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Development and Function of the Cardiac Conduction System in Health...
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Development and Function of the Cardiac Conduction System in Health and Disease

A special issue of Journal of Cardiovascular Development and Disease (ISSN 2308-3425).

Deadline for manuscript submissions: closed (31 October 2015) | Viewed by 110056

Special Issue Editors

Prof. Dr. Robert E. Poelmann

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Guest Editor
1. Dept. Cardiology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands
2. Institute of Biology IBL, University of Leiden, Sylviusweg 72, 2333BE Leiden, The Netherlands
Interests: cardiac development and septation; animal models; evolutionary biology; congenital anomalies; epicardium; biomechanics; imaging
Special Issues, Collections and Topics in MDPI journals
Dr. Monique R.M. Jongbloed

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Guest Editor
1. Department Anatomy & Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands
2. Department of Cardiology, Leiden University Medical Center, 2300RC Leiden, The Netherlands
Interests: congenital heart disease; cardiac development; conduction system development; animal models of congenital heart disease and arrhythmias; clinical aspects of arrhythmia; electrophysiology; cardiovascular morphology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

JCDD launches a Special Issue on "Development and function of the cardiac conduction system in health and disease". The rhythmical function of the heart has sparked the interest of humans, probably since many centuries. The molecular characterization of anatomically defined areas of the heart that have pacemaker functions as well as areas involved in conducting signals to the myocardium is more recent. This field is rapidly evolving using multiple approaches including but not restricted to optical mapping, MRI and CT-based imaging modalities, molecular and transgenic techniques, electrophysiological measurements both in vivo and in vitro, channelopathies, developmental phenotypes, organs-on-a-chip, and other both in human and animal models. This interesting combination of applications allows for new interpretations and analyses for understanding the evolutionary, developmental and functional origin of the cardiac conduction system. As a consequence, better strategies can be formulated for setting horizons for treatment of congenital anomalies and diseases related to cardiac conduction.

Prof. Dr. Robert E. Poelmann
Dr. Monique R.M. Jongbloed
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Cardiovascular Development and Disease is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cardiovascular development
  • Evolutionary biology
  • Conduction system
  • Perinatal arrhythmia
  • Molecular control
  • Imaging modalities
  • Optical mapping
  • Electrophysiology
  • Organ-on-a-chip
  • Animal models
  • Congenital heart disease

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Published Papers (12 papers)

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Research

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2775 KiB  
Article
Segregation of Central Ventricular Conduction System Lineages in Early SMA+ Cardiomyocytes Occurs Prior to Heart Tube Formation
by Caroline Choquet, Laetitia Marcadet, Sabrina Beyer, Robert G. Kelly and Lucile Miquerol
J. Cardiovasc. Dev. Dis. 2016, 3(1), 2; https://doi.org/10.3390/jcdd3010002 - 21 Jan 2016
Cited by 13 | Viewed by 6628
Abstract
The cardiac conduction system (CCS) transmits electrical activity from the atria to the ventricles to coordinate heartbeats. Atrioventricular conduction diseases are often associated with defects in the central ventricular conduction system comprising the atrioventricular bundle (AVB) and right and left branches (BBs). Conducting [...] Read more.
The cardiac conduction system (CCS) transmits electrical activity from the atria to the ventricles to coordinate heartbeats. Atrioventricular conduction diseases are often associated with defects in the central ventricular conduction system comprising the atrioventricular bundle (AVB) and right and left branches (BBs). Conducting and contractile working myocytes share common cardiomyogenic progenitors, however the time at which the CCS lineage becomes specified is unclear. In order to study the fate and the contribution to the CCS of cardiomyocytes during early heart tube formation, we performed a genetic lineage analysis using a Sma-CreERT2 mouse line. Lineage tracing experiments reveal a sequential contribution of early Sma expressing cardiomyocytes to different cardiac compartments, labeling at embryonic day (E) 7.5 giving rise to the interventricular septum and apical left ventricular myocardium. Early Sma expressing cardiomyocytes contribute to the AVB, BBs and left ventricular Purkinje fibers. Clonal analysis using the R26-confetti reporter mouse crossed with Sma-CreERT2 demonstrates that early Sma expressing cardiomyocytes include cells exclusively fated to give rise to the AVB. In contrast, lineage segregation is still ongoing for the BBs at E7.5. Overall this study highlights the early segregation of the central ventricular conduction system lineage within cardiomyocytes at the onset of heart tube formation. Full article
(This article belongs to the Special Issue Development and Function of the Cardiac Conduction System in Health and Disease)
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6869 KiB  
Article
Effect of Outflow Tract Banding on Embryonic Cardiac Hemodynamics
by Venkat Keshav Chivukula, Sevan Goenezen, Aiping Liu and Sandra Rugonyi
J. Cardiovasc. Dev. Dis. 2016, 3(1), 1; https://doi.org/10.3390/jcdd3010001 - 24 Dec 2015
Cited by 21 | Viewed by 5127
Abstract
We analyzed heart wall motion and blood flow dynamics in chicken embryos using in vivo optical coherence tomography (OCT) imaging and computational fluid dynamics (CFD) embryo-specific modeling. We focused on the heart outflow tract (OFT) region of day 3 embryos, and compared normal [...] Read more.
We analyzed heart wall motion and blood flow dynamics in chicken embryos using in vivo optical coherence tomography (OCT) imaging and computational fluid dynamics (CFD) embryo-specific modeling. We focused on the heart outflow tract (OFT) region of day 3 embryos, and compared normal (control) conditions to conditions after performing an OFT banding intervention, which alters hemodynamics in the embryonic heart and vasculature. We found that hemodynamics and cardiac wall motion in the OFT are affected by banding in ways that might not be intuitive a priori. In addition to the expected increase in ventricular blood pressure, and increase blood flow velocity and, thus, wall shear stress (WSS) at the band site, the characteristic peristaltic-like motion of the OFT was altered, further affecting flow and WSS. Myocardial contractility, however, was affected only close to the band site due to the physical restriction on wall motion imposed by the band. WSS were heterogeneously distributed in both normal and banded OFTs. Our results show how banding affects cardiac mechanics and can lead, in the future, to a better understanding of mechanisms by which altered blood flow conditions affect cardiac development leading to congenital heart disease. Full article
(This article belongs to the Special Issue Development and Function of the Cardiac Conduction System in Health and Disease)
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Review

