Journal of Cardiovascular Development and Disease

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Open AccessReview

Studies of Genes Involved in Congenital Heart Disease

by Tushar K. Ghosh, Javier T. Granados-Riveron, Sarah Buxton, Kerry Setchfield, Siobhan Loughna and J. David Brook

J. Cardiovasc. Dev. Dis. 2014, 1(1), 134-145; https://doi.org/10.3390/jcdd1010134 - 22 May 2014

Cited by 2 | Viewed by 8696

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 genes [...] 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

(This article belongs to the Special Issue Highlights of the 2013 Berlin Meeting of the ESC working group on Development, Anatomy and Pathology)

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Open AccessReview

The Popeye Domain Containing Genes and cAMP Signaling

by Thomas Brand, Kar Lai Poon, Subreena Simrick and Roland F. R. Schindler

J. Cardiovasc. Dev. Dis. 2014, 1(1), 121-133; https://doi.org/10.3390/jcdd1010121 - 21 May 2014

Cited by 10 | Viewed by 9954

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 as [...] 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

(This article belongs to the Special Issue Highlights of the 2013 Berlin Meeting of the ESC working group on Development, Anatomy and Pathology)

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Open AccessReview

The Ig CAM CAR is Implicated in Cardiac Development and Modulates Electrical Conduction in the Mature Heart

by Claudia Matthäus, Jadwiga Schreiber, René Jüttner and Fritz G. Rathjen

J. Cardiovasc. Dev. Dis. 2014, 1(1), 111-120; https://doi.org/10.3390/jcdd1010111 - 21 May 2014

Cited by 3 | Viewed by 7896

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 transmembrane [...] 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

(This article belongs to the Special Issue Highlights of the 2013 Berlin Meeting of the ESC working group on Development, Anatomy and Pathology)

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Wnt/β-Catenin Signaling during Cardiac Development and Repair

by Jan W. Buikema, Peter-Paul M. Zwetsloot, Pieter A. Doevendans, Ibrahim J. Domian and Joost P. G. Sluijter

J. Cardiovasc. Dev. Dis. 2014, 1(1), 98-110; https://doi.org/10.3390/jcdd1010098 - 21 May 2014

Cited by 15 | Viewed by 11620

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, whereas [...] 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

(This article belongs to the Special Issue Highlights of the 2013 Berlin Meeting of the ESC working group on Development, Anatomy and Pathology)

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Open AccessReview

Right Ventricular Adaptation in Congenital Heart Diseases

by Beatrijs Bartelds, Marinus A. J. Borgdorff and Rolf M. F. Berger

J. Cardiovasc. Dev. Dis. 2014, 1(1), 83-97; https://doi.org/10.3390/jcdd1010083 - 21 May 2014

Cited by 10 | Viewed by 10506

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 mortality. [...] 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

(This article belongs to the Special Issue Highlights of the 2013 Berlin Meeting of the ESC working group on Development, Anatomy and Pathology)

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The Hypothesis of “Embryonic Recall”: Mechanotransduction as Common Denominator Linking Normal Cardiogenesis to Recovery in Adult Failing Hearts

by Werner Mohl, Dejan Milasinovic, Thomas Aschacher, Alem Jusic, Abudunaibi Maimaitiaili and Frank Rattay

J. Cardiovasc. Dev. Dis. 2014, 1(1), 73-82; https://doi.org/10.3390/jcdd1010073 - 10 Apr 2014

Cited by 8 | Viewed by 7074

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 primitive [...] 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

(This article belongs to the Special Issue Highlights of the 2013 Berlin Meeting of the ESC working group on Development, Anatomy and Pathology)

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Left Right Patterning, Evolution and Cardiac Development

by Iain M. Dykes

J. Cardiovasc. Dev. Dis. 2014, 1(1), 52-72; https://doi.org/10.3390/jcdd1010052 - 8 Apr 2014

Cited by 9 | Viewed by 14178

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 impacts [...] 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

(This article belongs to the Special Issue Highlights of the 2013 Berlin Meeting of the ESC working group on Development, Anatomy and Pathology)

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Open AccessCommunication

miR-27b and miR-23b Modulate Cardiomyocyte Differentiation from Mouse Embryonic Stem Cells

by José Manuel Vilches, Antonio Pulido, Francisco Hernández-Torres, Diego Franco and Amelia Aránega

J. Cardiovasc. Dev. Dis. 2014, 1(1), 41-51; https://doi.org/10.3390/jcdd1010041 - 31 Mar 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 cardiomyocytes [...] 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

