Surgical correction in patients with TAPVC with a biventricular anatomy can achieve an acceptable outcome. Risk factors such as a younger age at the time of repair, infracardiac and mixed TAPVC, and preoperative PVO were associated with a poorer prognosis.
Background
Current right ventricular (RV) volume overload (VO) is established in adult mice. There are no neonatal mouse VO models and how VO affects postnatal RV development is largely unknown.
Methods and Results
Neonatal VO was induced by the fistula between abdominal aorta and inferior vena cava on postnatal day 7 and confirmed by abdominal ultrasound, echocardiography, and hematoxylin and eosin staining. The RNA‐sequencing results showed that the top 5 most enriched gene ontology terms in normal RV development were energy derivation by oxidation of organic compounds, generation of precursor metabolites and energy, cellular respiration, striated muscle tissue development, and muscle organ development. Under the influence of VO, the top 5 most enriched gene ontology terms were angiogenesis, regulation of cytoskeleton organization, regulation of vasculature development, regulation of mitotic cell cycle, and regulation of the actin filament‐based process. The top 3 enriched signaling pathways for the normal RV development were PPAR signaling pathway, citrate cycle (Tricarboxylic acid cycle), and fatty acid degradation. VO changed the signaling pathways to focal adhesion, the PI3K‐Akt signaling pathway, and pathways in cancer. The RNA sequencing results were confirmed by the examination of the markers of metabolic and cardiac muscle maturation and the markers of cell cycle and angiogenesis.
Conclusions
A neonatal mouse VO model was successfully established, and the main processes of postnatal RV development were metabolic and cardiac muscle maturation, and VO changed that to angiogenesis and cell cycle regulation.
Background
Current mammalian models for heart regeneration research are limited to neonatal apex amputation and myocardial infarction, both of which are controversial.
RNA
seq has demonstrated a very limited set of differentially expressed genes between sham and operated hearts in myocardial infarction models. Here, we investigated in rats whether pressure overload in the right ventricle, a common phenomenon in children with congenital heart disease, could be used as a better animal model for heart regeneration studies when considering cardiomyocyte proliferation as the most important index.
Methods and Results
In the rat model, pressure overload was induced by pulmonary artery banding on postnatal day 1 and confirmed by echocardiography and hemodynamic measurements at postnatal day 7.
RNA
sequencing analyses of purified right ventricular cardiomyocytes at postnatal day 7 from pulmonary artery banding and sham‐operated rats revealed that there were 5469 differentially expressed genes between these 2 groups. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that these genes mainly mediated mitosis and cell division. Cell proliferation assays indicated a continuous overproliferation of cardiomyocytes in the right ventricle after pulmonary artery banding, in particular for the first 3 postnatal days. We also validated the model using samples from overloaded right ventricles of human patients. There was an approximately 2‐fold increase of Ki67/
pHH
3/aurora B‐positive cardiomyocytes in human‐overloaded right ventricles compared with nonoverloaded right ventricles. Other features of this animal model included cardiomyocyte hypotrophy with no fibrosis.
Conclusions
Pressure overload profoundly promotes cardiomyocyte proliferation in the neonatal stage in both rats and human beings. This activates a regeneration‐specific gene program and may offer an alternative animal model for heart regeneration research.
Addition of a bidirectional cavopulmonary shunt to cone reconstruction of the tricuspid valve should be considered for young patients with severe Ebstein anomaly who are at high risk of right ventricular failure after the operation.
Operative resection is optimal for primary tumors of the heart in patients with obvious symptoms or hemodynamic changes. Rhabdomyomas have the potential for spontaneous regression, and nonoperative follow-up therefore is acceptable even if symptoms appear. Operative risk is greater in younger patients and in patients with cardiac valvular dysfunction.
These results indicate that GSK-3β inhibitor can promote human atrial cardiomyocyte proliferation. Although it remains to be determined whether the observations in atrial myocytes could be directly applicable to ventricular myocytes, the current findings imply that Wnt/β-catenin pathway may be a valuable pathway for manipulating endogenous human heart regeneration.
Acute LPA angulation is associated with adverse haemodynamic performance. This should be particularly addressed during the reconstruction of pulmonary artery in the repair of tetralogy of Fallot.
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