scholarly journals Zebrafish Models in Therapeutic Research of Cardiac Conduction Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Rui Gao ◽  
Jie Ren
Keyword(s):  
Molecular Mechanisms ◽  
Atrioventricular Node ◽  
Conduction System ◽  
Cardiac Conduction ◽  
External Fertilization ◽  
Evolutionarily Conserved ◽  
Cardiovascular Defects ◽  
Vertebrate Model ◽  
Life Threatening ◽  
Therapeutic Research

Malfunction in the cardiac conduction system (CCS) due to congenital anomalies or diseases can cause cardiac conduction disease (CCD), which results in disturbances in cardiac rhythm, leading to syncope and even sudden cardiac death. Insights into development of the CCS components, including pacemaker cardiomyocytes (CMs), atrioventricular node (AVN) and the ventricular conduction system (VCS), can shed light on the pathological and molecular mechanisms underlying CCD, provide approaches for generating human pluripotent stem cell (hPSC)-derived CCS cells, and thus improve therapeutic treatment for such a potentially life-threatening disorder of the heart. However, the cellular and molecular mechanisms controlling CCS development remain elusive. The zebrafish has become a valuable vertebrate model to investigate early development of CCS components because of its unique features such as external fertilization, embryonic optical transparency and the ability to survive even with severe cardiovascular defects during development. In this review, we highlight how the zebrafish has been utilized to dissect the cellular and molecular mechanisms of CCS development, and how the evolutionarily conserved developmental mechanisms discovered in zebrafish could be applied to directing the creation of hPSC-derived CCS cells, therefore providing potential therapeutic strategies that may contribute to better treatment for CCD patients.

Abstract 16005: Highly Efficient Derivation of Human Pacemaker Cells From Pluripotent Stem Cells in Chemically Defined Conditions

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Zaniar Ghazizadeh ◽  
Seyedeh Faranak Fattahi ◽  
Mehdi Sharifi-tabar ◽  
Shahab Mirshahvaladi ◽  
Parisa Shabani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathways ◽  
Pluripotent Stem Cells ◽  
Molecular Mechanisms ◽  
Disease Modeling ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Substantial Contribution ◽  
Cardiac Conduction System ◽  
Pacemaker Cells

The cardiac conduction system is a complex network of cells that together orchestrate the rhythmic and coordinated depolarization of the heart. Dysfunction of the cardiac conduction system plays a central role in the pathogenesis of arrhythmia. While much progress has been made understanding cardiomyocyte differentiation, the molecular mechanisms regulating the specification and patterning of cells that form this conductive network is largely unknown. The LIM-homeodomain transcription factor ISL1 is highly expressed in the secondary heart field (SHF) progenitor population that makes a substantial contribution to the developing heart, comprising most cells in the right ventricle, both atria and pacemaker cells. Pacemaker cells comprise the most proximal component of the cardiac conduction system, which have been proposed as the source of most arrhythmogenic events. Their dominance on other spontaneous beating cell types makes them a suitable target for pharmacologic compounds, making access to this cell lineage necessary for the study of new therapeutic agents. To identify the signaling pathways that control the differentiation of human embryonic stem cell (hESC)-derived SHF cells into pacemaker cells, we performed RNA sequencing to compare the hESC-derived ISL1 + population, non-enriched population and undifferentiated hESCs. Furthermore, using a small molecule screen we identified compounds that can improve differentiation of hESCs toward pacemaker cells. Pathway analysis identified the Wnt pathway as the most significant regulator of SHF specification. Further differentiation of human pluripotent stem cells by stage-specific activation of BMP and WNT signaling pathways resulted in phenotypic pacemaker cells, which display morphological characteristics. More than 80% of these cells stained positively for HCN4, Contactin2(CNTN2) and GATA6, key markers of pacemaker cells. The differentiated cells express pacemaker markers, including CNTN2, TBX2, TBX3, HCN4, TBX18, GATA6 indicated by qRT-PCR. They show inward potassium currents through HCN channels in patch clamp experiments. Our data provides a new strategy to obtain human cardiac conduction cells in large scale for disease modeling, drug screening and cell therapy.

