Special Issue "Highlights of the 2013 Berlin Meeting of the ESC working group on Development, Anatomy and Pathology"

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

Deadline for manuscript submissions: closed (1 February 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Silke R. Sperling (Website)

Department of Cardiovascular Genetics, Charité Medical Faculty and the Max Delbrück Center (MDC) for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany
Interests: Molecular mechanisms of cardiac development in mouse and human; genomics of congenital heart disease; cardiac transcription networks; epigenetics of heart development and disease; systems biology approaches

Special Issue Information

Dear Colleagues,

This inaugural issue of the Journal of Cardiovascular Development and Disease (JCDD) is composed of contributions by the presenters at the 2013 Meeting of the Working Group (WG) of Development, Anatomy and Pathology of the European Society of Cardiology (ESC). With its first meeting dating back more than 30 years, it can in part be seen as the European counterpart of the Weinstein Meetings, which were primarily initiated by Constance Weinstein for National Institute of Health (NIH) grant holders working on basic cardiovascular science, and where the idea for JCDD was born in spring 2013 at the Tucson Meeting. Over the last years, close collaborations have emerged between both meeting parties and thus the upcoming Weinstein meeting will be held in Europe (Madrid) and joined by the European WG.

The European WG and its meetings are dedicated to advance our understanding of heart development and its pathology from morphogenesis through molecular and cellular biology to genetics. This broad spectrum of knowledge was also presented at the 2013 Meeting and is reflected in the contributions of this inaugural issue. Here, an important aspect is the exchange of knowledge between basic scientists studying a range of model organisms from the fly, through zebrafish and chicken to the mouse and clinicians studying congenital heart defects. This special issue of the Journal of Cardiovascular Development and Disease provides a comprehensive overview of the current status of cardiac growth, progenitor cells, regeneration, developmental biology, cardiovascular evolution, cardiovascular genetics and epigenetics as well as translational research. Moreover, a review paper on the history of the WG is a welcome contribution to this special issue. I am very grateful to the experts who contributed articles or reviews and wish you an interesting and stimulating reading.

Prof. Dr. Silke R. Sperling
Guest Editor

Submission

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. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as 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 refereed through a 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 quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. For the first couple of issues the Article Processing Charge (APC) will be waived for well-prepared manuscripts. English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Published Papers (13 papers)

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Research

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Open AccessCommunication miR-27b and miR-23b Modulate Cardiomyocyte Differentiation from Mouse Embryonic Stem Cells
J. Cardiovasc. Dev. Dis. 2014, 1(1), 41-51; doi:10.3390/jcdd1010041
Received: 1 February 2014 / Revised: 21 March 2014 / Accepted: 24 March 2014 / Published: 31 March 2014
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Abstract
Diverse types of stem cells represent a potentially attractive source of cardiac cells for the treatment of cardiovascular diseases. However, most of the functional benefits reported for stem cell have been modest and mainly due to paracrine effects rather than differentiation into [...] Read more.
Diverse types of stem cells represent a potentially attractive source of cardiac cells for the treatment of cardiovascular diseases. However, most of the functional benefits reported for stem cell have been modest and mainly due to paracrine effects rather than differentiation into cardiomyocytes of the applied cells. Therefore, new tools need to be developed in order to improve the efficiency of stem cell differentiation towards specific cardiovascular lineages. Here we show that microRNAs that display early differential expression during ventricular maturation, such as miR-27b, inhibits cardiac differentiation from mouse embryonic stem cells whereas miRNAs that display late differential expression, such as miR-23b, regulates the beating phenotype during in vitro cardiac differentiation from Embryonic Stem Cells (ESCs). This study could have an impact on regenerative medicine since we showed that miR-27b and miR-23b overexpression differentially modify the ESC cell fate towards the cardiac lineage. Full article

