Leaders in Cardiovascular Research: A Special Issue Dedicated to Professor Adriana Gittenberger-De Groot

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

Deadline for manuscript submissions: closed (1 August 2021) | Viewed by 74617

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A printed edition of this Special Issue is available here.

Special Issue Editors

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
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

Special Issue Information

The arterial pole is one of the most complex parts of the heart both in development and disease. It involves the collaboration and orchestration of contributions from the first and second heart fields as well as the neural crest. The precursor cells differentiate into endocardial cushions and putative cardiac valves, the myocardium, and epicardium of the heart, but also into the different layers of the main arterial vessels. These include not only the aorta and the pulmonary trunk but also the pulmonary and coronary arteries, and during development, the arterial duct. Many transcriptional and signaling networks act in timely concert to acquire the proper asymmetric development and function and pressure and flow dynamics. This is not only a human or even mammalian ‘enterprise,’ but is also taking place in so-called ancestral forms from fish to reptiles, including birds. In humans, it is small wonder that many clinical syndromes may arise when something in this complexity is amiss.

In this special issue of JCDD, we welcome contributions focussed on the heart fields, congenital cardiac malformations and associated syndromes, with special emphasis on the cardiac outflow tract.

The issue is devoted to Prof. Dr. Adriana Gittenberger-de Groot, who dedicated her extensive career to research on cardiovascular development.

Dr. Monique R.M. Jongbloed
Prof. Dr. Robert Poelmann
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

  • Cardiac development
  • Congenital heart disease
  • Gene expression
  • Transcription
  • Signaling networks
  • Hemodynamics
  • Evolution
  • Aortic sac
  • Outflow tract septation
  • First/Second heart field
  • Neural crest
  • Pharyngeal arch arteries
  • Semilunar valves
  • Coronary arteries
  • Cardiopulmonary circulation
  • Ductus arteriosus

Published Papers (22 papers)

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Editorial

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9 pages, 1389 KiB  
Editorial
Introduction to Special Issue “Leaders in Cardiovascular Research, Dedicated to the Memory of Professor Adriana Gittenberger-de Groot”
J. Cardiovasc. Dev. Dis. 2022, 9(4), 92; https://doi.org/10.3390/jcdd9040092 - 23 Mar 2022
Viewed by 2118
Abstract
This Introduction provides both a short reflection on the scientific career of Adriana Gittenberger-de Groot and an overview of the papers that form the basis of this Special Issue giving them a proper perspective. The papers have as a central focus the outflow [...] Read more.
This Introduction provides both a short reflection on the scientific career of Adriana Gittenberger-de Groot and an overview of the papers that form the basis of this Special Issue giving them a proper perspective. The papers have as a central focus the outflow tract, and include contributions on development and pathology of the ventricles including AV valves, as well as developmental and pathomorphological aspects of the great arteries including semilunar valves and coronary arteries. Full article
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Research