Development of the cardiac conduction system

ESC CardioMed ◽  
2018 ◽  
pp. 49-52
Author(s):  
Jan Hendrik van Weerd ◽  
Vincent M. Christoffels
Keyword(s):  
Regulatory Networks ◽  
Atrioventricular Node ◽  
Ventricular Myocardium ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Cellular Mechanisms ◽  
Fibre Network ◽  
Electrical Impulses ◽  
And Function

The contraction of the heart is orchestrated by the components of the cardiac conduction system (CCS), which initiate and propagate the electrical impulses to coordinately activate the cardiac chambers. In the adult heart, the impulse is generated in the sinoatrial node and activates the atrial myocardium. Slow conduction of the impulse through the atrioventricular node allows for emptying of the atria and filling of the ventricles prior to ventricular contraction. Subsequent fast conduction through the atrioventricular bundle, bundle branches, and Purkinje fibre network activates the ventricular myocardium and causes the ventricles to contract. The development and function of the CCS involves complex regulatory networks of transcription factors acting in stage-, tissue-, and dose-dependent manners. Disrupted function or expression of these factors might lead to impaired development or function of the CCS components, associated with heart failure and sudden death. It is therefore crucial to understand the molecular and cellular mechanisms controlling the complex regulation of CCS development. This chapter summarizes current insight in the development and function of the different compartments of the CCS, and discusses the transcriptional networks underlying these processes.

Development of the cardiac conduction system

ESC CardioMed ◽  
2018 ◽  
pp. 49-52
Author(s):  
Jan Hendrik van Weerd ◽  
Vincent M. Christoffels
Keyword(s):  
Regulatory Networks ◽  
Atrioventricular Node ◽  
Ventricular Myocardium ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Cellular Mechanisms ◽  
Fibre Network ◽  
Electrical Impulses ◽  
And Function

The contraction of the heart is orchestrated by the components of the cardiac conduction system (CCS), which initiate and propagate the electrical impulses to coordinately activate the cardiac chambers. In the adult heart, the impulse is generated in the sinoatrial node and activates the atrial myocardium. Slow conduction of the impulse through the atrioventricular node allows for emptying of the atria and filling of the ventricles prior to ventricular contraction. Subsequent fast conduction through the atrioventricular bundle, bundle branches, and Purkinje fibre network activates the ventricular myocardium and causes the ventricles to contract. The development and function of the CCS involves complex regulatory networks of transcription factors acting in stage-, tissue-, and dose-dependent manners. Disrupted function or expression of these factors might lead to impaired development or function of the CCS components, associated with heart failure and sudden death. It is therefore crucial to understand the molecular and cellular mechanisms controlling the complex regulation of CCS development. This chapter summarizes current insight in the development and function of the different compartments of the CCS, and discusses the transcriptional networks underlying these processes.

Abstract 260: A miRNA-Hippo Pathway Promotes Cardiac Conduction System Regeneration

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Jun Wang ◽  
James F Martin
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Size Control ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Hippo Signaling ◽  
Cardiomyocyte Proliferation ◽  
Non Coding Rnas

The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats and CCS defects can give rise to cardiac arrhythmia, a leading cause for morbidity worldwide. Given the poor self-repair potential in the adult human CCS, it is critical to elucidate the molecular mechanisms limiting CCS regeneration to facilitate developing efficient cardiovascular therapies. microRNAs (miRs) are small non-coding RNAs that repress gene expression post-transcriptionally. The miR-17-92 cluster can induce cardiomyocyte proliferation and regeneration. Hippo signaling, an ancient organ size control pathway, represses cardiomyocyte proliferation and regeneration. Here we found that both miR-17-92 and Hippo signaling were active in CCS. Disruption of either miR-17-92 or Hippo signaling in heart gave rise to cardiac arrhythmias in mice. Notably, miR-17-92 regulates Hippo signaling through repressing Lats2, a core Hippo pathway component. In miR-17-92 null mutant hearts, up-regulated Lats2 led to increased Hippo pathway activity. Moreover, we performed chromatin immunoprecipitation deep sequencing (ChIP-Seq) using YAP, the Hippo signaling effector, which suggested that Hippo signaling regulates genes involved in CCS homeostasis. Together, we propose a novel miR-Hippo genetic pathway that promotes CCS regeneration.

scholarly journals SEM, TEM, and IHC Analysis of the Sinus Node and Its Implications for the Cardiac Conduction System