Review

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Open AccessReview Cellular Mechanisms of Drosophila Heart Morphogenesis
J. Cardiovasc. Dev. Dis. 2015, 2(1), 2-16; doi:10.3390/jcdd2010002
Received: 6 December 2014 / Revised: 7 February 2015 / Accepted: 11 February 2015 / Published: 16 February 2015
Cited by 1 | PDF Full-text (780 KB) | HTML Full-text | XML Full-text
Abstract
Many of the major discoveries in the fields of genetics and developmental biology have been made using the fruit fly, Drosophila melanogaster. With regard to heart development, the conserved network of core cardiac transcription factors that underlies cardiogenesis has been studied in [...] Read more.
Many of the major discoveries in the fields of genetics and developmental biology have been made using the fruit fly, Drosophila melanogaster. With regard to heart development, the conserved network of core cardiac transcription factors that underlies cardiogenesis has been studied in great detail in the fly, and the importance of several signaling pathways that regulate heart morphogenesis, such as Slit/Robo, was first shown in the fly model. Recent technological advances have led to a large increase in the genomic data available from patients with congenital heart disease (CHD). This has highlighted a number of candidate genes and gene networks that are potentially involved in CHD. To validate genes and genetic interactions among candidate CHD-causing alleles and to better understand heart formation in general are major tasks. The specific limitations of the various cardiac model systems currently employed (mammalian and fish models) provide a niche for the fly model, despite its evolutionary distance to vertebrates and humans. Here, we review recent advances made using the Drosophila embryo that identify factors relevant for heart formation. These underline how this model organism still is invaluable for a better understanding of CHD. Full article
Open AccessReview Studies of Genes Involved in Congenital Heart Disease
J. Cardiovasc. Dev. Dis. 2014, 1(1), 134-145; doi:10.3390/jcdd1010134
Received: 7 February 2014 / Revised: 4 May 2014 / Accepted: 12 May 2014 / Published: 22 May 2014
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Abstract
Congenital heart disease (CHD) affects the intricate structure and function of the heart and is one of the leading causes of death in newborns. The genetic basis of CHD is beginning to emerge. Our laboratory has been engaged in identifying mutations in [...] Read more.
Congenital heart disease (CHD) affects the intricate structure and function of the heart and is one of the leading causes of death in newborns. The genetic basis of CHD is beginning to emerge. Our laboratory has been engaged in identifying mutations in genes linked to CHD both in families and in sporadic cases. Over the last two decades, we have employed linkage analysis, targeted gene sequencing and genome wide association studies to identify genes involved in CHDs. Cardiac specific genes that encode transcription factors and sarcomeric proteins have been identified and linked to CHD. Functional analysis of the relevant mutant proteins has established the molecular mechanisms of CHDs in our studies. Full article
Open AccessReview Right Ventricular Adaptation in Congenital Heart Diseases
J. Cardiovasc. Dev. Dis. 2014, 1(1), 83-97; doi:10.3390/jcdd1010083
Received: 7 March 2014 / Revised: 28 April 2014 / Accepted: 30 April 2014 / Published: 21 May 2014
Cited by 4 | PDF Full-text (818 KB) | HTML Full-text | XML Full-text
Abstract
In the last four decades, enormous progress has been made in the treatment of congenital heart diseases (CHD); most patients now survive into adulthood, albeit with residual lesions. As a consequence, the focus has shifted from initial treatment to long-term morbidity and [...] Read more.
In the last four decades, enormous progress has been made in the treatment of congenital heart diseases (CHD); most patients now survive into adulthood, albeit with residual lesions. As a consequence, the focus has shifted from initial treatment to long-term morbidity and mortality. An important predictor for long-term outcome is right ventricular (RV) dysfunction, but knowledge on the mechanisms of RV adaptation and dysfunction is still scarce. This review will summarize the main features of RV adaptation to CHD, focusing on recent knowledge obtained in experimental models of the most prevalent abnormal loading conditions, i.e., pressure load and volume load. Models of increased pressure load for the RV have shown a similar pattern of responses, i.e., increased contractility, RV dilatation and hypertrophy. Evidence is accumulating that RV failure in response to increased pressure load is marked by progressive diastolic dysfunction. The mechanisms of this progressive dysfunction are insufficiently known. The RV response to pressure load shares similarities with that of the LV, but also has specific features, e.g., capillary rarefaction, oxidative stress and inflammation. The contribution of these pathways to the development of failure needs further exploration. The RV adaptation to increased volume load is an understudied area, but becomes increasingly important in the growing groups of survivors of CHD, especially with tetralogy of Fallot. Recently developed animal models may add to the investigation of the mechanisms of RV adaptation and failure, leading to the development of new RV-specific therapies. Full article
Figures