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19 pages, 6433 KiB  
Article
Ventricular Septation and Outflow Tract Development in Crocodilians Result in Two Aortas with Bicuspid Semilunar Valves
J. Cardiovasc. Dev. Dis. 2021, 8(10), 132; https://doi.org/10.3390/jcdd8100132 - 15 Oct 2021
Cited by 7 | Viewed by 1947
Abstract
Background: The outflow tract of crocodilians resembles that of birds and mammals as ventricular septation is complete. The arterial anatomy, however, presents with a pulmonary trunk originating from the right ventricular cavum, and two aortas originating from either the right or left [...] Read more.
Background: The outflow tract of crocodilians resembles that of birds and mammals as ventricular septation is complete. The arterial anatomy, however, presents with a pulmonary trunk originating from the right ventricular cavum, and two aortas originating from either the right or left ventricular cavity. Mixing of blood in crocodilians cannot occur at the ventricular level as in other reptiles but instead takes place at the aortic root level by a shunt, the foramen of Panizza, the opening of which is guarded by two facing semilunar leaflets of both bicuspid aortic valves. Methods: Developmental stages of Alligator mississipiensis, Crocodilus niloticus and Caiman latirostris were studied histologically. Results and Conclusions: The outflow tract septation complex can be divided into two components. The aorto-pulmonary septum divides the pulmonary trunk from both aortas, whereas the interaortic septum divides the systemic from the visceral aorta. Neural crest cells are most likely involved in the formation of both components. Remodeling of the endocardial cushions and both septa results in the formation of bicuspid valves in all three arterial trunks. The foramen of Panizza originates intracardially as a channel in the septal endocardial cushion. Full article
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17 pages, 9226 KiB  
Article
Deficient Myocardial Organization and Pathological Fibrosis in Fetal Aortic Stenosis—Association of Prenatal Ultrasound with Postmortem Histology
J. Cardiovasc. Dev. Dis. 2021, 8(10), 121; https://doi.org/10.3390/jcdd8100121 - 28 Sep 2021
Cited by 3 | Viewed by 2236
Abstract
In fetal aortic stenosis (AS), it remains challenging to predict left ventricular development over the course of pregnancy. Myocardial organization, differentiation and fibrosis could be potential biomarkers relevant for biventricular outcome. We present four cases of fetal AS with varying degrees of severity [...] Read more.
In fetal aortic stenosis (AS), it remains challenging to predict left ventricular development over the course of pregnancy. Myocardial organization, differentiation and fibrosis could be potential biomarkers relevant for biventricular outcome. We present four cases of fetal AS with varying degrees of severity and associate myocardial deformation on fetal ultrasound with postmortem histopathological characteristics. During routine fetal echocardiography, speckle tracking recordings of the cardiac four-chamber view were performed to assess myocardial strain as parameter for myocardial deformation. After pregnancy termination, postmortem cardiac specimens were examined using immunohistochemical labeling (IHC) of key markers for myocardial organization, differentiation and fibrosis and compared to normal fetal hearts. Two cases with critical AS presented extremely decreased left ventricular (LV) strain on fetal ultrasound. IHC showed overt endocardial fibro-elastosis, which correlated with pathological fibrosis patterns in the myocardium and extremely disturbed cardiomyocyte organization. The LV in severe AS showed mildly reduced myocardial strain and less severe disorganization of the cardiomyocytes. In conclusion, the degree of reduction in myocardial deformation corresponded with high extent to the amount of pathological fibrosis patterns and cardiomyocyte disorganization. Myocardial deformation on fetal ultrasound seems to hold promise as a potential biomarker for left ventricular structural damage in AS. Full article
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12 pages, 2435 KiB  
Article
Applicability of the Leiden Convention and the Lipton Classification in Patients with a Single Coronary Artery in the Setting of Congenital Heart Disease
J. Cardiovasc. Dev. Dis. 2021, 8(8), 93; https://doi.org/10.3390/jcdd8080093 - 04 Aug 2021
Cited by 6 | Viewed by 4082
Abstract
In single coronary artery (SCA) anatomy, all coronary tributaries arise from a single ostium, providing perfusion to the entire myocardium. Coronary classification systems can facilitate the description of SCA anatomy. Aim: Evaluation of the applicability of Lipton classification and the Leiden Convention coronary [...] Read more.