2013 ◽  
Vol 2013 ◽  
pp. 1-6
Author(s):  
D. Mandrioli ◽  
F. Ceci ◽  
T. Balbi ◽  
C. Ghimenton ◽  
G. Pierini
Keyword(s):  
Electron Microscopy ◽  
Sinus Node ◽  
Atrioventricular Node ◽  
Definite Description ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Ordered Structure ◽  
Healthy Individuals ◽  
Optical And Electron Microscopy

More than 100 years after the discovery of the sinus node (SN) by Keith and Flack, the function and structure of the SN have not been completely established yet. The anatomic architecture of the SN has often been described as devoid of an organized structure; the origin of the sinus impulse is still a matter of debate, and a definite description of the long postulated internodal specialized tract conducting the impulse from the SN to the atrioventricular node (AVN) is still missing. In our previously published study, we proposed a morphologically ordered structure for the SN. As a confirmation of what was presented then, we have added the results of additional observations regarding the structural particularities of the SN. We investigated the morphology of the sinus node in the human hearts of healthy individuals using histochemical, immunohistochemical, optical, and electron microscopy (SEM, TEM). Our results confirmed that the SN presents a previously unseen highly organized architecture.

scholarly journals Bioengineering the Cardiac Conduction System: Advances in Cellular, Gene, and Tissue Engineering for Heart Rhythm Regeneration

2021 ◽  
Vol 9 ◽  
Author(s):  
Nataliia Naumova ◽  
Laura Iop
Keyword(s):  
Electronic Devices ◽  
Somatic Growth ◽  
Heart Rhythm ◽  
Pharmacological Therapy ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Life Saving ◽  
Life Threatening ◽  
Experimental Approaches

Heart rhythm disturbances caused by different etiologies may affect pediatric and adult patients with life-threatening consequences. When pharmacological therapy is ineffective in treating the disturbances, the implantation of electronic devices to control and/or restore normal heart pacing is a unique clinical management option. Although these artificial devices are life-saving, they display many limitations; not least, they do not have any capability to adapt to somatic growth or respond to neuroautonomic physiological changes. A biological pacemaker could offer a new clinical solution for restoring heart rhythms in the conditions of disorder in the cardiac conduction system. Several experimental approaches, such as cell-based, gene-based approaches, and the combination of both, for the generation of biological pacemakers are currently established and widely studied. Pacemaker bioengineering is also emerging as a technology to regenerate nodal tissues. This review analyzes and summarizes the strategies applied so far for the development of biological pacemakers, and discusses current translational challenges toward the first-in-human clinical application.

Dissecting the Cardiac Conduction System: Is It Worthwhile?

2020 ◽  
Vol 23 (6) ◽  
pp. 413-423
Author(s):  
Serena Y Tan ◽  
Michael K Fritsch ◽  
Steven White ◽  
Nicoleta C Arva
Keyword(s):  
Sudden Death ◽  
Fibromuscular Dysplasia ◽  
Pediatric Patients ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Forensic Practice ◽  
Fibrotic Scar ◽  
Defect Repair ◽  
Life Threatening ◽  
Histologic Changes

Background Pathologic examination of conduction system (CS) is not routinely performed, and histologic changes are mostly reported in forensic practice. Methods We studied the value of dissecting the CS in a cohort of pediatric patients with unexplained sudden death or severe, inexplicable arrhythmias. Histopathologic changes present in CS components were recorded and correlated with findings noted in other cardiac structures. Results Twenty-one subjects (11 unexplained sudden deaths and 10 life-threatening arrhythmias) were identified; 18 (86%) had CS pathologic abnormalities. In 13 patients (62%), the CS findings mirrored those found in other cardiac sections (inflammation, allograft vasculopathy, vascular fibromuscular dysplasia, cardiomyopathy-related changes, and tumor/tumor-like conditions). Five cases (24%) had abnormalities restricted to CS (bundle of His [BH] with fibrotic scar and patch material following ventricular septal defect repair, inflammation, BH with fibrosis and calcifications, and intimal fibroplasia of sinoatrial node artery). Conclusions Pathologic changes within the CS are present in a high number of pediatric patients presenting with unexplained sudden death or life-threatening arrhythmias. Frequently, the findings mirror those observed in other cardiac structures. However, in a significant number of cases (24%), the changes are restricted to CS and likely explain the patients’ symptoms or cause of death, suggesting that systematic dissection of CS unveils valuable information.

