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Cardiovascular Development and Congenital Heart Disease Modeling in the Pig.

ABSTRACT: Background Modeling cardiovascular diseases in mice has provided invaluable insights into the cause of congenital heart disease. However, the small size of the mouse heart has precluded translational studies. Given current high-efficiency gene editing, congenital heart disease modeling in other species is possible. The pig is advantageous given its cardiac anatomy, physiology, and size are similar to human infants. We profiled pig cardiovascular development and generated genetically edited pigs with congenital heart defects. Methods and Results Pig conceptuses and fetuses were collected spanning 7 stages (day 20 to birth at day 115), with at least 3 embryos analyzed per stage. A combination of magnetic resonance imaging and 3-dimensional histological reconstructions with episcopic confocal microscopy were conducted. Gross dissections were performed in late-stage or term fetuses by using sequential segmental analysis of the atrial, ventricular, and arterial segments. At day 20, the heart has looped, forming a common atria and ventricle and an undivided outflow tract. Cardiac morphogenesis progressed rapidly, with atrial and outflow septation evident by day 26 and ventricular septation completed by day 30. The outflow and atrioventricular cushions seen at day 20 undergo remodeling to form mature valves, a process continuing beyond day 42. Genetically edited pigs generated with mutation in chromatin modifier SAP130 exhibited tricuspid dysplasia, with tricuspid atresia associated with early embryonic lethality. Conclusions The major events in pig cardiac morphogenesis are largely complete by day 30. The developmental profile is similar to human and mouse, indicating gene edited pigs may provide new opportunities for preclinical studies focused on outcome improvements for congenital heart disease.

SUBMITTER: Gabriel GC

PROVIDER: S-EPMC8483476 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Congenital heart disease (CHD) is the most common life-threatening congenital anomaly. CHD occurs due to defects in cardiovascular development, and the majority of CHDs are caused by a multifactorial inheritance mechanism, which refers to the interaction between genetic and environmental factors. During embryogenesis, the cardiovascular system is derived from at least four distinct cell lineages: the first heart field, second heart field, cardiac neural crest, and proepicardial organ. Understanding the genes involved in each lineage is essential to uncover the genomic architecture of CHD. Therefore, we provide an overview of recent research progress using animal models and mutation analyses to better understand the molecular mechanisms and pathways linking cardiovascular development and CHD. For example, we highlight our recent work on genes encoding three isoforms of inositol 1,4,5-trisphosphate receptors (IP3R1, 2, and 3) that regulate various vital and developmental processes, which have genetic redundancy during cardiovascular development. Specifically, IP3R1 and 2 have redundant roles in the atrioventricular cushion derived from the first heart field lineage, whereas IP3R1 and 3 exhibit redundancy in the right ventricle and the outflow tract derived from the second heart field lineage, respectively. Moreover, 22q11.2 deletion syndrome (22q11DS) is highly associated with CHD involving the outflow tract, characterized by defects of the cardiac neural crest lineage. However, our studies have shown that TBX1, a major genetic determinant of 22q11DS, was not expressed in the cardiac neural crest but rather in the second heart field, suggesting the importance of the cellular interaction between the cardiac neural crest and the second heart field. Comprehensive genetic analysis using the Japanese genome bank of CHD and mouse models revealed that a molecular regulatory network involving GATA6, FOXC1/2, TBX1, SEMA3C, and FGF8 was essential for reciprocal signaling between the cardiac neural crest and the second heart field during cardiovascular development. Elucidation of the genomic architecture of CHD using induced pluripotent stem cells and next-generation sequencing technology, in addition to genetically modified animal models and human mutation analyses, would facilitate the development of regenerative medicine and/or preventive medicine for CHD in the near future.

Project description:BackgroundAlthough lower-complexity cardiac malformations constitute the majority of adult congenital heart disease (ACHD), the long-term risks of adverse cardiovascular events and relationship with conventional risk factors in this population are poorly understood. We aimed to quantify the risk of adverse cardiovascular events associated with lower-complexity ACHD that is unmeasured by conventional risk factors.MethodsA multitiered classification algorithm was used to select individuals with lower-complexity ACHD and individuals without ACHD for comparison among >500 000 British adults in the UK Biobank. ACHD diagnoses were subclassified as isolated aortic valve and noncomplex defects. Time-to-event analyses were conducted for the primary end points of fatal or nonfatal acute coronary syndrome, ischemic stroke, heart failure, and atrial fibrillation and a secondary combined end point for major adverse cardiovascular events. Maximum follow-up time for the study period was 22 years with retrospectively and prospectively collected data from the UK Biobank.ResultsWe identified 2006 individuals with lower-complexity ACHD and 497 983 unexposed individuals in the UK Biobank (median age at enrollment, 58 [interquartile range, 51-63] years). Of the ACHD-exposed group, 59% were male, 51% were current or former smokers, 30% were obese, and 69%, 41%, and 7% were diagnosed or treated for hypertension, hyperlipidemia, and diabetes mellitus, respectively. After adjustment for 12 measured cardiovascular risk factors, ACHD remained strongly associated with the primary end points, with hazard ratios ranging from 2.0 (95% CI, 1.5-2.8; P<0.001) for acute coronary syndrome to 13.0 (95% CI, 9.4-18.1; P<0.001) for heart failure. ACHD-exposed individuals with ≤2 cardiovascular risk factors had a 29% age-adjusted incidence rate of major adverse cardiovascular events, in contrast to 13% in individuals without ACHD with ≥5 risk factors.ConclusionsIndividuals with lower-complexity ACHD had a higher burden of adverse cardiovascular events relative to the general population that was unaccounted for by conventional cardiovascular risk factors. These findings highlight the need for closer surveillance of patients with mild to moderate ACHD and further investigation into management and mechanisms of cardiovascular risk unique to this growing population of high-risk adults.

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Cardiovascular Development and Congenital Heart Disease Modeling in the Pig.

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