In single coronary artery (SCA) anatomy, all coronary tributaries arise from a single ostium, providing perfusion to the entire myocardium. Coronary classification systems can facilitate the description of SCA anatomy. Aim: Evaluation of the applicability of Lipton classification and the Leiden Convention coronary coding system in SCA. Methods: All patients (n = 6209) who underwent computed tomography (CT) scanning between 2014 and 2018 were retrospectively examined for the presence of SCA and classified, according to Lipton classification and the Leiden Convention coronary coding system. Results: The prevalence of SCA was 0.51% (32/6209). Twenty-eight patients (87.5%) had coexisting congenital heart disease (CHD), most frequently pulmonary atresia (9/32, 28.1%). Ten patients (10/32, 31.25%) could not be classified with either the Leiden Convention or Lipton classification (pulmonary atresia n = 9, common arterial trunk (CAT) n = 1). In one case with CAT, Lipton classification, but not the Leiden Convention, could be applied. In two cases with the transposition of the great arteries and in two cases of double outlet right ventricle, the Leiden Convention, but not the Lipton classification, could be applied. Conclusions: Both classifications are useful to detail information about SCA. As Lipton classification was not developed for structural heart disease cases, in complex CHD with abnormal position of the great arteries, the Leiden Convention is better applicable. The use of both systems is limited in pulmonary atresia. In this scenario, it is better to provide a precise description of the coronary origin and associated characteristics that might affect treatment and prognosis. Full article
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14 pages, 3271 KiB  
Article
Isolated Dissection of the Ductus Arteriosus Associated with Sudden Unexpected Intrauterine Death
J. Cardiovasc. Dev. Dis. 2021, 8(8), 91; https://doi.org/10.3390/jcdd8080091 - 31 Jul 2021
Cited by 1 | Viewed by 1839
Abstract
We report five cases of sudden intrauterine death due to premature closure of the ductus arteriosus. In four cases, this was caused by dissecting the hematoma of the ductus arteriosus with intimal flap and obliteration of the lumen. In one case, the ductus [...] Read more.
We report five cases of sudden intrauterine death due to premature closure of the ductus arteriosus. In four cases, this was caused by dissecting the hematoma of the ductus arteriosus with intimal flap and obliteration of the lumen. In one case, the ductus arteriosus was aneurysmatic, with lumen occlusion caused by thrombus stratification. No drug therapy or free medication consumption were reported during pregnancy. The time of stillbirth ranged between 26 and 33 gestational weeks. We performed TUNEL analysis for apoptosis quantification. The dissecting features were intimal tears with flap formation in four of the cases, just above the origin of the ductus arteriosus from the pulmonary artery. The dissecting hematoma of the ductus arteriosus extended downward to the descending aorta and backward to the aortic arch with involvement of the left carotid and left subclavian arteries. TUNEL analysis showed a high number of apoptotic smooth muscle cells in the media in two cases. Abnormal ductal remodeling with absence of subintimal cushions, lacunar spaces rich in glycosaminoglycans (cystic medial necrosis), and smooth muscle cell apoptosis were the pathological substrates accounting for failure of remodeling process and dissection. Full article
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14 pages, 6135 KiB  
Article
Superimposed Tissue Formation in Human Aortic Valve Disease: Differences between Regurgitant and Stenotic Valves
J. Cardiovasc. Dev. Dis. 2021, 8(7), 79; https://doi.org/10.3390/jcdd8070079 - 08 Jul 2021
Cited by 2 | Viewed by 1957
Abstract
The formation of superimposed tissue (SIT), a layer on top of the original valve leaflet, has been described in patients with mitral regurgitation as a major contributor to valve thickening and possibly as a result of increased mechanical stresses. However, little is known [...] Read more.
The formation of superimposed tissue (SIT), a layer on top of the original valve leaflet, has been described in patients with mitral regurgitation as a major contributor to valve thickening and possibly as a result of increased mechanical stresses. However, little is known whether SIT formation also occurs in aortic valve disease. We therefore performed histological analyses to assess SIT formation in aortic valve leaflets (n = 31) from patients with aortic stenosis (n = 17) or aortic regurgitation due to aortic dilatation (n = 14). SIT was observed in both stenotic and regurgitant aortic valves, both on the ventricular and aortic sides, but with significant differences in distribution and composition. Regurgitant aortic valves showed more SIT formation in the free edge, leading to a thicker leaflet at that level, while stenotic aortic valves showed relatively more SIT formation on the aortic side of the body part of the leaflet. SIT appeared to be a highly active area, as determined by large populations of myofibroblasts, with varied extracellular matrix composition (higher collagen content in stenotic valves). Further, the identification of the SIT revealed the presence of foldings of the free edge in the diseased aortic valves. Insights into SIT regulation may further help in understanding the pathophysiology of aortic valve disease and potentially lead to the development of new therapeutic treatments. Full article
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23 pages, 3751 KiB  
Article
Transcriptome Analysis Reveals Differential Gene Expression between the Closing Ductus Arteriosus and the Patent Ductus Arteriosus in Humans
J. Cardiovasc. Dev. Dis. 2021, 8(4), 45; https://doi.org/10.3390/jcdd8040045 - 16 Apr 2021
Cited by 6 | Viewed by 3333
Abstract