Simulation of Heartbeat Dynamics: A Nonlinear Model

1998 ◽  
Vol 08 (08) ◽  
pp. 1725-1731 ◽  
Author(s):  
Maria G. Signorini ◽  
Diego di Bernardo
Keyword(s):  
Mathematical Modeling ◽  
Simple Structure ◽  
Nonlinear Differential Equations ◽  
Atrioventricular Node ◽  
Nonlinear Oscillators ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Real Situation ◽  
Cardiac Dynamics

The mathematical modeling of biological systems has proven to be a valuable tool by allowing experiments which would otherwise be unfeasible in a real situation. In this work we propose a system of nonlinear differential equations describing the macroscopic behavior of the cardiac conduction system. The model describes the interactoin between the SinoAtrial and AtrioVentricular node. Its very simple structure consists of two nonlinear oscillators resistively coupled. The numerical analysis detects different kinds of bifurcations whose pathophysiological meanings are discussed. Moreover, the model is able to classify different pathologies, such as several classes of arrhythmic events, as well as to suggest hypothesis on the mechanisms that induce them. These results also show that the mechanisms generating the heartbeat obey complex laws. The model provides a wuite complete description of different pathological phenomena and its simplicity can be exploited for further studies on the control of cardiac dynamics.

scholarly journals Measurement of cAMP in the cardiac conduction system of rats.

1995 ◽  
Vol 43 (6) ◽  
pp. 601-605 ◽  
Author(s):  
A Sugiyama ◽  
S McKnite ◽  
P Wiegn ◽  
K G Lurie
Keyword(s):  
Atrioventricular Node ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Camp Production ◽  
Adrenergic Stimulation ◽  
Beta Adrenergic ◽  
His Bundle ◽  
Freeze Dried ◽  
Camp Levels

To characterize differences in regional cAMP production in the cardiac conduction system, 18 rats were anesthetized with pentobarbital (65 mg/kg IP) and randomized into a control (n = 9) and a stimulated group (n = 9). The stimulated group received aminophylline (20 mg/kg SC) and isoproterenol (16 micrograms/kg SC). The concentration of cAMP in freeze-dried, micro dissected pieces (1-3 micrograms) of cardiac tissue was measured using a new microanalytical method. The cAMP contents in right atrium, atrioventricular node, His bundle, and left ventricle (fmol/microgram dry weight, mean +/- SE) were 38.9 +/- 2.5, 39.0 +/- 4.3, 46.4 +/- 6.1, and 41.4 +/- 3.3 in controls and 72.9 +/- 6.7, 86.1 +/- 2.9, 115.0 +/- 11.5, and 79.5 +/- 7.3 in the stimulated group, respectively. Basal cAMP levels were similar throughout the heart, whereas isoproterenol increased cAMP levels in all regions (p < 0.01). Furthermore, cAMP levels in His bundle, after isoproterenol, were higher than in any other region (p < 0.05). These results demonstrate that: (a) cAMP can be measured in discrete portions of the cardiac conduction system; (b) there are significant regional differences of beta-adrenergic control in the cardiac conduction system; and (c) cAMP production after beta-adrenergic stimulation was lower than expected in the AV nodal region, based on previously described beta-adrenoceptor density measurements.

Electrophysiologic Study of the Conduction System in Normal Children

PEDIATRICS ◽  
1977 ◽  
Vol 60 (6) ◽  
pp. 858-863
Author(s):  
Nigel K. Roberts ◽  
Paul C. Gillette
Keyword(s):  
Recovery Time ◽  
Sinus Node ◽  
Atrioventricular Node ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Purkinje Fiber ◽  
Normal Children ◽  
Electrophysiologic Study ◽  
His Bundle ◽  
The Mean

Values for cardiac conduction intervals obtained from normal children are reported so that the data will be available for comparison with patients who are suspected of having abnormalities. Sinus node recovery time correlated linearly with the resting PP interval. The mean intra-atnal conduction was considerably shorter in children (&lt; 25 msec) than in adults (42 msec). The atrioventricular node had similar electrophysiologic properties in the child and adult. With aging, the His bundle to Purkinje fiber time increased significantly (P &lt; .01).

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