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2909 KiB  
Review
Development and Function of the Cardiac Conduction System in Health and Disease
by David S. Park and Glenn I. Fishman
J. Cardiovasc. Dev. Dis. 2017, 4(2), 7; https://doi.org/10.3390/jcdd4020007 - 7 Jun 2017
Cited by 31 | Viewed by 9534
Abstract
The generation and propagation of the cardiac impulse is the central function of the cardiac conduction system (CCS). Impulse initiation occurs in nodal tissues that have high levels of automaticity, but slow conduction properties. Rapid impulse propagation is a feature of the ventricular [...] Read more.
The generation and propagation of the cardiac impulse is the central function of the cardiac conduction system (CCS). Impulse initiation occurs in nodal tissues that have high levels of automaticity, but slow conduction properties. Rapid impulse propagation is a feature of the ventricular conduction system, which is essential for synchronized contraction of the ventricular chambers. When functioning properly, the CCS produces ~2.4 billion heartbeats during a human lifetime and orchestrates the flow of cardiac impulses, designed to maximize cardiac output. Abnormal impulse initiation or propagation can result in brady- and tachy-arrhythmias, producing an array of symptoms, including syncope, heart failure or sudden cardiac death. Underlying the functional diversity of the CCS are gene regulatory networks that direct cell fate towards a nodal or a fast conduction gene program. In this review, we will discuss our current understanding of the transcriptional networks that dictate the components of the CCS, the growth factor-dependent signaling pathways that orchestrate some of these transcriptional hierarchies and the effect of aberrant transcription factor expression on mammalian conduction disease. Full article
(This article belongs to the Special Issue Development and Function of the Cardiac Conduction System in Health and Disease)
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2425 KiB  
Review
Lineages of the Cardiac Conduction System
by Rajiv Mohan, Bas J. Boukens and Vincent M. Christoffels
J. Cardiovasc. Dev. Dis. 2017, 4(2), 5; https://doi.org/10.3390/jcdd4020005 - 2 May 2017
Cited by 9 | Viewed by 8547
Abstract
The cardiac conduction system (CCS) initiates and coordinately propagates the electrical impulse to orchestrate the heartbeat. It consists of a set of interconnected components with shared properties. A better understanding of the origin and specification of CCS lineages has allowed us to better [...] Read more.
The cardiac conduction system (CCS) initiates and coordinately propagates the electrical impulse to orchestrate the heartbeat. It consists of a set of interconnected components with shared properties. A better understanding of the origin and specification of CCS lineages has allowed us to better comprehend the etiology of CCS disease and has provided leads for development of therapies. A variety of technologies and approaches have been used to investigate CCS lineages, which will be summarized in this review. The findings imply that there is not a single CCS lineage. In contrast, early cell fate decisions segregate the lineages of the CCS components while they remain connected to each other. Full article
(This article belongs to the Special Issue Development and Function of the Cardiac Conduction System in Health and Disease)
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1287 KiB  
Review
On the Evolution of the Cardiac Pacemaker
by Silja Burkhard, Vincent Van Eif, Laurence Garric, Vincent M. Christoffels and Jeroen Bakkers
J. Cardiovasc. Dev. Dis. 2017, 4(2), 4; https://doi.org/10.3390/jcdd4020004 - 27 Apr 2017
Cited by 37 | Viewed by 13277
Abstract
The rhythmic contraction of the heart is initiated and controlled by an intrinsic pacemaker system. Cardiac contractions commence at very early embryonic stages and coordination remains crucial for survival. The underlying molecular mechanisms of pacemaker cell development and function are still not fully [...] Read more.
