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Article ; Online: Studying the role of chromatin organization in cardiovascular diseases: future perspectives.

Gladka, Monika M / Christoffels, Vincent M

2021 Volume 117, Issue 12, Page(s) e156–e158

MeSH term(s)	Cardiovascular Diseases/genetics ; Chromatin/genetics ; Embryonic Stem Cells ; Humans
Chemical Substances	Chromatin
Language	English
Publishing date	2021-10-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvab319
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Article ; Online: Role of Genetic Variation in Transcriptional Regulatory Elements in Heart Rhythm.

Jonker, Timo / Barnett, Phil / Boink, Gerard J J / Christoffels, Vincent M

Cells

2023 Volume 13, Issue 1

Abstract: Genetic predisposition to cardiac arrhythmias has been a field of intense investigation. Research initially focused on rare hereditary arrhythmias, but over the last two decades, the role of genetic variation (single nucleotide polymorphisms) in heart ... ...

Abstract	Genetic predisposition to cardiac arrhythmias has been a field of intense investigation. Research initially focused on rare hereditary arrhythmias, but over the last two decades, the role of genetic variation (single nucleotide polymorphisms) in heart rate, rhythm, and arrhythmias has been taken into consideration as well. In particular, genome-wide association studies have identified hundreds of genomic loci associated with quantitative electrocardiographic traits, atrial fibrillation, and less common arrhythmias such as Brugada syndrome. A significant number of associated variants have been found to systematically localize in non-coding regulatory elements that control the tissue-specific and temporal transcription of genes encoding transcription factors, ion channels, and other proteins. However, the identification of causal variants and the mechanism underlying their impact on phenotype has proven difficult due to the complex tissue-specific, time-resolved, condition-dependent, and combinatorial function of regulatory elements, as well as their modest conservation across different model species. In this review, we discuss research efforts aimed at identifying and characterizing-trait-associated variant regulatory elements and the molecular mechanisms underlying their impact on heart rate or rhythm.
MeSH term(s)	Humans ; Genome-Wide Association Study ; Regulatory Elements, Transcriptional ; Atrial Fibrillation/genetics ; Brugada Syndrome ; Polymorphism, Single Nucleotide
Language	English
Publishing date	2023-12-19
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells13010004
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Article ; Online: Genetics of sinoatrial node function and heart rate disorders.

van der Maarel, Lieve E / Postma, Alex V / Christoffels, Vincent M

Disease models & mechanisms

2023 Volume 16, Issue 5

Abstract: The sinoatrial node (SAN) is the primary pacemaker of the mammalian heart, initiating its electrical activation and ensuring that the heart's functional cardiac output meets physiological demand. SAN dysfunction (SND) can cause complex cardiac ... ...

Abstract	The sinoatrial node (SAN) is the primary pacemaker of the mammalian heart, initiating its electrical activation and ensuring that the heart's functional cardiac output meets physiological demand. SAN dysfunction (SND) can cause complex cardiac arrhythmias that can manifest as severe sinus bradycardia, sinus arrest, chronotropic incompetence and increased susceptibility to atrial fibrillation, among other cardiac conditions. SND has a complex aetiology, with both pre-existing disease and heritable genetic variation predisposing individuals to this pathology. In this Review, we summarize the current understanding of the genetic contributions to SND and the insights that they provide into this disorder's underlying molecular mechanisms. With an improved understanding of these molecular mechanisms, we can improve treatment options for SND patients and develop new therapeutics.
MeSH term(s)	Animals ; Humans ; Sinoatrial Node/pathology ; Sinoatrial Node/physiology ; Heart Rate ; Atrial Fibrillation/genetics ; Atrial Fibrillation/pathology ; Mammals
Language	English
Publishing date	2023-05-17
Publishing country	England
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.050101
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Article ; Online: Reptiles as a Model System to Study Heart Development.

Jensen, Bjarke / Christoffels, Vincent M

Cold Spring Harbor perspectives in biology

2020 Volume 12, Issue 5

Abstract: A chambered heart is common to all vertebrates, but reptiles show unparalleled variation in ventricular septation, ranging from almost absent in tuataras to full in crocodilians. Because mammals and birds evolved independently from reptile lineages, ... ...