Open AccessReview Wnt/β-Catenin Signaling during Cardiac Development and Repair
J. Cardiovasc. Dev. Dis. 2014, 1(1), 98-110; doi:10.3390/jcdd1010098
Received: 21 February 2014 / Revised: 28 April 2014 / Accepted: 30 April 2014 / Published: 21 May 2014
Cited by 3 | PDF Full-text (553 KB) | HTML Full-text | XML Full-text
Abstract
Active Wnt/β-catenin signaling is essential for proper cardiac specification, progenitor expansion and myocardial growth. During development, the mass of the embryonic heart increases multiple times to achieve the dimensions of adult ventricular chambers. Cell division in the embryonic heart is fairly present, [...] Read more.
Active Wnt/β-catenin signaling is essential for proper cardiac specification, progenitor expansion and myocardial growth. During development, the mass of the embryonic heart increases multiple times to achieve the dimensions of adult ventricular chambers. Cell division in the embryonic heart is fairly present, whereas cell turnover in the adult myocardium is extremely low. Understanding of embryonic cardiomyocyte cell-replication, therefore, could improve strategies for cardiac regenerative therapeutics. Here, we review which role Wnt signaling plays in cardiac development and highlight a selection of attempts that have been made to modulate Wnt signaling after cardiac ischemic injury to improve cardiac function and reduce infarct size. Full article
Open AccessReview The Ig CAM CAR is Implicated in Cardiac Development and Modulates Electrical Conduction in the Mature Heart
J. Cardiovasc. Dev. Dis. 2014, 1(1), 111-120; doi:10.3390/jcdd1010111
Received: 31 January 2014 / Revised: 30 April 2014 / Accepted: 6 May 2014 / Published: 21 May 2014
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Abstract
The coxsackievirus and adenovirus receptor (CAR, CXADR) is a multi-functional cell adhesion molecule which forms with CLMP, BT-IgSF, ESAM and CTX a structural subgroup within the Ig superfamily. These proteins share an overall domain organization with two extracellular Ig domains, a [...] Read more.
The coxsackievirus and adenovirus receptor (CAR, CXADR) is a multi-functional cell adhesion molecule which forms with CLMP, BT-IgSF, ESAM and CTX a structural subgroup within the Ig superfamily. These proteins share an overall domain organization with two extracellular Ig domains, a transmembrane region and a cytoplasmic tail which includes a PDZ binding motif. CAR is strongly expressed in brain and heart during embryonic development and becomes down-regulated in early postnatal stages. Cell adhesion experiments, binding studies and as well as crystallographic investigations on the extracellular domain reveal a flexible ectodomain for CAR that mediates homophilic and heterophilic binding. Several animal models showed an essential role for CAR during embryonic heart development and for electrical conduction between neighboring cardiomyocytes at mature stages. CAR gets re-expressed in diseased or damaged cardiac tissue, probably to induce regeneration and remodeling of the cardiac muscle. Full article
Open AccessReview The Popeye Domain Containing Genes and cAMP Signaling
J. Cardiovasc. Dev. Dis. 2014, 1(1), 121-133; doi:10.3390/jcdd1010121
Received: 3 April 2014 / Revised: 6 May 2014 / Accepted: 7 May 2014 / Published: 21 May 2014
Cited by 1 | PDF Full-text (471 KB) | HTML Full-text | XML Full-text
Abstract
3'-5'-cyclic adenosine monophosphate (cAMP) is a second messenger, which plays an important role in the heart. It is generated in response to activation of G-protein-coupled receptors (GPCRs). Initially, it was thought that protein kinase A (PKA) exclusively mediates cAMP-induced cellular responses such [...] Read more.
3'-5'-cyclic adenosine monophosphate (cAMP) is a second messenger, which plays an important role in the heart. It is generated in response to activation of G-protein-coupled receptors (GPCRs). Initially, it was thought that protein kinase A (PKA) exclusively mediates cAMP-induced cellular responses such as an increase in cardiac contractility, relaxation, and heart rate. With the identification of the exchange factor directly activated by cAMP (EPAC) and hyperpolarizing cyclic nucleotide-gated (HCN) channels as cAMP effector proteins it became clear that a protein network is involved in cAMP signaling. The Popeye domain containing (Popdc) genes encode yet another family of cAMP-binding proteins, which are prominently expressed in the heart. Loss-of-function mutations in mice are associated with cardiac arrhythmia and impaired skeletal muscle regeneration. Interestingly, the cardiac phenotype, which is present in both, Popdc1 and Popdc2 null mutants, is characterized by a stress-induced sinus bradycardia, suggesting that Popdc proteins participate in cAMP signaling in the sinuatrial node. The identification of the two-pore channel TREK-1 and Caveolin 3 as Popdc-interacting proteins represents a first step into understanding the mechanisms of heart rate modulation triggered by Popdc proteins. Full article
Figures