The ductus arteriosus (DA) immediately starts closing after birth. This dynamic process involves DA-specific properties, including highly differentiated smooth muscle, sparse elastic fibers, and intimal thickening (IT). Although several studies have demonstrated DA-specific gene expressions using animal tissues and human fetuses, the transcriptional [...] Read more.
The ductus arteriosus (DA) immediately starts closing after birth. This dynamic process involves DA-specific properties, including highly differentiated smooth muscle, sparse elastic fibers, and intimal thickening (IT). Although several studies have demonstrated DA-specific gene expressions using animal tissues and human fetuses, the transcriptional profiles of the closing DA and the patent DA remain largely unknown. We performed transcriptome analysis using four human DA samples. The three closing DA samples exhibited typical DA morphology, but the patent DA exhibited aorta-like elastic lamellae and poorly formed IT. A cluster analysis revealed that samples were clearly divided into two major clusters, the closing DA and patent DA clusters, and showed distinct gene expression profiles in IT and the tunica media of the closing DA samples. Cardiac neural crest-related genes such as JAG1 were highly expressed in the tunica media and IT of the closing DA samples compared to the patent DA sample. Abundant protein expressions of jagged 1 and the differentiated smooth muscle marker calponin were observed in the closing DA samples but not in the patent DA sample. Second heart field-related genes such as ISL1 were enriched in the patent DA sample. These data indicate that the patent DA may have different cell lineages compared to the closing DA. Full article
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10 pages, 713 KiB  
Article
Asymptomatic Patients with Severe Aortic Stenosis and the Impact of Intervention
J. Cardiovasc. Dev. Dis. 2021, 8(4), 35; https://doi.org/10.3390/jcdd8040035 - 31 Mar 2021
Cited by 6 | Viewed by 1853
Abstract
Objectives the exact timing of aortic valve replacement (AVR) in asymptomatic patients with severe aortic stenosis (AS) remains a matter of debate. Therefore, we described the natural history of asymptomatic patients with severe AS, and the effect of AVR on long-term survival. Methods: [...] Read more.
Objectives the exact timing of aortic valve replacement (AVR) in asymptomatic patients with severe aortic stenosis (AS) remains a matter of debate. Therefore, we described the natural history of asymptomatic patients with severe AS, and the effect of AVR on long-term survival. Methods: Asymptomatic patients who were found to have severe AS between June 2006 and May 2009 were included. Severe aortic stenosis was defined as peak aortic jet velocity Vmax ≥ 4.0 m/s or aortic valve area (AVA) ≤ 1 cm2. Development of symptoms, the incidence of AVR, and all-cause mortality were assessed. Results: A total of 59 asymptomatic patients with severe AS were followed, with a mean follow-up of 8.9 ± 0.4 years. A total of 51 (86.4%) patients developed AS related symptoms, and subsequently 46 patients underwent AVR. The mean 1-year, 2-year, 5-year, and 10-year overall survival rates were higher in patients receiving AVR compared to those who did not undergo AVR during follow-up (100%, 93.5%, 89.1%, and 69.4%, versus 92.3%, 84.6%, 65.8%, and 28.2%, respectively; p < 0.001). Asymptomatic patients with severe AS receiving AVR during follow-up showed an incremental benefit in survival of up to 31.9 months compared to conservatively managed patients (p = 0.002). Conclusions: The majority of asymptomatic patients turn symptomatic during follow-up. AVR during follow-up is associated with better survival in asymptomatic severe AS patients. Full article
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15 pages, 12281 KiB  
Article
Myocardium-Specific Deletion of Rac1 Causes Ventricular Noncompaction and Outflow Tract Defects
J. Cardiovasc. Dev. Dis. 2021, 8(3), 29; https://doi.org/10.3390/jcdd8030029 - 15 Mar 2021
Cited by 8 | Viewed by 2835
Abstract
Background: Left ventricular noncompaction (LVNC) is a cardiomyopathy that can lead to arrhythmias, embolic events and heart failure. Despite our current knowledge of cardiac development, the mechanisms underlying noncompaction of the ventricular myocardium are still poorly understood. The small GTPase Rac1 acts as [...] Read more.
Background: Left ventricular noncompaction (LVNC) is a cardiomyopathy that can lead to arrhythmias, embolic events and heart failure. Despite our current knowledge of cardiac development, the mechanisms underlying noncompaction of the ventricular myocardium are still poorly understood. The small GTPase Rac1 acts as a crucial regulator of numerous developmental events. The present study aimed to investigate the cardiomyocyte specific role of Rac1 in embryonic heart development. Methods and Results: The Nkx2.5-Cre transgenic mice were crossed with Rac1f/f mice to generate mice with a cardiomyocyte specific deletion of Rac1 (Rac1Nkx2.5) during heart development. Embryonic Rac1Nkx2.5 hearts at E12.5–E18.5 were collected for histological analysis. Overall, Rac1Nkx2.5 hearts displayed a bifid apex, along with hypertrabeculation and a thin compact myocardium. Rac1Nkx2.5 hearts also exhibited ventricular septal defects (VSDs) and double outlet right ventricle (DORV) or overriding aorta. Cardiomyocytes had a rounded morphology and were highly disorganized, and the myocardial expression of Scrib, a planar cell polarity protein, was reduced in Rac1Nkx2.5 hearts. In addition, cell proliferation rate was significantly decreased in the Rac1Nkx2.5 ventricular myocardium at E9.5. Conclusions: Rac1 deficiency in the myocardium impairs cardiomyocyte elongation and organization, and proliferative growth of the heart. A spectrum of CHDs arises in Rac1Nkx2.5 hearts, implicating Rac1 signaling in the ventricular myocardium as a crucial regulator of OFT alignment, along with compact myocardium growth and development. Full article
