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Birth defects contribute to ∼0.3% of global infant mortality in the first month of life, and congenital heart disease (CHD) is the most common birth defect among newborns worldwide. Despite the significant impact on human health, most treatments available for this heterogenous group of disorders are palliative at best. For this reason, the complex process of cardiogenesis, governed by multiple interlinked and dose-dependent pathways, is well investigated. Tissue, animal and, more recently, computerized models of the developing heart have facilitated important discoveries that are helping us to understand the genetic, epigenetic and mechanobiological contributors to CHD aetiology. In this Review, we discuss the strengths and limitations of different models of normal and abnormal cardiogenesis, ranging from single-cell systems and 3D cardiac organoids, to small and large animals and organ-level computational models. These investigative tools have revealed a diversity of pathogenic mechanisms that contribute to CHD, including genetic pathways, epigenetic regulators and shear wall stresses, paving the way for new strategies for screening and non-surgical treatment of CHD. As we discuss in this Review, one of the most-valuable advances in recent years has been the creation of highly personalized platforms with which to study individual diseases in clinically relevant settings.
Fig. 1. Cardiac development in the human embryo. This schematic shows the embryonic development of the human heart through first and second heart field (HF) formation, heart tube formation and pumping, looping, neural crest migration and septation, resulting in a fully developed heart at the end of gestation. Boxed areas highlight structures typically affected by congenital malformations (solid lines: atrial and ventricular septal defects; dotted lines: hypoplastic ventricles; dashed lines: aortic and pulmonary valve defects and defects of the great vessels, such as transposition).
Fig. 2. Classification of CHD into acyanotic and cyanotic CHD, and the status of pulmonary blood flow (PBF).
Fig. 3. In vitro modeling of CHD. (A) Patient-derived fibroblasts or other somatic cells are induced into pluripotent stem cells (iPSC) by addition of the Yamanaka factors POU5F1, SOX2, KLF4 and MYC. The resulting iPSCs are subsequently reprogrammed in differentiation medium containing differentiation and growth factors, such as human BMP4, activin, Wnt/β-catenin and FGF to yield cardiomyocytes bearing the gene defects of interest; i.e. reduced gene expression (HLHS), mutations (TOF, septal defects). (B) The resulting individual iPSCs can be used to study the cellular and molecular signatures in 2D cell structures relevant in a number of CHDs or can be further cultured in 3D to form cardiac organoids to study other environmental interactions. TNNT2, cardiac troponin 2; WT1, WT1 transcription factor (Wilms tumor 1); TJP, tight junction proteins 1, 2 and 3; THY1, Thy-1 cell surface antigen, VIM, vimentin; PECAM1, platelet and endothelial cell adhesion molecule 1; NFATC1, nuclear factor of activated T cells 1 (cytoplasmic).
Fig. 4. Computational simulation of the human fetal heart. Summary of the steps involved in in-silico modeling based on biomechanics derived from clinical ultrasound images. From left to right: Images are first processed to reconstruct the anatomy of the relevant cardiac structures. Motion tracking and modeling, as well as digital reconstruction can be carried out to accurately extract and mathematically model their motion. This is followed by finite element modeling of myocardial mechanics to understand myocardial stresses and strains, and to evaluate cardiac function under hypothetical conditions. Computational fluid dynamics can be simulated to reveal details of flow patterns and forces. Clinical and computational reconstruction images captured and developed by C.H.Y.
