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DOI: 10.1055/s-0043-1761852
Normal Tissue Homeostasis but Increased Cell Cycle Activity in the Myocardium of Children with Hypoplastic Left Heart Syndrome (HLHS)
Background: Hypoplastic left heart syndrome (HLHS) is a rare congenital cardiac malformation of unclear etiology influenced by genetic and hemodynamic factors. It is characterized by underdevelopment of left-sided heart structures and a hypoplastic, non-functional left ventricle. Growth of the embryonic and fetal heart occurs through proliferation of cardiomyocytes, so that impaired cell cycle activity might be involved in the pathogenesis of HLHS. The aim of this study was to identify molecular and cellular adaptations of cardiac growth in the postnatal heart of children with HLHS.
Method: Myocardial tissue from the left (LV) and right (RV) ventricle of HLHS patients (n = 5, aged 1–6 months), was compared to age-matched LV of controls (n = 5), RV of Fallot patients (n = 3) or DCM hearts (LV and RV, n = 5). Immunofluorescence for Ki67 and the mitosis marker phospho-histone H3 was performed to analyze cell cycle activity. Tissue homeostasis was studied by quantification of cardiomyocyte and fibroblast nuclei, as well as fibrosis, arterial vessels and capillary density. Western blot was performed to characterize growth and cell cycle regulating signaling pathways.
Results: Immunofluorescence staining showed a tendency for increased mitotic rates in both cardiomyocytes and non-myocytes in the LV but not RV of HLHS patients compared to controls. The latter was confirmed by a significantly increased number of Ki67-positive cardiomyocyte nuclei in LV myocardium (2.28 ± 0.92 in HLHS vs. 0.02 ± 0.01 in controls, p < 0.05). The ratio of cardiomyocyte nuclei to non-myocyte nuclei as well as cardiomyocyte cross sectional area appears unchanged in HLHS LV and RV. Similarly, density of intramyocardial arteries and capillaries is not altered in HLHS hearts, neither is the level of fibrosis or the relative number of fibroblasts. Western blots show a tendency for activation of p42/p44 MAP kinases and YAP signaling in HLHS LV compared to DCM hearts. Other signaling pathways involved in cardiac growth such as p38 MAPK und Akt/mTOR, as well as cell cycle regulating genes were not significantly changed.
Conclusion: Myocardial tissue homeostasis and cell composition is mainly normal in postnatal HLHS hearts and no major pathological remodeling is evident. Increased cell cycle activity could indicate cardiomyocyte immaturity in HLHS LV potentially allowing cell division to compensate for hypoplasia but could also show terminal differentiation resulting in binucleation or polyploidy.
Publikationsverlauf
Artikel online veröffentlicht:
28. Januar 2023
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