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Article
| Open Access
Sinus venosus adaptation models prolonged cardiovascular disease and reveals insights into evolutionary transitions of the vertebrate heart
Nr2fs are conserved transcription factors that regulate atrial chamber and venous development. Here, the authors use adult zebrafish nr2f1a mutants to investigate compensatory remodeling of the inflow tract and hypotheses of cardiac evolution.
- Jacob T. Gafranek
- , Enrico D’Aniello
- & Joshua S. Waxman
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Article
| Open Access
Defects in placental syncytiotrophoblast cells are a common cause of developmental heart disease
Placental dysfunction can affect heart development, but the prevalence of this causality has not been well established. Here, the authors use mouse genetic tools to show that the placenta may constitute a significant source of congenital heart defects.
- Bethany N. Radford
- , Xiang Zhao
- & Myriam Hemberger
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Article
| Open Access
Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease
There is a pressing need to develop representative organ-like platforms recapitulating complex in vivo phenotypes to study human development and disease in vitro. Here the authors present a method to generate human heart organoids by self-assembly using pluripotent stem cells, compare these to age-matched fetal cardiac tissues and recreate a model of pregestational diabetes.
- Yonatan R. Lewis-Israeli
- , Aaron H. Wasserman
- & Aitor Aguirre
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Article
| Open Access
De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes
Large whole-exome sequencing studies have suggested that the genetic architecture of syndromic congenital heart disease (CHD) is different from sporadic forms. Here, Watkins et al. estimate the relative contribution of damaging recessive and de novo genotypes to CHD in 2391 trios and find them to be associated with different gene functions.
- W. Scott Watkins
- , E. Javier Hernandez
- & Martin Tristani-Firouzi
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Article
| Open Access
Weakly supervised classification of aortic valve malformations using unlabeled cardiac MRI sequences
The availability of labelled training data is one of the practical obstacles towards wide application of machine learning models in medicine. Here the authors develop a weakly supervised deep learning model for the classification of aortic malformations using unlabelled cardiac MRI sequences from the UK biobank.
- Jason A. Fries
- , Paroma Varma
- & James R. Priest
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Article
| Open Access
Combined loss of LAP1B and LAP1C results in an early onset multisystemic nuclear envelopathy
Nuclear envelopathies are a group of diseases caused by genetic mutations in essential nuclear envelope genes. Here, the authors report a nuclear envelopathy with a homozygous nonsense variant in TOR1AIP1 which leads to changes in the nuclear morphology including large nuclear-spanning channels in patients’ fibroblasts.
- Boris Fichtman
- , Fadia Zagairy
- & Ronen Spiegel
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Article
| Open Access
NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network
A gene regulatory network, including the transcription factor Nkx2-5, regulates cardiac development. Here, the authors show that on deletion of NKX2-5 from human embryonic stem cells, there is impaired cardiomyogenesis and changes in action potentials, and that this is regulated via HEY2.
- David J. Anderson
- , David I. Kaplan
- & David A. Elliott
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Article
| Open Access
Genome-wide analysis yields new loci associating with aortic valve stenosis
Aortic valve stenosis (AS) is the most common valvular heart disease. Here the authors identify two new AS loci that also associate with bicuspid aortic valve, aortic root diameter and/or coronary artery disease implicating both developmental abnormalities and atherosclerosis-like processes in AS.
- Anna Helgadottir
- , Gudmar Thorleifsson
- & Kari Stefansson
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Article
| Open Access
Endothelial deletion of Ino80 disrupts coronary angiogenesis and causes congenital heart disease
Heart development requires compaction of the ventricular wall into a dense myocardium at mid-gestation. Here, Rhee and colleagues show that the chromatin remodeller Ino80 is critical for the formation of the coronary vasculature, and show that coronary vessels are needed for successful cardiac compaction during embryonic development.
- Siyeon Rhee
- , Jae I. Chung
- & Kristy Red-Horse
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Article
| Open Access
Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve
Bicuspid aortic valve (BAV) is the most common human congenital cardiovascular malformation. Here, the authors perform a genome-wide association study for BAV and identify risk variants in the gene region of cardiac-specific transcription factor GATA4 and implicate GATA4 in heart valve development.
- Bo Yang
- , Wei Zhou
- & Cristen J. Willer
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Article
| Open Access
Loss of RNA expression and allele-specific expression associated with congenital heart disease
Congenital heart disease (CHD) is a disorder that occurs in ∼1% of live births. Here the authors describe a genome-wide allele-specific expression analyses in CHD patients, identifying five new genes involved in CHD and showing that paternally-expressed imprinted genes are monoallelic, while maternally-expressed imprinted genes are biallelic.
- David M. McKean
- , Jason Homsy
- & J. G. Seidman
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Article
| Open Access
Genetic link between renal birth defects and congenital heart disease
Using forward genetic screen in fetal mice, Gregory Pazour and colleagues describe mutants affecting kidney/urinary tract development. The authors also show that mutants that cause kidney defects overlaps with those leading to congenital heart defects, thus linking renal anomalies and congenital heart disease.
- Jovenal T. San Agustin
- , Nikolai Klena
- & Gregory J. Pazour
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Association analysis identifies new risk loci for congenital heart disease in Chinese populations
Genome-wide association studies in Chinese and Europeans have identified multiple loci associated with congenital heart disease. Here the authors use existing GWAS data to conduct an extended three-stage analysis in Han Chinese and identify four novel loci linked to disease risk in this population.
- Yuan Lin
- , Xuejiang Guo
- & Zhibin Hu
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Exercise at depth alters bradycardia and incidence of cardiac anomalies in deep-diving marine mammals
Deep-sea diving mammals routinely undergo extreme physiological challenges not experienced by their terrestrial counterparts. Using high-resolution electrocardiographic recorders fitted to seals and dolphins, Williams et al. report an increased frequency of cardiac arrhythmias at greater exercise intensity and dive depth.
- Terrie M. Williams
- , Lee A. Fuiman
- & Randall W. Davis
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Article
| Open Access
Chromatin remodelling complex dosage modulates transcription factor function in heart development
Inherited congenital heart defects are prevalent in the human population, but the molecular mechanisms are poorly understood. In this article, deficiency in the chromatin remodelling factor, Brg1, is shown to alter cardiac development in both mouse and zebrafish laboratory models.
- Jun K. Takeuchi
- , Xin Lou
- & Benoit G. Bruneau
Congenital heart disease detection by pediatric electrocardiogram based deep learning integrated with human concepts