The rhythmic contraction of the heart is initiated and controlled by an intrinsic pacemaker system. Cardiac contractions commence at very early embryonic stages and coordination remains crucial for survival. The underlying molecular mechanisms of pacemaker cell development and function are still not fully understood. Heart form and function show high evolutionary conservation. Even in simple contractile cardiac tubes in primitive invertebrates, cardiac function is controlled by intrinsic, autonomous pacemaker cells. Understanding the evolutionary origin and development of cardiac pacemaker cells will help us outline the important pathways and factors involved. Key patterning factors, such as the homeodomain transcription factors Nkx2.5 and Shox2, and the LIM-homeodomain transcription factor Islet-1, components of the T-box (Tbx), and bone morphogenic protein (Bmp) families are well conserved. Here we compare the dominant pacemaking systems in various organisms with respect to the underlying molecular regulation. Comparative analysis of the pathways involved in patterning the pacemaker domain in an evolutionary context might help us outline a common fundamental pacemaker cell gene programme. Special focus is given to pacemaker development in zebrafish, an extensively used model for vertebrate development. Finally, we conclude with a summary of highly conserved key factors in pacemaker cell development and function. Full article
(This article belongs to the Special Issue Development and Function of the Cardiac Conduction System in Health and Disease)
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4146 KiB  
Review
Part and Parcel of the Cardiac Autonomic Nerve System: Unravelling Its Cellular Building Blocks during Development
by Anna M. D. Végh, Sjoerd N. Duim, Anke M. Smits, Robert E. Poelmann, Arend D. J. Ten Harkel, Marco C. DeRuiter, Marie José Goumans and Monique R. M. Jongbloed
J. Cardiovasc. Dev. Dis. 2016, 3(3), 28; https://doi.org/10.3390/jcdd3030028 - 12 Sep 2016
Cited by 35 | Viewed by 19343
Abstract
The autonomic nervous system (cANS) is essential for proper heart function, and complications such as heart failure, arrhythmias and even sudden cardiac death are associated with an altered cANS function. A changed innervation state may underlie (part of) the atrial and ventricular arrhythmias [...] Read more.
The autonomic nervous system (cANS) is essential for proper heart function, and complications such as heart failure, arrhythmias and even sudden cardiac death are associated with an altered cANS function. A changed innervation state may underlie (part of) the atrial and ventricular arrhythmias observed after myocardial infarction. In other cardiac diseases, such as congenital heart disease, autonomic dysfunction may be related to disease outcome. This is also the case after heart transplantation, when the heart is denervated. Interest in the origin of the autonomic nerve system has renewed since the role of autonomic function in disease progression was recognized, and some plasticity in autonomic regeneration is evident. As with many pathological processes, autonomic dysfunction based on pathological innervation may be a partial recapitulation of the early development of innervation. As such, insight into the development of cardiac innervation and an understanding of the cellular background contributing to cardiac innervation during different phases of development is required. This review describes the development of the cANS and focuses on the cellular contributions, either directly by delivering cells or indirectly by secretion of necessary factors or cell-derivatives. Full article
(This article belongs to the Special Issue Development and Function of the Cardiac Conduction System in Health and Disease)
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3623 KiB  
Review
The Popeye Domain Containing Genes and Their Function in Striated Muscle
by Roland F. R. Schindler, Chiara Scotton, Vanessa French, Alessandra Ferlini and Thomas Brand
J. Cardiovasc. Dev. Dis. 2016, 3(2), 22; https://doi.org/10.3390/jcdd3020022 - 15 Jun 2016
Cited by 14 | Viewed by 4659
Abstract
The Popeye domain containing (POPDC) genes encode a novel class of cAMP effector proteins, which are abundantly expressed in heart and skeletal muscle. Here, we will review their role in striated muscle as deduced from work in cell and animal models and the [...] Read more.