Open AccessReview The Hypothesis of “Embryonic Recall”: Mechanotransduction as Common Denominator Linking Normal Cardiogenesis to Recovery in Adult Failing Hearts
J. Cardiovasc. Dev. Dis. 2014, 1(1), 73-82; doi:10.3390/jcdd1010073
Received: 12 February 2014 / Revised: 1 April 2014 / Accepted: 2 April 2014 / Published: 10 April 2014
Cited by 2 | PDF Full-text (715 KB) | HTML Full-text | XML Full-text
Abstract
Cardiac regeneration remains a clinical target regardless of numerous therapeutic concepts. We formulated a hypothesis claiming that periodic coronary venous pressure elevation (PICSO; Pressure controlled Intermittent Coronary Sinus Occlusion) initiates embedded, but dormant developmental processes in adult jeopardized hearts. Hemodynamics in the [...] Read more.
Cardiac regeneration remains a clinical target regardless of numerous therapeutic concepts. We formulated a hypothesis claiming that periodic coronary venous pressure elevation (PICSO; Pressure controlled Intermittent Coronary Sinus Occlusion) initiates embedded, but dormant developmental processes in adult jeopardized hearts. Hemodynamics in the primitive beating heart tube is sensed transducing “mechanical” epigenetic information during normal cardiac development. In analogy mechanotransduction via shear stress and pulsatile stretch induced by periodic elevation of blood pressure in cardiac veins reconnects this dormant developmental signal, setting regenerative impulses in the adult heart. Significant increase of hemeoxygenase-1 gene expression (p < 0.001) and vascular endothelial growth factor (VEGF) (p < 0.002) as well as production of VEGRF2 in experimental infarction underscores the resurgence of developmental stimuli by PICSO. Molecular findings correspond with risk reduction (p < 0.0001) in patients with acute coronary syndromes as well as observations in heart failure patients showing substantial risk reduction up to 5 years endorsing our hypothesis and preclinical experience that PICSO via hemodynamic power activates regenerative processes also in adult human hearts. These results emphasize that our proposed hypothesis “embryonic recall” claiming revival of an imbedded albeit dormant “epigenetic” process is able not only to sculpture myocardium in the embryo, but also to redesign structure in the adult and failing heart. Full article
Figures

Open AccessReview Left Right Patterning, Evolution and Cardiac Development
J. Cardiovasc. Dev. Dis. 2014, 1(1), 52-72; doi:10.3390/jcdd1010052
Received: 30 January 2014 / Revised: 24 March 2014 / Accepted: 28 March 2014 / Published: 8 April 2014
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Abstract
Many aspects of heart development are determined by the left right axis and as a result several congenital diseases have their origins in aberrant left-right patterning. Establishment of this axis occurs early in embryogenesis before formation of the linear heart tube yet [...] Read more.
Many aspects of heart development are determined by the left right axis and as a result several congenital diseases have their origins in aberrant left-right patterning. Establishment of this axis occurs early in embryogenesis before formation of the linear heart tube yet impacts upon much later morphogenetic events. In this review I discuss the differing mechanisms by which left-right polarity is achieved in the mouse and chick embryos and comment on the evolution of this system. I then discus three major classes of cardiovascular defect associated with aberrant left-right patterning seen in mouse mutants and human disease. I describe phenotypes associated with the determination of atrial identity and venous connections, looping morphogenesis of the heart tube and finally the asymmetric remodelling of the embryonic branchial arch arterial system to form the leftward looped arch of aorta and associated great arteries. Where appropriate, I consider left right patterning defects from an evolutionary perspective, demonstrating how developmental processes have been modified in species over time and illustrating how comparative embryology can aide in our understanding of congenital heart disease. Full article
Open AccessReview Molecular Control of Cardiac Fetal/Neonatal Remodeling
J. Cardiovasc. Dev. Dis. 2014, 1(1), 29-36; doi:10.3390/jcdd1010029
Received: 19 December 2013 / Revised: 19 March 2014 / Accepted: 21 March 2014 / Published: 26 March 2014
Cited by 1 | PDF Full-text (318 KB) | HTML Full-text | XML Full-text
Abstract
Immediately following birth, the mammalian heart switches from generating ATP via glycolysis to β-oxidation of lipid. Coincident with this metabolic remodeling, cardiomyocyte mitosis ceases and regenerative capacity is lost. Recently, our understanding of the molecular pathways linking physiological stimuli with gene expression [...] Read more.
Immediately following birth, the mammalian heart switches from generating ATP via glycolysis to β-oxidation of lipid. Coincident with this metabolic remodeling, cardiomyocyte mitosis ceases and regenerative capacity is lost. Recently, our understanding of the molecular pathways linking physiological stimuli with gene expression and phenotype changes around birth has increased, although fundamental gaps remain. This review discusses recent work that sheds light on this important area of mammalian cardiovascular development. Full article
Open AccessReview Evolution of the Sinus Venosus from Fish to Human
J. Cardiovasc. Dev. Dis. 2014, 1(1), 14-28; doi:10.3390/jcdd1010014
Received: 1 February 2014 / Revised: 10 March 2014 / Accepted: 10 March 2014 / Published: 21 March 2014
Cited by 3 | PDF Full-text (591 KB) | HTML Full-text | XML Full-text
Abstract
The sinus venosus, the cardiac chamber upstream of the (right) atrium, is a severely underinvestigated structure. Yet, its myocardium harbors the cardiac pacemaker in all vertebrates. In human, ectopic pacemaking and subsequent pathologies may originate from sinus venosus-derived myocardium surrounding the coronary [...] Read more.
The sinus venosus, the cardiac chamber upstream of the (right) atrium, is a severely underinvestigated structure. Yet, its myocardium harbors the cardiac pacemaker in all vertebrates. In human, ectopic pacemaking and subsequent pathologies may originate from sinus venosus-derived myocardium surrounding the coronary sinus and the superior caval vein. In ectothermic vertebrates, i.e., fishes, amphibians and reptiles, the sinus venosus aids atrial filling by contracting prior to the atrium (atria). This is facilitated by the sinuatrial delay of approximately the same duration as the atrioventricular delay, which facilitates atrial filling of the ventricles. In mammals, the sinuatrial delay is lost, and the sinus venosus-derived myocardium persists as an extensive myocardial sheet surrounding the caval veins, which is activated in synchrony with the myocardium of the atria. The caval vein myocardium is hardly of significance in the healthy formed heart, but we suggest that the sinus venosus functions as a chamber during development when cardiac output, heart rate, blood pressure and architecture is much more like that of ectothermic vertebrates. The remodeling of the sinus venosus in mammals may be an adaptation associated with the high heart rates necessary for postnatal endothermy. If so, the endothermic birds should exhibit a similar remodeling as mammals, which remains to be investigated. Full article
Figures

