Abnormal Cardiac Development in the Absence of Heart Glycogen

ABSTRACT Glycogen serves as a repository of glucose in many mammalian tissues. Mice lacking this glucose reserve in muscle, heart, and several other tissues were generated by disruption of the GYS1 gene, which encodes an isoform of glycogen synthase. Crossing mice heterozygous for the GYS1 disruption resulted in a significant underrepresentation of GYS1-null mice in the offspring. Timed matings established that Mendelian inheritance was followed for up to 18.5 days postcoitum (dpc) and that ∼90% of GYS1-null animals died soon after birth due to impaired cardiac function. Defects in cardiac development began between 11.5 and 14.5 dpc. At 18.5 dpc, the hearts were significantly smaller, with reduced ventricular chamber size and enlarged atria. Consistent with impaired cardiac function, edema, pooling of blood, and hemorrhagic liver were seen. Glycogen synthase and glycogen were undetectable in cardiac muscle and skeletal muscle from the surviving null mice, and the hearts showed normal morphology and function. Congenital heart disease is one of the most common birth defects in humans, at up to 1 in 50 live births. The results provide the first direct evidence that the ability to synthesize glycogen in cardiac muscle is critical for normal heart development and hence that its impairment could be a significant contributor to congenital heart defects.

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Placental epigenetics for evaluation of fetal congenital heart defects: Ventricular septal defect (VSD)

10.1101/355768 ◽

2018 ◽

Author(s):

Ray Bahado-Singh ◽

Samet Albayrak ◽

Rita Zafra ◽

Alosh Baraa ◽

Avinash M Veerappa ◽

...

Keyword(s):

Ventricular Septal Defect ◽

Cardiac Muscle ◽

Heart Development ◽

Congenital Heart ◽

Septal Defect ◽

Heart Defects ◽

Characteristic Curve ◽

A Genome ◽

Differentially Methylated Genes ◽

Cardiac Ventricle

AbstractVentricular Septal Defect (VSD), the most common congenital heart defect, is characterized by a hole in the septum between the right and left ventricles. The pathogenesis of VSD is unknown in most clinical cases. There is a paucity of data relevant to epigenetic changes in VSD. The placenta is a fetal tissue and is a potentially useful surrogate for the evaluation of fetal organ development. To understand epigenetic mechanisms that may play a role in the development of VSD, a genome-wide DNA methylation assay of the placentas of 8 term subjects with isolated VSD and no known or suspected genetic syndromes and 10 normal controls was performed using the Illumina HumanMethylation450 BeadChip assay. The study identified a total of 80 highly accurate potential epigenomic markers in 80 genes for the detection of VSD; area under the receiver operating characteristic curve (AUC ROC) = 1.0 with significant 95% CI (FDR) p-values < 0.05. The biological processes and functions for these differentially methylated genes are known to be associated with heart development or heart disease, including cardiac ventricle development (HEY2, ISL1), heart looping (SRF), cardiac muscle cell differentiation (ACTC1, HEY2), cardiac septum development (ISL1), heart morphogenesis (SRF, HEY2, ISL1, HEYL), Notch signaling pathway (HEY2, HEYL), cardiac chamber development (ISL1), and cardiac muscle tissue development (ACTC1, ISL1). The study also identified eight microRNA genes that have the potential to be biomarkers for the early detection of VSD including miR-191, miR-548F1, miR-148A, miR-423, miR-92B, miR-611, miR-2110, and miR-548H4. To our knowledge this is the first report in which placental analysis has been used for determining the pathogenesis of and predicting CHD.