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8 pages, 1216 KiB  
Article
Surgical Aortic Valve Replacement with Concomitant Aortic Surgery in Patients with Purely Bicuspid Aortic Valve and Associated Aortopathy
J. Cardiovasc. Dev. Dis. 2021, 8(2), 16; https://doi.org/10.3390/jcdd8020016 - 10 Feb 2021
Cited by 1 | Viewed by 1786
Abstract
The bicuspid aortic valve (BAV) is the most common congenital cardiac malformation associated with aortopathy. The current study provides surgical clinical data on the patient characteristics and long-term survival of this less common adult purely BAV population undergoing surgical aortic valve replacement (SAVR) [...] Read more.
The bicuspid aortic valve (BAV) is the most common congenital cardiac malformation associated with aortopathy. The current study provides surgical clinical data on the patient characteristics and long-term survival of this less common adult purely BAV population undergoing surgical aortic valve replacement (SAVR) with concomitant aortic surgery. Adult patients with purely BAV who underwent SAVR and concomitant aortic surgery were included. Prevalence, predictors of survival, and outcomes for this patient population were analyzed. A total of 48 patients (mean age 58.7 ± 13.2 years, 33% female) with purely BAV underwent SAVR and concomitant aortic surgery between 1987 and 2016. The majority (62%) of the patients had pure aortic stenosis (AS). A total of 12 patients died. Survival was 92%, 73%, and 69% at 1, 5, and 20 years of follow-up. At 15 years of follow-up, the survival was close to that of the Dutch population, with a relative survival of 77%. Adult patients with a purely bicuspid aortic valve morphology undergoing SAVR and concomitant aortic root and/or ascending aorta present with excellent survival. Full article
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12 pages, 1998 KiB  
Article
A Systematic Histopathologic Evaluation of Type-A Aortic Dissections Implies a Uniform Multiple-Hit Causation
J. Cardiovasc. Dev. Dis. 2021, 8(2), 12; https://doi.org/10.3390/jcdd8020012 - 27 Jan 2021
Cited by 17 | Viewed by 2348
Abstract
(1) Background: The pathophysiologic basis of an acute type A aortic dissection (TAAD) is largely unknown. In an effort to evaluate vessel wall defects, we systematically studied aortic specimens in TAAD patients. (2) Methods: Ascending aortic wall specimens (n = 58, mean [...] Read more.
(1) Background: The pathophysiologic basis of an acute type A aortic dissection (TAAD) is largely unknown. In an effort to evaluate vessel wall defects, we systematically studied aortic specimens in TAAD patients. (2) Methods: Ascending aortic wall specimens (n = 58, mean age 63 years) with TAAD were collected. Autopsy tissues (n = 17, mean age 63 years) served as controls. All sections were studied histopathologically. (3) Results: Pathomorphology in TAAD showed predominantly moderate elastic fiber fragmentation/loss, elastic fiber thinning, elastic fiber degeneration, mucoid extracellular matrix accumulation, smooth muscle cell nuclei loss, and overall medial degeneration. The control group showed significantly fewer signs of those histopathological features (none-mild, p = 0.00). It was concluded that the dissection plane consistently coincides with the vasa vasorum network, and that TAAD associates with a significantly thinner intimal layer p = 0.005). (4) Conclusions: On the basis of the systematic evaluation and the consistent presence of diffuse, pre-existing medial defects, we hypothesize that TAAD relates to a developmental defect of the ascending aorta and is caused by a triple-hit mechanism that involves (I) an intimal tear; and (II) a diseased media, which allows (III) propagation of the tear towards the plane of the vasa vasorum where the dissection further progresses. Full article
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17 pages, 2925 KiB  
Article
The Needle in the Haystack—Searching for Genetic and Epigenetic Differences in Monozygotic Twins Discordant for Tetralogy of Fallot
J. Cardiovasc. Dev. Dis. 2020, 7(4), 55; https://doi.org/10.3390/jcdd7040055 - 02 Dec 2020
Cited by 10 | Viewed by 2747
Abstract
Congenital heart defects (CHDs) are the most common birth defect in human with an incidence of almost 1% of all live births. Most cases have a multifactorial origin with both genetics and the environment playing a role in its development and progression. Adding [...] Read more.
