-C coupling'. The relevance to normal heart cell function of ‘local control, theory and the recent confocal data on spontaneous Ca2+ ‘sparks', and on electrically evoked local [Ca2+]i-transients has been unknown however, because the previous studies were all conducted on slack, internally perfused, single, enzymatically dissociated cardiac cells, at room temperature, usually with Cs+ replacing K+, and often in the presence of Ca2-channel blockers. The present work was undertaken to establish whether or not the concepts derived from these studies are in fact relevant to normal cardiac tissue under physiological conditions, by attempting to record local [Ca2+]i-transients, sparks (and Ca2+ waves) in intact, multi-cellular cardiac tissue.

scholarly journals Cardiac Organoids to Model and Heal Heart Failure and Cardiomyopathies

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 563
Author(s):  
Magali Seguret ◽  
Eva Vermersch ◽  
Charlène Jouve ◽  
Jean-Sébastien Hulot
Keyword(s):  
Tissue Engineering ◽  
Drug Testing ◽  
Cardiac Tissue ◽  
Cardiac Tissue Engineering ◽  
Cardiac Cells ◽  
Cardiac Functions ◽  
Different Types ◽  
Recent Developments ◽  
Human Cardiac Tissue ◽  
Key Aspects

Cardiac tissue engineering aims at creating contractile structures that can optimally reproduce the features of human cardiac tissue. These constructs are becoming valuable tools to model some of the cardiac functions, to set preclinical platforms for drug testing, or to alternatively be used as therapies for cardiac repair approaches. Most of the recent developments in cardiac tissue engineering have been made possible by important advances regarding the efficient generation of cardiac cells from pluripotent stem cells and the use of novel biomaterials and microfabrication methods. Different combinations of cells, biomaterials, scaffolds, and geometries are however possible, which results in different types of structures with gradual complexities and abilities to mimic the native cardiac tissue. Here, we intend to cover key aspects of tissue engineering applied to cardiology and the consequent development of cardiac organoids. This review presents various facets of the construction of human cardiac 3D constructs, from the choice of the components to their patterning, the final geometry of generated tissues, and the subsequent readouts and applications to model and treat cardiac diseases.

scholarly journals Suppressing Pyroptosis Augments Post-Transplant Survival of Stem Cells and Cardiac Function Following Ischemic Injury

2021 ◽  
Vol 22 (15) ◽  
pp. 7946
Author(s):  
Chang Youn Lee ◽  
Seahyoung Lee ◽  
Seongtae Jeong ◽  
Jiyun Lee ◽  
Hyang-Hee Seo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Stem Cell ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion ◽  
Cardiac Cells ◽  
Transplant Survival ◽  
Post Transplant ◽  
Heart Functions ◽  
Cell Death Mechanisms

The acute demise of stem cells following transplantation significantly compromises the efficacy of stem cell-based cell therapeutics for infarcted hearts. As the stem cells transplanted into the damaged heart are readily exposed to the hostile environment, it can be assumed that the acute death of the transplanted stem cells is also inflicted by the same environmental cues that caused massive death of the host cardiac cells. Pyroptosis, a highly inflammatory form of programmed cell death, has been added to the list of important cell death mechanisms in the damaged heart. However, unlike the well-established cell death mechanisms such as necrosis or apoptosis, the exact role and significance of pyroptosis in the acute death of transplanted stem cells have not been explored in depth. In the present study, we found that M1 macrophages mediate the pyroptosis in the ischemia/reperfusion (I/R) injured hearts and identified miRNA-762 as an important regulator of interleukin 1b production and subsequent pyroptosis. Delivery of exogenous miRNA-762 prior to transplantation significantly increased the post-transplant survival of stem cells and also significantly ameliorated cardiac fibrosis and heart functions following I/R injury. Our data strongly suggest that suppressing pyroptosis can be an effective adjuvant strategy to enhance the efficacy of stem cell-based therapeutics for diseased hearts.

scholarly journals Recapitulating Cardiac Structure and Function In Vitro from Simple to Complex Engineering

Micromachines ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 386
Author(s):  
Ana Santos ◽  
Yongjun Jang ◽  
Inwoo Son ◽  
Jongseong Kim ◽  
Yongdoo Park
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Computational Modeling ◽  
Cardiac Tissue ◽  
Cardiac Development ◽  
Heart Tissue ◽  
Cardiac Tissue Engineering ◽  
Cardiac Cells

Cardiac tissue engineering aims to generate in vivo-like functional tissue for the study of cardiac development, homeostasis, and regeneration. Since the heart is composed of various types of cells and extracellular matrix with a specific microenvironment, the fabrication of cardiac tissue in vitro requires integrating technologies of cardiac cells, biomaterials, fabrication, and computational modeling to model the complexity of heart tissue. Here, we review the recent progress of engineering techniques from simple to complex for fabricating matured cardiac tissue in vitro. Advancements in cardiomyocytes, extracellular matrix, geometry, and computational modeling will be discussed based on a technology perspective and their use for preparation of functional cardiac tissue. Since the heart is a very complex system at multiscale levels, an understanding of each technique and their interactions would be highly beneficial to the development of a fully functional heart in cardiac tissue engineering.

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