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Molecular Control of Development and Function of the Cardiac Conduction...
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Molecular Control of Development and Function of the Cardiac Conduction System

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

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 28648

Special Issue Editors

Prof. Dr. Thomas Brand

E-Mail Website
Guest Editor
National Heart & Lung Institute, Imperial College London, Hammersmith Campus, London W12 0NN, UK
Interests: heart development; cardiac pacemaker development and function; popeye genes; cAMP signaling
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Takashi Mikawa

E-Mail Website
Guest Editor
Camilla and George D. Smith Distinguished Professor in Science and Medicine, University of California San Francisco, Cardiovascular Research Institute, 555 Mission Bay Blvd South, MC3120, Room 352Z, PO Box 589001, San Francisco, CA 94158-9001, USA
Interests: morphogenesis; development; body axis; patterning; cell-to-cell communication; cell architecture; cell fate diversification, cardiovascular system; cardiac conduction system; central nervous system; haemodynamics; growth factor signaling

Special Issue Information

Dear Colleagues,

In recent years our understanding of the molecular basis of cardiac conduction system (CCS) development has significantly improved. The transcriptional and signalling networks controlling CCS development have been unravelled to a significant extent. The origin and function of different cell lineages contributing to the CCS have been studied in model organisms. A comparative analysis of the CCS in different vertebrate species has helped to recognize the different building blocks and define their evolutionary origins. Until recently, the cardiac autonomous nervous system (CANS) was considered just a dispensable source for modulating the heart rate. However, recent research suggests that the CANS has a much more complex role and is for example also responsible for sinus node dysfunction, modulating cardiac hypertrophy and being essential for cardiac regeneration. We are still learning about the mechanisms of cardiac pacemaking, its modulation by the CANS and the role of cAMP compartmentation in pacemaker cells. The molecular basis of sinus node dysfunction. Our understanding of the molecular basis of CCS disfunction has improved. Likewise, the prospects of developing biological pacemakers is at the horizon. The goal of this issue is to stimulate new investigations into CCS development and its pathological and clinical implications. We invite you to consider contributing a research paper or review article on any aspect related to the topic of this Special Issue. This may be an opportunity for doctoral and post-doctoral trainees to contribute to a review articles and showcase their areas of expertise.

Prof. Dr. Takashi Mikawa
Prof. Dr. Thomas Brand
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

  • conduction system
  • sinus node
  • atrioventricular node
  • His bundle
  • bundle branches
  • Purkinje fibres
  • arrhythmia
  • development
  • patterning
  • intracardiac nervous system
  • adrenergic signalling
  • transcriptional control

Published Papers (7 papers)