Congenital heart defects (CHDs) are the most common birth defect in human with an incidence of almost 1% of all live births. Most cases have a multifactorial origin with both genetics and the environment playing a role in its development and progression. Adding an epigenetic component to this aspect is exemplified by monozygotic twins which share the same genetic background but have a different disease status. As a result, the interplay between the genetic, epigenetic and the environmental conditions might contribute to the etiology and phenotype. To date, the underlying causes of the majority of CHDs remain poorly understood. In this study, we performed genome-wide high-throughput sequencing to examine the genetic, structural genomic and epigenetic differences of two identical twin pairs discordant for Tetralogy of Fallot (TOF), representing the most common cyanotic form of CHDs. Our results show the almost identical genetic and structural genomic identity of the twins. In contrast, several epigenetic alterations could be observed given by DNA methylation changes in regulatory regions of known cardiac-relevant genes. Overall, this study provides first insights into the impact of genetic and especially epigenetic factors underlying monozygotic twins discordant for CHD like TOF. Full article
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22 pages, 12647 KiB  
Article
Early Embryonic Expression of AP-2α Is Critical for Cardiovascular Development
J. Cardiovasc. Dev. Dis. 2020, 7(3), 27; https://doi.org/10.3390/jcdd7030027 - 23 Jul 2020
Cited by 6 | Viewed by 3366
Abstract
Congenital cardiovascular malformation is a common birth defect incorporating abnormalities of the outflow tract and aortic arch arteries, and mice deficient in the transcription factor AP-2α (Tcfap2a) present with complex defects affecting these structures. AP-2α is expressed in the pharyngeal surface [...] Read more.
Congenital cardiovascular malformation is a common birth defect incorporating abnormalities of the outflow tract and aortic arch arteries, and mice deficient in the transcription factor AP-2α (Tcfap2a) present with complex defects affecting these structures. AP-2α is expressed in the pharyngeal surface ectoderm and neural crest at mid-embryogenesis in the mouse, but the precise tissue compartment in which AP-2α is required for cardiovascular development has not been identified. In this study we describe the fully penetrant AP-2α deficient cardiovascular phenotype on a C57Bl/6J genetic background and show that this is associated with increased apoptosis in the pharyngeal ectoderm. Neural crest cell migration into the pharyngeal arches was not affected. Cre-expressing transgenic mice were used in conjunction with an AP-2α conditional allele to examine the effect of deleting AP-2α from the pharyngeal surface ectoderm and the neural crest, either individually or in combination, as well as the second heart field. This, surprisingly, was unable to fully recapitulate the global AP-2α deficient cardiovascular phenotype. The outflow tract and arch artery phenotype was, however, recapitulated through early embryonic Cre-mediated recombination. These findings indicate that AP-2α has a complex influence on cardiovascular development either being required very early in embryogenesis and/or having a redundant function in many tissue layers. Full article
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21 pages, 5143 KiB  
Article
Transforming Growth Factor Beta3 is Required for Cardiovascular Development
J. Cardiovasc. Dev. Dis. 2020, 7(2), 19; https://doi.org/10.3390/jcdd7020019 - 24 May 2020
Cited by 19 | Viewed by 4082
Abstract
Transforming growth factor beta3 (TGFB3) gene mutations in patients of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD1) and Loeys-Dietz syndrome-5 (LDS5)/Rienhoff syndrome are associated with cardiomyopathy, cardiac arrhythmia, cardiac fibrosis, cleft palate, aortic aneurysms, and valvular heart disease. Although the developing heart of [...] Read more.
Transforming growth factor beta3 (TGFB3) gene mutations in patients of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD1) and Loeys-Dietz syndrome-5 (LDS5)/Rienhoff syndrome are associated with cardiomyopathy, cardiac arrhythmia, cardiac fibrosis, cleft palate, aortic aneurysms, and valvular heart disease. Although the developing heart of embryos express Tgfb3, its overarching role remains unclear in cardiovascular development and disease. We used histological, immunohistochemical, and molecular analyses of Tgfb3−/− fetuses and compared them to wildtype littermate controls. The cardiovascular phenotypes were diverse with approximately two thirds of the Tgfb3−/− fetuses having one or more cardiovascular malformations, including abnormal ventricular myocardium (particularly of the right ventricle), outflow tract septal and alignment defects, abnormal aortic and pulmonary trunk walls, and thickening of semilunar and/or atrioventricular valves. Ventricular septal defects (VSD) including the perimembranous VSDs were observed in Tgfb3−/− fetuses with myocardial defects often accompanied by the muscular type VSD. In vitro studies using TGFβ3-deficient fibroblasts in 3-D collagen lattice formation assays indicated that TGFβ3 was required for collagen matrix reorganization. Biochemical studies indicated the ‘paradoxically’ increased activation of canonical (SMAD-dependent) and noncanonical (MAP kinase-dependent) pathways. TGFβ3 is required for cardiovascular development to maintain a balance of canonical and noncanonical TGFβ signaling pathways. Full article
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Review