(This article belongs to the Special Issue Highlights of the 2013 Berlin Meeting of the ESC working group on Development, Anatomy and Pathology)

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Open AccessCommentary

An Introduction to the ESC Working Group on Development, Anatomy and Pathology

by Diego Franco, S. Yen Ho and Robert G. Kelly

J. Cardiovasc. Dev. Dis. 2014, 1(1), 37-40; https://doi.org/10.3390/jcdd1010037 - 27 Mar 2014

Viewed by 6186

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 provides [...] 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

(This article belongs to the Special Issue Highlights of the 2013 Berlin Meeting of the ESC working group on Development, Anatomy and Pathology)

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Open AccessReview

Molecular Control of Cardiac Fetal/Neonatal Remodeling

by Ross A. Breckenridge

J. Cardiovasc. Dev. Dis. 2014, 1(1), 29-36; https://doi.org/10.3390/jcdd1010029 - 26 Mar 2014

Cited by 5 | Viewed by 6253

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 and [...] 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

(This article belongs to the Special Issue Highlights of the 2013 Berlin Meeting of the ESC working group on Development, Anatomy and Pathology)

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Open AccessReview

Evolution of the Sinus Venosus from Fish to Human

by Bjarke Jensen, Bastiaan J. D. Boukens, Tobias Wang, Antoon F. M. Moorman and Vincent M. Christoffels

J. Cardiovasc. Dev. Dis. 2014, 1(1), 14-28; https://doi.org/10.3390/jcdd1010014 - 21 Mar 2014

Cited by 33 | Viewed by 20104

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 sinus [...] 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

(This article belongs to the Special Issue Highlights of the 2013 Berlin Meeting of the ESC working group on Development, Anatomy and Pathology)

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Open AccessReview

Anterior Hox Genes in Cardiac Development and Great Artery Patterning

by Brigitte Laforest, Nicolas Bertrand and Stéphane Zaffran

J. Cardiovasc. Dev. Dis. 2014, 1(1), 3-13; https://doi.org/10.3390/jcdd1010003 - 3 Mar 2014

Cited by 5 | Viewed by 8687

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). Since [...] 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

(This article belongs to the Special Issue Highlights of the 2013 Berlin Meeting of the ESC working group on Development, Anatomy and Pathology)

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Open AccessEditorial

Cardiovascular Developmental Biology Research— Elucidating Mechanisms Underlying Congenital and Acquired Heart Diseases

by Andy Wessels

J. Cardiovasc. Dev. Dis. 2014, 1(1), 1-2; https://doi.org/10.3390/jcdd1010001 - 8 Nov 2013

Cited by 6 | Viewed by 5497

Abstract

Cardiovascular diseases (CVDs) are the number one cause of death worldwide. According to a recent report from the World Health Organization, an estimated 17.3 million people died from CVDs in 2008, representing 30% of all global deaths. Despite significant advances in surgical approaches [...] Read more.

Cardiovascular diseases (CVDs) are the number one cause of death worldwide. According to a recent report from the World Health Organization, an estimated 17.3 million people died from CVDs in 2008, representing 30% of all global deaths. Despite significant advances in surgical approaches and increased survival rate, congenital heart disease (CHD) is still the primary cause of birth defect-related deaths in the western world. More than half of all babies born with a cardiac abnormality will require at least one invasive surgery in their lifetime. As a result of improvement in surgical procedures, many babies who once would have died of CHD now survive into adulthood. In fact, the number of adults with CHD in the USA is now greater than the number of babies born with CHD. However, many adults with congenital heart disease are suffering from functional abnormalities, including arrhythmias and heart failure [1,2] and require lifelong care. The cardiovascular problems can be either intrinsic to the perturbation of developmental events that led to the structural malformations in the first place, or can result from acquired conditions related to scar tissues resulting from the surgical procedures. The primary goals of cardiovascular developmental research are to elucidate the mechanisms that govern normal cardiac development and to determine the molecular and cellular mechanisms involved in the etiology of CHD. In addition, as it becomes increasingly clear that many so-called acquired heart diseases may also have developmental origins, an additional goal of cardiovascular developmental biologists is to identify the early events that may play a role in the pathogenesis of acquired diseases, such as mitral valve prolapse. [...] Full article

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J. Cardiovasc. Dev. Dis., Volume 1, Issue 1 (June 2014) – 13 articles , Pages 1-145

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