Open AccessReview Anterior Hox Genes in Cardiac Development and Great Artery Patterning
J. Cardiovasc. Dev. Dis. 2014, 1(1), 3-13; doi:10.3390/jcdd1010003
Received: 28 January 2014 / Revised: 21 February 2014 / Accepted: 24 February 2014 / Published: 3 March 2014
Cited by 1 | PDF Full-text (429 KB) | HTML Full-text | XML Full-text
Abstract
During early development, the heart tube grows by progressive addition of progenitor cells to the arterial and venous poles. These cardiac progenitor cells, originally identified in 2001, are located in the splanchnic mesoderm in a region termed the second heart field (SHF). [...] Read more.
During early development, the heart tube grows by progressive addition of progenitor cells to the arterial and venous poles. These cardiac progenitor cells, originally identified in 2001, are located in the splanchnic mesoderm in a region termed the second heart field (SHF). Since its discovery, our view of heart development has been refined and it is well established that perturbation in the addition of SHF cells results in a spectrum of congenital heart defects. We have previously shown that anterior Hox genes, including Hoxb1, Hoxa1 and Hoxa3, are expressed in distinct subdomains of the SHF that contribute to atrial and subpulmonary myocardium. It is well known that Hox proteins exert their function through interaction with members of the TALE family, including Pbx and Meis factors. The expression profile of Pbx and Meis factors overlaps with that of anterior Hox factors in the embryonic heart, and recent data suggest that they may interact together during cardiac development. This review aims to bring together recent findings in vertebrates that strongly suggest an important function for Hox, Pbx and Meis factors in heart development and disease. Full article

Other

Jump to: Research, Review

Open AccessCommentary An Introduction to the ESC Working Group on Development, Anatomy and Pathology
J. Cardiovasc. Dev. Dis. 2014, 1(1), 37-40; doi:10.3390/jcdd1010037
Received: 7 February 2014 / Accepted: 19 March 2014 / Published: 27 March 2014
PDF Full-text (588 KB) | HTML Full-text | XML Full-text
Abstract
The articles and reviews in this inaugural edition of the Journal of Cardiovascular Development and Disease have been written by presenters at the 2013 Meeting of the European Society of Cardiology’s Working Group (WG) on Development, Anatomy and Pathology. The WG meeting [...] Read more.
The articles and reviews in this inaugural edition of the Journal of Cardiovascular Development and Disease have been written by presenters at the 2013 Meeting of the European Society of Cardiology’s Working Group (WG) on Development, Anatomy and Pathology. The WG meeting provides an annual forum for researchers and clinicians interested in cardiac development and pathology to exchange expertise and present and debate new results, with the goal of furthering our understanding of the origins of congenital heart defects and cardiac pathology. Here we introduce the WG through a short account of the WG’s history and current activities. Full article

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