Abstract	A chambered heart is common to all vertebrates, but reptiles show unparalleled variation in ventricular septation, ranging from almost absent in tuataras to full in crocodilians. Because mammals and birds evolved independently from reptile lineages, studies on reptile development may yield insight into the evolution and development of the full ventricular septum. Compared with reptiles, mammals and birds have evolved several other adaptations, including compact chamber walls and a specialized conduction system. These adaptations appear to have evolved from precursor structures that can be studied in present-day reptiles. The increase in the number of studies on reptile heart development has been greatly facilitated by sequencing of several genomes and the availability of good staging systems. Here, we place reptiles in their phylogenetic context with a focus on features that are primitive when compared with the homologous features of mammals. Further, an outline of major developmental events is given, and variation between reptile species is discussed.
MeSH term(s)	Alligators and Crocodiles ; Animals ; Biological Evolution ; Birds ; Disease Models, Animal ; Electrophysiology ; Genome ; Heart/embryology ; Heart/growth & development ; Humans ; Mammals ; Mice ; Models, Biological ; Myocytes, Cardiac/metabolism ; Organogenesis ; Phylogeny ; Reptiles/physiology
Language	English
Publishing date	2020-05-01
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1943-0264
ISSN (online)	1943-0264
DOI	10.1101/cshperspect.a037226
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Article ; Online: An Appreciation of Anatomy in the Molecular World.

Jensen, Bjarke / Christoffels, Vincent M / Moorman, Antoon F M

Journal of cardiovascular development and disease

2020 Volume 7, Issue 4

Abstract: Robert H. Anderson is one of the most important and accomplished cardiac anatomists of the last decades, having made major contributions to our understanding of the anatomy of normal hearts and the pathologies of acquired and congenital heart diseases. ... ...

Abstract	Robert H. Anderson is one of the most important and accomplished cardiac anatomists of the last decades, having made major contributions to our understanding of the anatomy of normal hearts and the pathologies of acquired and congenital heart diseases. While cardiac anatomy as a research discipline has become largely subservient to molecular biology, anatomists like Professor Anderson demonstrate anatomy has much to offer. Here, we provide cases of early anatomical insights on the heart that were rediscovered, and expanded on, by molecular techniques: migration of neural crest cells to the heart was deduced from histological observations (1908) and independently shown again with experimental interventions; pharyngeal mesoderm is added to the embryonic heart (1973) in what is now defined as the molecularly distinguishable second heart field; chambers develop from the heart tube as regional pouches in what is now considered the ballooning model by the molecular identification of regional differentiation and proliferation. The anatomical discovery of the conduction system by Purkinje, His, Tawara, Keith, and Flack is a special case because the main findings were never neglected in later molecular studies. Professor Anderson has successfully demonstrated that sound knowledge of anatomy is indispensable for proper understanding of cardiac development.
Language	English
Publishing date	2020-10-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2777082-5
ISSN	2308-3425 ; 2308-3425
ISSN (online)	2308-3425
ISSN	2308-3425
DOI	10.3390/jcdd7040044
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Article ; Online: Retinoic acid signaling in heart development: Application in the differentiation of cardiovascular lineages from human pluripotent stem cells.

Wiesinger, Alexandra / Boink, Gerard J J / Christoffels, Vincent M / Devalla, Harsha D

Stem cell reports

2021 Volume 16, Issue 11, Page(s) 2589–2606

Abstract: Retinoic acid (RA) signaling plays an important role during heart development in establishing anteroposterior polarity, formation of inflow and outflow tract progenitors, and growth of the ventricular compact wall. RA is also utilized as a key ingredient ...

Abstract	Retinoic acid (RA) signaling plays an important role during heart development in establishing anteroposterior polarity, formation of inflow and outflow tract progenitors, and growth of the ventricular compact wall. RA is also utilized as a key ingredient in protocols designed for generating cardiac cell types from pluripotent stem cells (PSCs). This review discusses the role of RA in cardiogenesis, currently available protocols that employ RA for differentiation of various cardiovascular lineages, and plausible transcriptional mechanisms underlying this fate specification. These insights will inform further development of desired cardiac cell types from human PSCs and their application in preclinical and clinical research.
MeSH term(s)	Animals ; Cell Differentiation/genetics ; Cell Differentiation/physiology ; Cell Lineage/genetics ; Cell Lineage/physiology ; Gene Expression Regulation, Developmental ; Heart/embryology ; Heart/physiology ; Humans ; Models, Cardiovascular ; Myocardium/cytology ; Myocardium/metabolism ; Pluripotent Stem Cells/cytology ; Pluripotent Stem Cells/metabolism ; Receptors, Retinoic Acid/genetics ; Receptors, Retinoic Acid/metabolism ; Signal Transduction/genetics ; Signal Transduction/physiology ; Sinoatrial Node/cytology ; Sinoatrial Node/embryology ; Sinoatrial Node/metabolism ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/metabolism ; Tretinoin/metabolism
Chemical Substances	Receptors, Retinoic Acid ; T-Box Domain Proteins ; T-box transcription factor 5 ; Tretinoin (5688UTC01R)
Language	English
Publishing date	2021-10-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2021.09.010
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Article ; Online: Lack of morphometric evidence for ventricular compaction in humans.