The Popeye domain containing (POPDC) genes encode a novel class of cAMP effector proteins, which are abundantly expressed in heart and skeletal muscle. Here, we will review their role in striated muscle as deduced from work in cell and animal models and the recent analysis of patients carrying a missense mutation in POPDC1. Evidence suggests that POPDC proteins control membrane trafficking of interacting proteins. Furthermore, we will discuss the current catalogue of established protein-protein interactions. In recent years, the number of POPDC-interacting proteins has been rising and currently includes ion channels (TREK-1), sarcolemma-associated proteins serving functions in mechanical stability (dystrophin), compartmentalization (caveolin 3), scaffolding (ZO-1), trafficking (NDRG4, VAMP2/3) and repair (dysferlin) or acting as a guanine nucleotide exchange factor for Rho-family GTPases (GEFT). Recent evidence suggests that POPDC proteins might also control the cellular level of the nuclear proto-oncoprotein c-Myc. These data suggest that this family of cAMP-binding proteins probably serves multiple roles in striated muscle. Full article
(This article belongs to the Special Issue Development and Function of the Cardiac Conduction System in Health and Disease)
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1560 KiB  
Review
Postnatal Cardiac Autonomic Nervous Control in Pediatric Congenital Heart Disease
by Ineke Nederend, Monique R. M. Jongbloed, Eco J. C. De Geus, Nico A. Blom and Arend D. J. Ten Harkel
J. Cardiovasc. Dev. Dis. 2016, 3(2), 16; https://doi.org/10.3390/jcdd3020016 - 15 Apr 2016
Cited by 13 | Viewed by 14833
Abstract
Congenital heart disease is the most common congenital defect. During childhood, survival is generally good but, in adulthood, late complications are not uncommon. Abnormal autonomic control in children with congenital heart disease may contribute considerably to the pathophysiology of these long term sequelae. [...] Read more.
Congenital heart disease is the most common congenital defect. During childhood, survival is generally good but, in adulthood, late complications are not uncommon. Abnormal autonomic control in children with congenital heart disease may contribute considerably to the pathophysiology of these long term sequelae. This narrative review of 34 studies aims to summarize current knowledge on function of the autonomic nervous system in children with a congenital heart defect. Large scale studies that measure both branches of the nervous system for prolonged periods of time in well-defined patient cohorts in various phases of childhood and adolescence are currently lacking. Pending such studies, there is not yet a good grasp on the extent and direction of sympathetic and parasympathetic autonomic function in pediatric congenital heart disease. Longitudinal studies in homogenous patient groups linking autonomic nervous system function and clinical outcome are warranted. Full article
(This article belongs to the Special Issue Development and Function of the Cardiac Conduction System in Health and Disease)
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556 KiB  
Review
The “Dead-End Tract” and Its Role in Arrhythmogenesis
by Lennart De Vries, Astrid Hendriks and Tamas Szili-Torok
J. Cardiovasc. Dev. Dis. 2016, 3(2), 11; https://doi.org/10.3390/jcdd3020011 - 5 Apr 2016
Cited by 19 | Viewed by 5661
Abstract
Idiopathic outflow tract ventricular arrhythmias (VAs) represent a significant proportion of all VAs. The mechanism is thought to be catecholamine-mediated delayed after depolarizations and triggered activity, although other etiologies should be considered. In the adult cardiac conduction system it has been demonstrated that [...] Read more.
Idiopathic outflow tract ventricular arrhythmias (VAs) represent a significant proportion of all VAs. The mechanism is thought to be catecholamine-mediated delayed after depolarizations and triggered activity, although other etiologies should be considered. In the adult cardiac conduction system it has been demonstrated that sometimes an embryonic branch, the so-called “dead-end tract”, persists beyond the bifurcation of the right and left bundle branch (LBB). Several findings suggest an involvement of this tract in idiopathic VAs (IVAs). The aim of this review is to summarize our current knowledge and the possible clinical significance of this tract. Full article
(This article belongs to the Special Issue Development and Function of the Cardiac Conduction System in Health and Disease)
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3485 KiB  
Review
Probing the Electrophysiology of the Developing Heart
by Michiko Watanabe, Andrew M. Rollins, Luis Polo-Parada, Pei Ma, Shi Gu and Michael W. Jenkins