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Review

22 pages, 1646 KiB  
Review
The Role of POPDC Proteins in Cardiac Pacemaking and Conduction
by Lena Gruscheski and Thomas Brand
J. Cardiovasc. Dev. Dis. 2021, 8(12), 160; https://0-doi-org.brum.beds.ac.uk/10.3390/jcdd8120160 - 23 Nov 2021
Cited by 6 | Viewed by 3278
Abstract
The Popeye domain-containing (POPDC) gene family, consisting of Popdc1 (also known as Bves), Popdc2, and Popdc3, encodes transmembrane proteins abundantly expressed in striated muscle. POPDC proteins have recently been identified as cAMP effector proteins and have been proposed to [...] Read more.
The Popeye domain-containing (POPDC) gene family, consisting of Popdc1 (also known as Bves), Popdc2, and Popdc3, encodes transmembrane proteins abundantly expressed in striated muscle. POPDC proteins have recently been identified as cAMP effector proteins and have been proposed to be part of the protein network involved in cAMP signaling. However, their exact biochemical activity is presently poorly understood. Loss-of-function mutations in animal models causes abnormalities in skeletal muscle regeneration, conduction, and heart rate adaptation after stress. Likewise, patients carrying missense or nonsense mutations in POPDC genes have been associated with cardiac arrhythmias and limb-girdle muscular dystrophy. In this review, we introduce the POPDC protein family, and describe their structure function, and role in cAMP signaling. Furthermore, the pathological phenotypes observed in zebrafish and mouse models and the clinical and molecular pathologies in patients carrying POPDC mutations are described. Full article
(This article belongs to the Special Issue Molecular Control of Development and Function of the Cardiac Conduction System)
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18 pages, 1780 KiB  
Review
From Mice to Mainframes: Experimental Models for Investigation of the Intracardiac Nervous System
by Matthew R. Stoyek, Luis Hortells and T. Alexander Quinn
J. Cardiovasc. Dev. Dis. 2021, 8(11), 149; https://0-doi-org.brum.beds.ac.uk/10.3390/jcdd8110149 - 04 Nov 2021
Cited by 6 | Viewed by 2861
Abstract
The intracardiac nervous system (IcNS), sometimes referred to as the “little brain” of the heart, is involved in modulating many aspects of cardiac physiology. In recent years our fundamental understanding of autonomic control of the heart has drastically improved, and the IcNS is [...] Read more.
The intracardiac nervous system (IcNS), sometimes referred to as the “little brain” of the heart, is involved in modulating many aspects of cardiac physiology. In recent years our fundamental understanding of autonomic control of the heart has drastically improved, and the IcNS is increasingly being viewed as a therapeutic target in cardiovascular disease. However, investigations of the physiology and specific roles of intracardiac neurons within the neural circuitry mediating cardiac control has been hampered by an incomplete knowledge of the anatomical organisation of the IcNS. A more thorough understanding of the IcNS is hoped to promote the development of new, highly targeted therapies to modulate IcNS activity in cardiovascular disease. In this paper, we first provide an overview of IcNS anatomy and function derived from experiments in mammals. We then provide descriptions of alternate experimental models for investigation of the IcNS, focusing on a non-mammalian model (zebrafish), neuron-cardiomyocyte co-cultures, and computational models to demonstrate how the similarity of the relevant processes in each model can help to further our understanding of the IcNS in health and disease. Full article
(This article belongs to the Special Issue Molecular Control of Development and Function of the Cardiac Conduction System)
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17 pages, 2794 KiB  
Review
New Insights into the Development and Morphogenesis of the Cardiac Purkinje Fiber Network: Linking Architecture and Function
by Caroline Choquet, Lucie Boulgakoff, Robert G. Kelly and Lucile Miquerol
J. Cardiovasc. Dev. Dis. 2021, 8(8), 95; https://0-doi-org.brum.beds.ac.uk/10.3390/jcdd8080095 - 07 Aug 2021
Cited by 8 | Viewed by 3790
Abstract
The rapid propagation of electrical activity through the ventricular conduction system (VCS) controls spatiotemporal contraction of the ventricles. Cardiac conduction defects or arrhythmias in humans are often associated with mutations in key cardiac transcription factors that have been shown to play important roles [...] Read more.