Faber, Jaeike W / D'Silva, Andrew / Christoffels, Vincent M / Jensen, Bjarke

Journal of cardiology

2021 Volume 78, Issue 5, Page(s) 397–405

Abstract: The remodeling of the compact wall by incorporation of trabecular myocardium, referred to as compaction, receives much attention because it is thought that its failure causes left ventricular non-compaction cardiomyopathy (LVNC). Although the notion of ... ...

Abstract	The remodeling of the compact wall by incorporation of trabecular myocardium, referred to as compaction, receives much attention because it is thought that its failure causes left ventricular non-compaction cardiomyopathy (LVNC). Although the notion of compaction is broadly accepted, the nature and strength of the evidence supporting this process is underexposed. Here, we review the literature that quantitatively investigated the development of the ventricular wall to understand the extent of compaction in humans, mice, and chickens. We queried PubMed using several search terms, screened 1127 records, and selected 56 publications containing quantitative data on ventricular growth. For humans, only 34 studies quantified wall development. The key premise of compaction, namely a reduction of the trabecular layer, was never documented. Instead, the trabecular layer grows slower than the compact wall in later development and this changes wall architecture. There were no reports of a sudden enlargement of the compact layer (from incorporated trabeculae), be it in thickness, area, or volume. Therefore, no evidence for compaction was found. Only in chickens, a sudden increase in compact myocardial thickness layer was reported coinciding with a decrease in trabecular thickness. In mice, morphometric and lineage tracing investigations have yielded conflicting results that allow for limited compaction to occur. In conclusion, compaction in human development is not supported while rapid intrinsic growth of the compact wall is supported in all species. If compaction takes place, it likely plays a much smaller role in determining wall architecture than intrinsic growth of the compact wall.
MeSH term(s)	Animals ; Chickens ; Heart Ventricles/diagnostic imaging ; Humans ; Isolated Noncompaction of the Ventricular Myocardium ; Mice ; Myocardium
Language	English
Publishing date	2021-04-08
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	639364-0
ISSN	1876-4738 ; 0386-2887 ; 0914-5087
ISSN (online)	1876-4738
ISSN	0386-2887 ; 0914-5087
DOI	10.1016/j.jjcc.2021.03.006
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Article ; Online: Quantified growth of the human embryonic heart.

Faber, Jaeike W / Hagoort, Jaco / Moorman, Antoon F M / Christoffels, Vincent M / Jensen, Bjarke

Biology open

2021 Volume 10, Issue 2

Abstract: The size and growth patterns of the components of the human embryonic heart have remained largely undefined. To provide these data, three-dimensional heart models were generated from immunohistochemically stained sections of ten human embryonic hearts ... ...

Abstract	The size and growth patterns of the components of the human embryonic heart have remained largely undefined. To provide these data, three-dimensional heart models were generated from immunohistochemically stained sections of ten human embryonic hearts ranging from Carnegie stage 10 to 23. Fifty-eight key structures were annotated and volumetrically assessed. Sizes of the septal foramina and atrioventricular canal opening were also measured. The heart grows exponentially throughout embryonic development. There was consistently less left than right atrial myocardium, and less right than left ventricular myocardium. We observed a later onset of trabeculation in the left atrium compared to the right. Morphometry showed that the rightward expansion of the atrioventricular canal starts in week 5. The septal foramina are less than 0.1 mm
MeSH term(s)	Biomarkers ; Embryonic Development ; Fluorescent Antibody Technique ; Heart/embryology ; Heart/growth & development ; Humans ; Models, Biological ; Morphogenesis ; Organogenesis
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-02-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2632264-X
ISSN	2046-6390 ; 2046-6390
ISSN (online)	2046-6390
ISSN	2046-6390
DOI	10.1242/bio.057059
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Article ; Online: Developmental Origin of the Cardiac Conduction System: Insight from Lineage Tracing.

