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Hypoplastic left heart syndrome (HLHS) is a rare but deadly congenital malformation, which can be created experimentally in the chick embryo by left atrial ligation (LAL). The goal of this study was to examine the cellular changes leading to the profound remodeling of ventricular myocardial architecture that occurs in this model. Hypoplasia of left heart structures was produced after 3H-thymidine prelabeling by partial LAL at stage 24, thereby reducing its volume, and redistributing blood preferentially to the developing right ventricle (RV). Controls included both sham-operated and intact stage-matched embryos. Survivors were studied 4 days after the ligation, when the heart organogenesis was essentially complete. Paraffin sections of the hearts were subjected to autoradiography and immunohistochemistry to detect changes in history of cell proliferation and expression of myosin, and growth factors implicated in cardiomyocyte proliferation. Sampling for apoptosis detection using TUNEL assay was done at stages 29 and 34. LAL resulted in decreased levels of proliferation in the left ventricular compact layer and trabeculae. The right ventricular compact layer also showed a slight decrease, but the trabeculae showed no differences. Anti-myosin staining was significantly reduced in all compartments. The expression levels of growth factors were altered as well. Apoptosis was increased in the right atrioventricular mesenchyme, with no changes in the working myocardium. These data suggest that changes in cardiomyocyte proliferation play a significant role in the pathogenesis of HLHS.
Sedmera et al. (Tue,) studied this question.