The rapid propagation of electrical activity through the ventricular conduction system (VCS) controls spatiotemporal contraction of the ventricles. Cardiac conduction defects or arrhythmias in humans are often associated with mutations in key cardiac transcription factors that have been shown to play important roles in VCS morphogenesis in mice. Understanding of the mechanisms of VCS development is thus crucial to decipher the etiology of conduction disturbances in adults. During embryogenesis, the VCS, consisting of the His bundle, bundle branches, and the distal Purkinje network, originates from two independent progenitor populations in the primary ring and the ventricular trabeculae. Differentiation into fast-conducting cardiomyocytes occurs progressively as ventricles develop to form a unique electrical pathway at late fetal stages. The objectives of this review are to highlight the structure–function relationship between VCS morphogenesis and conduction defects and to discuss recent data on the origin and development of the VCS with a focus on the distal Purkinje fiber network. Full article
(This article belongs to the Special Issue Molecular Control of Development and Function of the Cardiac Conduction System)
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14 pages, 1953 KiB  
Review
How Cardiac Embryology Translates into Clinical Arrhythmias
by Mathilde R. Rivaud, Michiel Blok, Monique R. M. Jongbloed and Bastiaan J. Boukens
J. Cardiovasc. Dev. Dis. 2021, 8(6), 70; https://0-doi-org.brum.beds.ac.uk/10.3390/jcdd8060070 - 13 Jun 2021
Cited by 7 | Viewed by 5390
Abstract
The electrophysiological signatures of the myocardium in cardiac structures, such as the atrioventricular node, pulmonary veins or the right ventricular outflow tract, are established during development by the spatial and temporal expression of transcription factors that guide expression of specific ion channels. Genome-wide [...] Read more.
The electrophysiological signatures of the myocardium in cardiac structures, such as the atrioventricular node, pulmonary veins or the right ventricular outflow tract, are established during development by the spatial and temporal expression of transcription factors that guide expression of specific ion channels. Genome-wide association studies have shown that small variations in genetic regions are key to the expression of these transcription factors and thereby modulate the electrical function of the heart. Moreover, mutations in these factors are found in arrhythmogenic pathologies such as congenital atrioventricular block, as well as in specific forms of atrial fibrillation and ventricular tachycardia. In this review, we discuss the developmental origin of distinct electrophysiological structures in the heart and their involvement in cardiac arrhythmias. Full article
(This article belongs to the Special Issue Molecular Control of Development and Function of the Cardiac Conduction System)
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14 pages, 1684 KiB  
Review
Regulation of Cardiac Conduction and Arrhythmias by Ankyrin/Spectrin-Based Macromolecular Complexes
by Drew Nassal, Jane Yu, Dennison Min, Cemantha Lane, Rebecca Shaheen, Daniel Gratz and Thomas J. Hund
J. Cardiovasc. Dev. Dis. 2021, 8(5), 48; https://0-doi-org.brum.beds.ac.uk/10.3390/jcdd8050048 - 29 Apr 2021
Cited by 6 | Viewed by 3350
Abstract
The cardiac conduction system is an extended network of excitable tissue tasked with generation and propagation of electrical impulses to signal coordinated contraction of the heart. The fidelity of this system depends on the proper spatio-temporal regulation of ion channels in myocytes throughout [...] Read more.
The cardiac conduction system is an extended network of excitable tissue tasked with generation and propagation of electrical impulses to signal coordinated contraction of the heart. The fidelity of this system depends on the proper spatio-temporal regulation of ion channels in myocytes throughout the conduction system. Importantly, inherited or acquired defects in a wide class of ion channels has been linked to dysfunction at various stages of the conduction system resulting in life-threatening cardiac arrhythmia. There is growing appreciation of the role that adapter and cytoskeletal proteins play in organizing ion channel macromolecular complexes critical for proper function of the cardiac conduction system. In particular, members of the ankyrin and spectrin families have emerged as important nodes for normal expression and regulation of ion channels in myocytes throughout the conduction system. Human variants impacting ankyrin/spectrin function give rise to a broad constellation of cardiac arrhythmias. Furthermore, chronic neurohumoral and biomechanical stress promotes ankyrin/spectrin loss of function that likely contributes to conduction disturbances in the setting of acquired cardiac disease. Collectively, this review seeks to bring attention to the significance of these cytoskeletal players and emphasize the potential therapeutic role they represent in a myriad of cardiac disease states. Full article
(This article belongs to the Special Issue Molecular Control of Development and Function of the Cardiac Conduction System)
