Molecular Phenotype of the Developing Heart with a Congenital Anomaly
A high prevalence of congenital heart malformations accounts for defects in the outflow tract accompanied with right ventricular hypertrophy (KVH), such as in case of tetralogy of Fallot (ToF) and in pulmonary atresia (PA) with a ventricular septal defect (VSD). The etiology and contributing molecular events in cardiovascular malformations are poorly understood. These patients require primary corrective surgical repair at young age, which is now a treatment of choice where closing of the VSD and removing the right ventricular outflow tract obstruction are performed. In the past years, we have been investigating the myocardial molecular phenotype at various stages of KVH in ToF and PA/VSD. In the study, summarised in this chapter, we assessed the surface area of cells in right ventricular biopsies and examined the myocardial fibrosis by measuring total collagen and fibronectin expression both at mRNA and protein level. Assessment of myocardial cell hypertrophy revealed significantly enlarged (p < 0.01) cells in adult (>25yr.) patients with ToF as compared to age matched controls. Immunohistochemical staining of biopsies for collagen followed by video image analysis showed significantly enhanced interstitial collagen levels in adult ToF as compared to young (<2yr.) controls (p < 0.05) and young ToF patients (p < 0.01). In PA/VSD patients however, interstitial collagen levels did not change as compared to respective age matched controls. Interestingly, peri-vascular collagen deposition increased in young ToF patients as compared to young and adult controls. In contrast, the staining levels of both collagens and fibronectin were lower in the PA/VSD patients as compared to respective controls. Interstitial expression of fibronectin in ToF patents remained unchanged. RT-PCR analysis for collagen la, collagen III and fibronectin expression levels in PA/VSD patients showed only higher collagen III mRNA expression in PA/VSD patients as compared to respective age matched controls. We conclude that the enhanced myocyte size and increased extracellular matrix deposition and disarray of collagen and fibronectin are signs of fibrosis during RVH that contribute to diminished right ventricular function in patients with ToF and PA/VSD.
Key wordstetralogy of Fallot right ventricle hypertrophy pulmonary atresia and fibrosis
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