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From Stripes to a Beating Heart: Early Cardiac Development in Zebrafish

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8020017 ◽

2021 ◽

Vol 8 (2) ◽

pp. 17

Author(s):

Cassie L. Kemmler ◽

Fréderike W. Riemslagh ◽

Hannah R. Moran ◽

Christian Mosimann

Keyword(s):

Congenital Heart Defects ◽

Heart Development ◽

Congenital Heart ◽

Cardiac Development ◽

Heart Defects ◽

Lineage Tracing ◽

Genetic Lineage ◽

Zebrafish Model ◽

Lateral Plate ◽

Cardiac Progenitors

The heart is the first functional organ to form during vertebrate development. Congenital heart defects are the most common type of human birth defect, many originating as anomalies in early heart development. The zebrafish model provides an accessible vertebrate system to study early heart morphogenesis and to gain new insights into the mechanisms of congenital disease. Although composed of only two chambers compared with the four-chambered mammalian heart, the zebrafish heart integrates the core processes and cellular lineages central to cardiac development across vertebrates. The rapid, translucent development of zebrafish is amenable to in vivo imaging and genetic lineage tracing techniques, providing versatile tools to study heart field migration and myocardial progenitor addition and differentiation. Combining transgenic reporters with rapid genome engineering via CRISPR-Cas9 allows for functional testing of candidate genes associated with congenital heart defects and the discovery of molecular causes leading to observed phenotypes. Here, we summarize key insights gained through zebrafish studies into the early patterning of uncommitted lateral plate mesoderm into cardiac progenitors and their regulation. We review the central genetic mechanisms, available tools, and approaches for modeling congenital heart anomalies in the zebrafish as a representative vertebrate model.

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From Stem Cells to Populations—Using hiPSC, Next-Generation Sequencing, and GWAS to Explore the Genetic and Molecular Mechanisms of Congenital Heart Defects

Genes ◽

10.3390/genes12060921 ◽

2021 ◽

Vol 12 (6) ◽

pp. 921

Author(s):

Martin Broberg ◽

Johanna Hästbacka ◽

Emmi Helle

Keyword(s):

Stem Cells ◽

Congenital Heart Defects ◽

Heart Development ◽

Congenital Heart ◽

Molecular Mechanisms ◽

Association Studies ◽

Heart Defects ◽

Cell Types ◽

Mendelian Inheritance ◽

Genome Wide Association Studies

Congenital heart defects (CHD) are developmental malformations affecting the heart and the great vessels. Early heart development requires temporally regulated crosstalk between multiple cell types, signaling pathways, and mechanical forces of early blood flow. While both genetic and environmental factors have been recognized to be involved, identifying causal genes in non-syndromic CHD has been difficult. While variants following Mendelian inheritance have been identified by linkage analysis in a few families with multiple affected members, the inheritance pattern in most familial cases is complex, with reduced penetrance and variable expressivity. Furthermore, most non-syndromic CHD are sporadic. Improved sequencing technologies and large biobank collections have enabled genome-wide association studies (GWAS) in non-syndromic CHD. The ability to generate human to create human induced pluripotent stem cells (hiPSC) and further differentiate them to organotypic cells enables further exploration of genotype–phenotype correlations in patient-derived cells. Here we review how these technologies can be used in unraveling the genetics and molecular mechanisms of heart development.

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Embryonic Mouse Cardiodynamic OCT Imaging

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd7040042 ◽

2020 ◽

Vol 7 (4) ◽

pp. 42

Author(s):

Andrew L. Lopez ◽

Shang Wang ◽

Irina V. Larina

Keyword(s):

Blood Flow ◽

Congenital Heart Defects ◽

Heart Development ◽

Congenital Heart ◽

Cardiac Development ◽

Heart Defects ◽

Cellular Level ◽

Mouse Heart ◽

Embryonic Mouse ◽

Insight Into

The embryonic heart is an active and developing organ. Genetic studies in mouse models have generated great insight into normal heart development and congenital heart defects, and suggest mechanical forces such as heart contraction and blood flow to be implicated in cardiogenesis and disease. To explore this relationship and investigate the interplay between biomechanical forces and cardiac development, live dynamic cardiac imaging is essential. Cardiodynamic imaging with optical coherence tomography (OCT) is proving to be a unique approach to functional analysis of the embryonic mouse heart. Its compatibility with live culture systems, reagent-free contrast, cellular level resolution, and millimeter scale imaging depth make it capable of imaging the heart volumetrically and providing spatially resolved information on heart wall dynamics and blood flow. Here, we review the progress made in mouse embryonic cardiodynamic imaging with OCT, highlighting leaps in technology to overcome limitations in resolution and acquisition speed. We describe state-of-the-art functional OCT methods such as Doppler OCT and OCT angiography for blood flow imaging and quantification in the beating heart. As OCT is a continuously developing technology, we provide insight into the future developments of this area, toward the investigation of normal cardiogenesis and congenital heart defects.