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17 pages, 3770 KiB  
Review
Dissecting the Complexity of Early Heart Progenitor Cells
J. Cardiovasc. Dev. Dis. 2022, 9(1), 5; https://doi.org/10.3390/jcdd9010005 - 26 Dec 2021
Cited by 7 | Viewed by 4064
Abstract
Early heart development depends on the coordinated participation of heterogeneous cell sources. As pioneer work from Adriana C. Gittenberger-de Groot demonstrated, characterizing these distinct cell sources helps us to understand congenital heart defects. Despite decades of research on the segregation of lineages that [...] Read more.
Early heart development depends on the coordinated participation of heterogeneous cell sources. As pioneer work from Adriana C. Gittenberger-de Groot demonstrated, characterizing these distinct cell sources helps us to understand congenital heart defects. Despite decades of research on the segregation of lineages that form the primitive heart tube, we are far from understanding its full complexity. Currently, single-cell approaches are providing an unprecedented level of detail on cellular heterogeneity, offering new opportunities to decipher its functional role. In this review, we will focus on three key aspects of early heart morphogenesis: First, the segregation of myocardial and endocardial lineages, which yields an early lineage diversification in cardiac development; second, the signaling cues driving differentiation in these progenitor cells; and third, the transcriptional heterogeneity of cardiomyocyte progenitors of the primitive heart tube. Finally, we discuss how single-cell transcriptomics and epigenomics, together with live imaging and functional analyses, will likely transform the way we delve into the complexity of cardiac development and its links with congenital defects. Full article
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26 pages, 35031 KiB  
Review
Pathology of the Aorta and Aorta as Homograft
J. Cardiovasc. Dev. Dis. 2021, 8(7), 76; https://doi.org/10.3390/jcdd8070076 - 29 Jun 2021
Cited by 6 | Viewed by 6128
Abstract
The aorta is not a rigid tube, it is an “organ” with lamellar units, consisting of elastic fibers, extracellular matrix and smooth muscle cells in between as parenchyma. Several diseases may occur in the natural history of the aorta, requiring replacement of both [...] Read more.
The aorta is not a rigid tube, it is an “organ” with lamellar units, consisting of elastic fibers, extracellular matrix and smooth muscle cells in between as parenchyma. Several diseases may occur in the natural history of the aorta, requiring replacement of both semilunar cusps and ascending aorta. They may be congenital defects, such as bicuspid aortic valve and isthmal coarctation with aortopathy; genetically determined, such as Marfan and William syndromes; degenerative diseases, such as atherosclerosis and medial necrosis with aortic dilatation, valve incompetence and dissecting aneurysm; inflammatory diseases such as Takayasu arteritis, syphilis, giant cell and IgM4 aortitis; neoplasms; and trauma. Aortic homografts from cadavers, including both the sinus portion with semilunar cusps and the tubular portion, are surgically employed to replace a native sick ascending aorta. However, the antigenicity of allograft cells, in the lamellar units and interstitial cells in the cusps, is maintained. Thus, an immune reaction may occur, limiting durability. After proper decellularization and 6 months’ implantation in sheep, endogenous cell repopulation was shown to occur in both the valve and aortic wall, including the endothelium, without evidence of inflammation and structural deterioration/calcification in the mid-term. The allograft was transformed into an autograft. Full article
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18 pages, 4273 KiB  
Review
Role of the Epicardium in the Development of the Atrioventricular Valves and Its Relevance to the Pathogenesis of Myxomatous Valve Disease
J. Cardiovasc. Dev. Dis. 2021, 8(5), 54; https://doi.org/10.3390/jcdd8050054 - 12 May 2021
Cited by 3 | Viewed by 3330
Abstract
This paper is dedicated to the memory of Dr. Adriana “Adri” Gittenberger-de Groot and in appreciation of her work in the field of developmental cardiovascular biology and the legacy that she has left behind. During her impressive career, Dr. Gittenberger-de Groot studied many [...] Read more.
This paper is dedicated to the memory of Dr. Adriana “Adri” Gittenberger-de Groot and in appreciation of her work in the field of developmental cardiovascular biology and the legacy that she has left behind. During her impressive career, Dr. Gittenberger-de Groot studied many aspects of heart development, including aspects of cardiac valve formation and disease and the role of the epicardium in the formation of the heart. In this contribution, we review some of the work on the role of epicardially-derived cells (EPDCs) in the development of the atrioventricular valves and their potential involvement in the pathogenesis of myxomatous valve disease (MVD). We provide an overview of critical events in the development of the atrioventricular junction, discuss the role of the epicardium in these events, and illustrate how interfering with molecular mechanisms that are involved in the epicardial-dependent formation of the atrioventricular junction leads to a number of abnormalities. These abnormalities include defects of the AV valves that resemble those observed in humans that suffer from MVD. The studies demonstrate the importance of the epicardium for the proper formation and maturation of the AV valves and show that the possibility of epicardial-associated developmental defects should be taken into consideration when determining the genetic origin and pathogenesis of MVD. Full article
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25 pages, 2297 KiB  
Review
The Role of Cell Tracing and Fate Mapping Experiments in Cardiac Outflow Tract Development, New Opportunities through Emerging Technologies
J. Cardiovasc. Dev. Dis. 2021, 8(5), 47; https://doi.org/10.3390/jcdd8050047 - 26 Apr 2021
Cited by 2 | Viewed by 2990
Abstract
Whilst knowledge regarding the pathophysiology of congenital heart disease (CHDs) has advanced greatly in recent years, the underlying developmental processes affecting the cardiac outflow tract (OFT) such as bicuspid aortic valve, tetralogy of Fallot and transposition of the great arteries remain poorly understood. [...] Read more.
Whilst knowledge regarding the pathophysiology of congenital heart disease (CHDs) has advanced greatly in recent years, the underlying developmental processes affecting the cardiac outflow tract (OFT) such as bicuspid aortic valve, tetralogy of Fallot and transposition of the great arteries remain poorly understood. Common among CHDs affecting the OFT, is a large variation in disease phenotypes. Even though the different cell lineages contributing to OFT development have been studied for many decades, it remains challenging to relate cell lineage dynamics to the morphologic variation observed in OFT pathologies. We postulate that the variation observed in cellular contribution in these congenital heart diseases might be related to underlying cell lineage dynamics of which little is known. We believe this gap in knowledge is mainly the result of technical limitations in experimental methods used for cell lineage analysis. The aim of this review is to provide an overview of historical fate mapping and cell tracing techniques used to study OFT development and introduce emerging technologies which provide new opportunities that will aid our understanding of the cellular dynamics underlying OFT pathology. Full article
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16 pages, 1240 KiB  
Review
Outflow Tract Formation—Embryonic Origins of Conotruncal Congenital Heart Disease
J. Cardiovasc. Dev. Dis. 2021, 8(4), 42; https://doi.org/10.3390/jcdd8040042 - 09 Apr 2021
Cited by 17 | Viewed by 4499
Abstract
Anomalies in the cardiac outflow tract (OFT) are among the most frequent congenital heart defects (CHDs). During embryogenesis, the cardiac OFT is a dynamic structure at the arterial pole of the heart. Heart tube elongation occurs by addition of cells from pharyngeal, splanchnic [...] Read more.
Anomalies in the cardiac outflow tract (OFT) are among the most frequent congenital heart defects (CHDs). During embryogenesis, the cardiac OFT is a dynamic structure at the arterial pole of the heart. Heart tube elongation occurs by addition of cells from pharyngeal, splanchnic mesoderm to both ends. These progenitor cells, termed the second heart field (SHF), were first identified twenty years ago as essential to the growth of the forming heart tube and major contributors to the OFT. Perturbation of SHF development results in common forms of CHDs, including anomalies of the great arteries. OFT development also depends on paracrine interactions between multiple cell types, including myocardial, endocardial and neural crest lineages. In this publication, dedicated to Professor Andriana Gittenberger-De Groot and her contributions to the field of cardiac development and CHDs, we review some of her pioneering studies of OFT development with particular interest in the diverse origins of the many cell types that contribute to the OFT. We also discuss the clinical implications of selected key findings for our understanding of the etiology of CHDs and particularly OFT malformations. Full article
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Other