Mohan, Rajiv A / Boukens, Bastiaan J / Christoffels, Vincent M

Pediatric cardiology

2018 Volume 39, Issue 6, Page(s) 1107–1114

Abstract: The components of the cardiac conduction system (CCS) generate and propagate the electrical impulse that initiates cardiac contraction. These interconnected components share properties, such as automaticity, that set them apart from the working ... ...

Abstract	The components of the cardiac conduction system (CCS) generate and propagate the electrical impulse that initiates cardiac contraction. These interconnected components share properties, such as automaticity, that set them apart from the working myocardium of the atria and ventricles. A variety of tools and approaches have been used to define the CCS lineages. These include genetic labeling of cells expressing lineage markers and fate mapping of dye labeled cells, which we will discuss in this review. We conclude that there is not a single CCS lineage, but instead early cell fate decisions segregate the lineages of the CCS components while they remain interconnected. The latter is relevant for development of therapies for conduction system disease that focus on reprogramming cardiomyocytes or instruction of pluripotent stem cells.
MeSH term(s)	Animals ; Cell Differentiation ; Heart Conduction System/cytology ; Heart Conduction System/embryology ; Heart Ventricles/cytology ; Heart Ventricles/embryology ; Humans ; Myocardium/cytology ; Myocytes, Cardiac
Language	English
Publishing date	2018-05-17
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	800857-7
ISSN	1432-1971 ; 0172-0643
ISSN (online)	1432-1971
ISSN	0172-0643
DOI	10.1007/s00246-018-1906-8
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Article ; Online: Structure and function of the Nppa-Nppb cluster locus during heart development and disease.

Man, Joyce / Barnett, Phil / Christoffels, Vincent M

Cellular and molecular life sciences : CMLS

2018 Volume 75, Issue 8, Page(s) 1435–1444

Abstract: Atrial natriuretic factor and brain natriuretic peptide are two important biomarkers in clinical cardiology. These two natriuretic peptide hormones are encoded by the paralogous genes Nppa and Nppb, which are evolutionary conserved. Both genes are ... ...

Abstract	Atrial natriuretic factor and brain natriuretic peptide are two important biomarkers in clinical cardiology. These two natriuretic peptide hormones are encoded by the paralogous genes Nppa and Nppb, which are evolutionary conserved. Both genes are predominantly expressed by the heart muscle during the embryonic and fetal stages, and in particular Nppa expression is strongly reduced in the ventricles after birth. Upon cardiac stress, Nppa and Nppb are strongly upregulated in the ventricular myocardium. Much is known about the molecular and physiological ques inducing Nppa and Nppb expression; however, the transcriptional regulatory mechanisms of the Nppa-Nppb cluster in vivo has proven to be quite complex and is not well understood. In this review, we will provide recent insights into the dynamic and complex regulation of Nppa and Nppb during heart development and hypertrophy, and the association of this gene cluster with the cardiomyocyte-intrinsic program of heart regeneration.
MeSH term(s)	Animals ; Atrial Natriuretic Factor/genetics ; Atrial Natriuretic Factor/metabolism ; Cardiomegaly/genetics ; Cardiomegaly/metabolism ; Cardiomegaly/pathology ; Embryo, Mammalian ; Epigenesis, Genetic ; Fetus ; Heart Ventricles/cytology ; Heart Ventricles/metabolism ; Humans ; Mice ; Multigene Family ; Myocardium/cytology ; Myocardium/metabolism ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/metabolism ; Receptors, Atrial Natriuretic Factor/genetics ; Receptors, Atrial Natriuretic Factor/metabolism ; Regeneration/genetics ; Signal Transduction ; Zebrafish
Chemical Substances	NPPA protein, human ; Atrial Natriuretic Factor (85637-73-6) ; Receptors, Atrial Natriuretic Factor (EC 4.6.1.2) ; atrial natriuretic factor receptor B (EC 4.6.1.2)
Language	English
Publishing date	2018-01-04
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-017-2737-0
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