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Outflow Tract Formation—Embryonic Origins of Conotruncal Congenital Heart Disease

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8040042 ◽

2021 ◽

Vol 8 (4) ◽

pp. 42

Author(s):

Sonia Stefanovic ◽

Heather C. Etchevers ◽

Stéphane Zaffran

Keyword(s):

Congenital Heart ◽

Cardiac Development ◽

Heart Defects ◽

Dynamic Structure ◽

Cell Types ◽

Outflow Tract ◽

Heart Tube ◽

Heart Field ◽

Multiple Cell ◽

The Many

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.

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Focused Strategies for Defining the Genetic Architecture of Congenital Heart Defects

Genes ◽

10.3390/genes12060827 ◽

2021 ◽

Vol 12 (6) ◽

pp. 827

Author(s):

Lisa J. Martin ◽

D Woodrow Benson

Keyword(s):

Genetic Variation ◽

Congenital Heart Defects ◽

Heart Development ◽

Genetic Architecture ◽

Congenital Heart ◽

Rare Variants ◽

Heart Defects ◽

Genetic Origin ◽

Genetic Studies ◽

The Ideal

Congenital heart defects (CHD) are malformations present at birth that occur during heart development. Increasing evidence supports a genetic origin of CHD, but in the process important challenges have been identified. This review begins with information about CHD and the importance of detailed phenotyping of study subjects. To facilitate appropriate genetic study design, we review DNA structure, genetic variation in the human genome and tools to identify the genetic variation of interest. Analytic approaches powered for both common and rare variants are assessed. While the ideal outcome of genetic studies is to identify variants that have a causal role, a more realistic goal for genetic analytics is to identify variants in specific genes that influence the occurrence of a phenotype and which provide keys to open biologic doors that inform how the genetic variants modulate heart development. It has never been truer that good genetic studies start with good planning. Continued progress in unraveling the genetic underpinnings of CHD will require multidisciplinary collaboration between geneticists, quantitative scientists, clinicians, and developmental biologists.

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Abstract 791: A Critical Role for Bmper (BMP-binding Endothelial cell precursor-derived Regulator) in Cardiac Muscle Mass Regulation during Development and Pressure Overload Induced Hypertrophy

Circulation ◽

10.1161/circ.116.suppl_16.ii_152-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Monte Willis ◽

Rongqin Ren ◽

Cam Patterson

Keyword(s):