18 pages, 2742 KiB  
Systematic Review
The Coronary Arteries in Adults after the Arterial Switch Operation: A Systematic Review
J. Cardiovasc. Dev. Dis. 2021, 8(9), 102; https://doi.org/10.3390/jcdd8090102 - 26 Aug 2021
Cited by 8 | Viewed by 3857
Abstract
Coronary artery status in adults long after the arterial switch operation (ASO) is unclear. We conducted a systematic review to provide an overview of coronary complications during adulthood and to evaluate the value of routine coronary imaging in adults after ASO, in light [...] Read more.
Coronary artery status in adults long after the arterial switch operation (ASO) is unclear. We conducted a systematic review to provide an overview of coronary complications during adulthood and to evaluate the value of routine coronary imaging in adults after ASO, in light of current guidelines. Articles were screened for the inclusion of adult ASO patients and data on coronary complications and findings of coronary imaging were collected. A total of 993 adults were followed with a median available follow-up of only 2.0 years after reaching adulthood. Myocardial ischemia was suspected in 17/192 patients (8.9%). The number of coronary interventions was four (0.4%), and coronary death was reported in four (0.4%) patients. A lack of ischemia-related symptoms cannot be excluded because innervation studies indicated deficient cardiac innervation after ASO, although data is limited. Anatomical high-risk features found by routine coronary computed tomography (cCT) included stenosis (4%), acute angle (40%), kinking (24%) and inter-arterial course (11%). No coronary complications were reported during pregnancy (n = 45), although, remarkably, four (9%) patients developed heart failure. The 2020 European Society of Cardiology (ESC) guidelines state that routine screening for coronary pathologies is questionable. Based on current findings and in line with the 2018 American ACC/AHA guidelines a baseline assessment of the coronary arteries in all ASO adults seems justifiable. Thereafter, an individualized coronary follow-up strategy is advisable at least until significant duration of follow-up is available. Full article
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3 pages, 413 KiB  
Perspective
Coronary Anatomy in Congenital Heart Disease: The Important Contributions of Professor Dr. Adriana Gittenberger-de Groot
J. Cardiovasc. Dev. Dis. 2021, 8(3), 27; https://doi.org/10.3390/jcdd8030027 - 09 Mar 2021
Cited by 2 | Viewed by 3149
Abstract
The contributions of Professor Dr. Adriana Gittenberger-de Groot in relation to coronary artery development and classification are described from the viewpoint of a pediatric cardiac surgeon. Full article
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16 pages, 9961 KiB  
Case Report
The Clinical Spectrum of Kommerell’s Diverticulum in Adults with a Right-Sided Aortic Arch: A Case Series and Literature Overview
J. Cardiovasc. Dev. Dis. 2021, 8(3), 25; https://doi.org/10.3390/jcdd8030025 - 26 Feb 2021
Cited by 12 | Viewed by 8272
Abstract
Background: Kommerell’s diverticulum is a rare vascular anomaly characterized as an outpouch at the onset of an aberrant subclavian artery. In the variant of a right-sided aortic arch, the trachea and esophagus are enclosed dorsally by the arch. In the configuration of an [...] Read more.
Background: Kommerell’s diverticulum is a rare vascular anomaly characterized as an outpouch at the onset of an aberrant subclavian artery. In the variant of a right-sided aortic arch, the trachea and esophagus are enclosed dorsally by the arch. In the configuration of an aberrant left subclavian artery, a Kommerell’s diverticulum and persisting ductus arteriosus or ductal ligament enclose the lateral side, forming a vascular ring which may result in (symptomatic) esophageal or tracheal compression. Spontaneous rupture of an aneurysmatic Kommerell’s diverticulum has also been reported. Due to the rarity of this condition and underreporting in the literature, the clinical implications of a Kommerell’s diverticulum are not well defined. Case summary: We describe seven consecutive adult patients with a right-sided aortic arch and an aberrant course of the left subclavian artery (arteria lusoria), and a Kommerell’s diverticulum, diagnosed in our tertiary hospital. One patient had severe symptoms related to the Kommerell’s diverticulum and underwent surgical repair. In total, two of the patients experienced mild non-limiting dyspnea complaints and in four patients the Kommerell’s diverticulum was incidentally documented on a computed tomography (CT) scan acquired for a different indication. The size of the Kommerell’s diverticulum ranged from 19 × 21 mm to 30 × 29 mm. In the six patients that did not undergo surgery, a strategy of periodic follow-up with structural imaging was pursued. No significant growth of the Kommerell’s diverticulum was observed and none of the patients experienced an acute aortic syndrome to date. Discussion: Kommerell’s diverticulum in the setting of a right-sided aortic arch with an aberrant left subclavian artery is frequently associated with tracheal and esophageal compression and this may result in a varying range of symptoms. Guidelines on management of Kommerell’s diverticulum are currently lacking. This case series and literature overview suggests that serial follow-up is warranted in adult patients with a Kommerell’s diverticulum with small dimensions and no symptoms, however, that surgical intervention should be considered when patients become symptomatic or when the diameter exceeds 30 mm in the absence of symptoms. Full article
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