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The adult mammalian heart is incapable of regeneration after injury, as shown by the limited amount of cardiomyocyte proliferation and poor neovascularization. We recently showed that neonatal mice have a remarkable ability to regenerate damaged heart after apical resection or myocardial infarction (MI), which includes complete reconstruction of myocardial wall with vascular network [2, 3]. Although lineage tracing showed that the main source of newly formed cardiomyocyte is preexisting cardiomyocytes, it is still possible that there is a minor contribution of other types of cells to the cardiomyocyte. In addition, lineage origin of the newly formed vasculature during postnatal cardiac maturation and neonatal heart regeneration remains unclear (Fig. 50.1).

Congenital heart disease (CHD) behaves like a complex genetic trait in most instances. Recent advances in genomics have provided tools for uncovering genetic variants underlying complex traits that are now being applied to study CHD. Massively parallel DNA sequencing has shown that de novo mutations contribute to ~10 % of severe CHD and implicated chromatin remodeling in pathogenesis. Genome scanning methods for copy number variants (CNVs) identify likely pathogenic genomic alterations in 10 % of infants with hypoplastic left heart syndrome and related single ventricle forms of CHD. The growth and neurocognitive development of children with CHD and those CNVs is worse, and clinical examination is relatively insensitive for detecting those CNVs. In sum, new opportunities for preventing and ameliorating CHD and its comorbidities are anticipated as its genetic architecture is elaborated through the use of state-of-the-art genomic approaches.

Jacobsen syndrome (11q-) is a rare chromosomal disorder characterized by multiple problems including congenital heart defects, behavioral problems, intellectual disability, dysmorphic features, and bleeding problems. Septal defects, including double outlet right ventricle (DORV), are among the most common CHDs that occur in 11q-. One possible mechanism underlying the CHDs and other problems in 11q- is a defect in neural crest cell function. The E26 avian leukemia 1, 5′ domain (ETS-1) gene is a member of the ETS-domain transcription factor family. ETS-1 is deleted in every 11q- patient with CHDs, and gene-targeted deletion of the ETS-1 gene in C57/B6 mice causes DORV with 100 % penetrance. Normal murine cardiac development requires precisely regulated specification of the cardiac neural crest cells (cNCCs). To begin to define the role of ETS-1 in mammalian cardiac development, we have demonstrated that ETS-1 is strongly expressed in mouse cNCCs during early heart development. Sox10 is a key regulator for the neural crest cell gene regulatory network. It is also an early marker for NCCs, and its expression can facilitate the analysis of cNCC function during embryonic development. We have demonstrated that loss of ETS-1 causes decreased migrating Sox10-expressing cells in E10.5 C57/B6 mouse embryos. These results suggest a NCC migration defect in ETS-1 mutants. Our data support the hypothesis that ETS-1 is required for specification and migration of cNCCs and for regulating a cNCC-specific gene regulatory network that is required for normal cardiac development.

Bicuspid aortic valve (BAV) is the most common type of cardiac malformation with an estimated prevalence of 1 % in the population. BAV results in significant morbidity usually during adulthood due to its association with aortic valve calcification and ascending aortic aneurysms. Mutations in the signaling and transcriptional regulator, , are a cause of bicuspid aortic valve in non-syndromic autosomal dominant human pedigrees. The Notch signaling pathway is critical for multiple cellular processes during both development and disease and is expressed in the developing and adult aortic valve consistent with the cardiac phenotypes identified in affected family members. Recent work has begun to elucidate the molecular mechanisms underlying the link between Notch1 signaling and the development of BAV and valve calcification. Using in vitro approaches, loss of Notch signaling has been shown to contribute to aortic valve calcification via Runx2-, Sox9-, and Bmp2-dependent mechanisms. In addition, Notch1 signaling has been shown to be responsive to nitric oxide signaling during this disease process. A new highly penetrant mouse model of aortic valve disease using haploinsufficient mice that are backcrossed in an endothelial nitric oxide synthase ()- background was generated. and compound mutant mice (;) display a nearly 100 % incidence of aortic valve malformations, most commonly BAV. The aortic valves of adult mutant mice are thickened and have associated stenosis and regurgitation. Based upon the initial discovery of mutations in humans with aortic valve disease, subsequent studies have provided significant molecular insights into BAV-associated diseases.

In this study we found four CITED2 coding region mutations (c.550G>A, c.574A>G, c.573–578del6) which led to alterations of amino acid sequence (p.Gly184Ser, p.Ser192Gly, p.Ser192fs) in 120 children with congenital heart disease. The CITED2 mutation associated with the dysregulation of HIF-1α, TFAP2c, and CITED2 methylation accompanied with its decrease in mRNA expression might be involved in the pathological process of congenital heart disease.