Cardiac Function ◽

Cardiac Muscle ◽

Muscle Mass ◽

Cardiac Development ◽

Critical Role ◽

Pressure Overload ◽

Posterior Wall ◽

Fractional Shortening

Bone morphogenetic proteins (BMPs) of the TGF-beta superfamily, have been implicated in multiple processes during cardiac development. Our laboratory recently described an unprecedented role for Bmper in antagonizing BMP-2, BMP-4, and BMP-6. To determine the role of Bmper on cardiac development in vivo, we created Bmper null (Bmper −/−) mice by replacing exons 1 and 2 with GFP. Since Bmper −/− mice are perinatally lethal, we determined pre-natal cardiac function of Bmper −/− mice in utero just before birth. By echocardiography, E18.5 Bmper −/− embryos had decreased cardiac function (24.2 +/− 8.1% fractional shortening) compared to Bmper +/− and Bmper +/+ siblings (52.2 +/− 1.6% fractional shortening) (N=4/group). To further characterize the role of Bmper on cardiac function in adult mice, we performed echocardiography on 8-week old male and female Bmper +/− and littermate control Bmper +/+. Bmper +/− mice had an approximately 15% decrease in anterior and posterior wall thickness compared to sibling Bmper +/+ mice at baseline (n=10/group). Cross-sectional areas of Bmper +/− cardiomyocytes were approximately 20% less than wild type controls, indicating cardiomyocyte hypoplasia in adult Bmper +/− mice at baseline. Histologically, no significant differences were identified in representative H&E and trichrome stained adult Bmper +/− and Bmper +/+ cardiac sections at baseline. To determine the effects of Bmper expression on the development of cardiac hypertrophy, both Bmper +/− and Bmper +/+ sibling controls underwent transaortic constriction (TAC), followed by weekly echocardiography. While a deficit was identified in Bmper +/− mice at baseline, both anterior and posterior wall thicknesses increased after TAC, such that identical wall thicknesses were identified in Bmper +/− and Bmper +/+ mice 1–4 weeks after TAC. Notably, cardiac function (fractional shortening %) and histological evaluation revealed no differences between Bmper +/− and Bmper +/+ any time after TAC. These studies identify for the first time that Bmper expression plays a critical role in regulating cardiac muscle mass during development, and that Bmper regulates the development of hypertrophy in response to pressure overload in vivo.

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Drosophila Heart as a Model for Cardiac Development and Diseases

Cells ◽

10.3390/cells10113078 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3078

Author(s):

Anissa Souidi ◽

Krzysztof Jagla

Keyword(s):

Cardiac Dysfunction ◽

Congenital Heart ◽

Cardiac Development ◽

Heart Diseases ◽

Heart Defects ◽

Fruit Fly ◽

Model System ◽

Fast Imaging

The Drosophila heart, also referred to as the dorsal vessel, pumps the insect blood, the hemolymph. The bilateral heart primordia develop from the most dorsally located mesodermal cells, migrate coordinately, and fuse to form the cardiac tube. Though much simpler, the fruit fly heart displays several developmental and functional similarities to the vertebrate heart and, as we discuss here, represents an attractive model system for dissecting mechanisms of cardiac aging and heart failure and identifying genes causing congenital heart diseases. Fast imaging technologies allow for the characterization of heartbeat parameters in the adult fly and there is growing evidence that cardiac dysfunction in human diseases could be reproduced and analyzed in Drosophila, as discussed here for heart defects associated with the myotonic dystrophy type 1. Overall, the power of genetics and unsuspected conservation of genes and pathways puts Drosophila at the heart of fundamental and applied cardiac research.

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Epigenetic Regulation of Cardiac Neural Crest Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.678954 ◽

2021 ◽

Vol 9 ◽

Author(s):

Shun Yan ◽

Jin Lu ◽

Kai Jiao

Keyword(s):

Neural Crest ◽

Epigenetic Regulation ◽

Heart Development ◽

Congenital Heart ◽

Heart Diseases ◽

Heart Defects ◽

Neural Crest Cells ◽

Abnormal Development ◽

Cardiac Neural Crest ◽

Epigenetic Regulators

The cardiac neural crest cells (cNCCs) is a transient, migratory cell population that contribute to the formation of major arteries and the septa and valves of the heart. Abnormal development of cNCCs leads to a spectrum of congenital heart defects that mainly affect the outflow region of the hearts. Signaling molecules and transcription factors are the best studied regulatory events controlling cNCC development. In recent years, however, accumulated evidence supports that epigenetic regulation also plays an important role in cNCC development. Here, we summarize the functions of epigenetic regulators during cNCC development as well as cNCC related cardiovascular defects. These factors include ATP-dependent chromatin remodeling factors, histone modifiers and DNA methylation modulators. In many cases, mutations in the genes encoding these factors are known to cause inborn heart diseases. A better understanding of epigenetic regulators, their activities and their roles during heart development will ultimately contribute to the development of new clinical applications for patients with congenital heart disease.

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