J. Cardiovasc. Dev. Dis. 2016, 3(1), 10; https://doi.org/10.3390/jcdd3010010 - 22 Mar 2016
Cited by 8 | Viewed by 8177
Abstract
Many diseases that result in dysfunction and dysmorphology of the heart originate in the embryo. However, the embryonic heart presents a challenging subject for study: especially challenging is its electrophysiology. Electrophysiological maturation of the embryonic heart without disturbing its physiological function requires the [...] Read more.
Many diseases that result in dysfunction and dysmorphology of the heart originate in the embryo. However, the embryonic heart presents a challenging subject for study: especially challenging is its electrophysiology. Electrophysiological maturation of the embryonic heart without disturbing its physiological function requires the creation and deployment of novel technologies along with the use of classical techniques on a range of animal models. Each tool has its strengths and limitations and has contributed to making key discoveries to expand our understanding of cardiac development. Further progress in understanding the mechanisms that regulate the normal and abnormal development of the electrophysiology of the heart requires integration of this functional information with the more extensively elucidated structural and molecular changes. Full article
(This article belongs to the Special Issue Development and Function of the Cardiac Conduction System in Health and Disease)
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5492 KiB  
Review
Genetic Regulation of Sinoatrial Node Development and Pacemaker Program in the Venous Pole
by Wenduo Ye, Yingnan Song, Zhen Huang, Yanding Zhang and Yiping Chen
J. Cardiovasc. Dev. Dis. 2015, 2(4), 282-298; https://doi.org/10.3390/jcdd2040282 - 30 Nov 2015
Cited by 20 | Viewed by 6464
Abstract
The definitive sinoatrial node (SAN), the primary pacemaker of the mammalian heart, develops from part of pro-pacemaking embryonic venous pole that expresses both Hcn4 and the transcriptional factor Shox2. It is noted that ectopic pacemaking activities originated from the myocardial sleeves of the [...] Read more.
The definitive sinoatrial node (SAN), the primary pacemaker of the mammalian heart, develops from part of pro-pacemaking embryonic venous pole that expresses both Hcn4 and the transcriptional factor Shox2. It is noted that ectopic pacemaking activities originated from the myocardial sleeves of the pulmonary vein and systemic venous return, both derived from the Shox2+ pro-pacemaking cells in the venous pole, cause atrial fibrillation. However, the developmental link between the pacemaker properties in the embryonic venous pole cells and the SAN remains largely uncharacterized. Furthermore, the genetic program for the development of heterogeneous populations of the SAN is also under-appreciated. Here, we review the literature for a better understanding of the heterogeneous development of the SAN in relation to that of the sinus venosus myocardium and pulmonary vein myocardium. We also attempt to revisit genetic models pertinent to the development of pacemaker activities in the perspective of a Shox2-Nkx2-5 epistatic antagonism. Finally, we describe recent efforts in deciphering the regulatory networks for pacemaker development by genome-wide approaches. Full article
(This article belongs to the Special Issue Development and Function of the Cardiac Conduction System in Health and Disease)
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Other

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4993 KiB  
Comment
Of Tracts, Rings, Nodes, Cusps, Sinuses, and Arrhythmias—A Comment on Szili-Torok et al.’s Paper Entitled “The ‘Dead-End Tract’ and Its Role in Arrhythmogenesis”. J. Cardiovasc. Dev. Dis. 2016, 3, 11
by Robert H. Anderson, Diane E. Spicer and Shumpei Mori
J. Cardiovasc. Dev. Dis. 2016, 3(2), 17; https://doi.org/10.3390/jcdd3020017 - 19 Apr 2016
Cited by 4 | Viewed by 4841
Abstract
In the review, now published as part of the special issue devoted to the development of the conduction tissues, de Vries and his colleagues discuss the potential role of the so-called “dead-end tract” as a substrate for arrhythmogenesis [1].[...] Full article
(This article belongs to the Special Issue Development and Function of the Cardiac Conduction System in Health and Disease)
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