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19 pages, 3930 KiB  
Review
Cellular and Molecular Mechanisms of Functional Hierarchy of Pacemaker Clusters in the Sinoatrial Node: New Insights into Sick Sinus Syndrome
by Di Lang and Alexey V. Glukhov
J. Cardiovasc. Dev. Dis. 2021, 8(4), 43; https://0-doi-org.brum.beds.ac.uk/10.3390/jcdd8040043 - 13 Apr 2021
Cited by 11 | Viewed by 4217
Abstract
The sinoatrial node (SAN), the primary pacemaker of the heart, consists of a heterogeneous population of specialized cardiac myocytes that can spontaneously produce action potentials, generating the rhythm of the heart and coordinating heart contractions. Spontaneous beating can be observed from very early [...] Read more.
The sinoatrial node (SAN), the primary pacemaker of the heart, consists of a heterogeneous population of specialized cardiac myocytes that can spontaneously produce action potentials, generating the rhythm of the heart and coordinating heart contractions. Spontaneous beating can be observed from very early embryonic stage and under a series of genetic programing, the complex heterogeneous SAN cells are formed with specific biomarker proteins and generate robust automaticity. The SAN is capable to adjust its pacemaking rate in response to environmental and autonomic changes to regulate the heart’s performance and maintain physiological needs of the body. Importantly, the origin of the action potential in the SAN is not static, but rather dynamically changes according to the prevailing conditions. Changes in the heart rate are associated with a shift of the leading pacemaker location within the SAN and accompanied by alterations in P wave morphology and PQ interval on ECG. Pacemaker shift occurs in response to different interventions: neurohormonal modulation, cardiac glycosides, pharmacological agents, mechanical stretch, a change in temperature, and a change in extracellular electrolyte concentrations. It was linked with the presence of distinct anatomically and functionally defined intranodal pacemaker clusters that are responsible for the generation of the heart rhythm at different rates. Recent studies indicate that on the cellular level, different pacemaker clusters rely on a complex interplay between the calcium (referred to local subsarcolemmal Ca2+ releases generated by the sarcoplasmic reticulum via ryanodine receptors) and voltage (referred to sarcolemmal electrogenic proteins) components of so-called “coupled clock pacemaker system” that is used to describe a complex mechanism of SAN pacemaking. In this review, we examine the structural, functional, and molecular evidence for hierarchical pacemaker clustering within the SAN. We also demonstrate the unique molecular signatures of intranodal pacemaker clusters, highlighting their importance for physiological rhythm regulation as well as their role in the development of SAN dysfunction, also known as sick sinus syndrome. Full article
(This article belongs to the Special Issue Molecular Control of Development and Function of the Cardiac Conduction System)
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21 pages, 2301 KiB  
Review
Assembly of the Cardiac Pacemaking Complex: Electrogenic Principles of Sinoatrial Node Morphogenesis
by Marietta Easterling, Simone Rossi, Anthony J Mazzella and Michael Bressan
J. Cardiovasc. Dev. Dis. 2021, 8(4), 40; https://0-doi-org.brum.beds.ac.uk/10.3390/jcdd8040040 - 08 Apr 2021
Cited by 10 | Viewed by 4724
Abstract
Cardiac pacemaker cells located in the sinoatrial node initiate the electrical impulses that drive rhythmic contraction of the heart. The sinoatrial node accounts for only a small proportion of the total mass of the heart yet must produce a stimulus of sufficient strength [...] Read more.
Cardiac pacemaker cells located in the sinoatrial node initiate the electrical impulses that drive rhythmic contraction of the heart. The sinoatrial node accounts for only a small proportion of the total mass of the heart yet must produce a stimulus of sufficient strength to stimulate the entire volume of downstream cardiac tissue. This requires balancing a delicate set of electrical interactions both within the sinoatrial node and with the downstream working myocardium. Understanding the fundamental features of these interactions is critical for defining vulnerabilities that arise in human arrhythmic disease and may provide insight towards the design and implementation of the next generation of potential cellular-based cardiac therapeutics. Here, we discuss physiological conditions that influence electrical impulse generation and propagation in the sinoatrial node and describe developmental events that construct the tissue-level architecture that appears necessary for sinoatrial node function. Full article
(This article belongs to the Special Issue Molecular Control of Development and Function of the Cardiac Conduction System)
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