Right Atrial Myocardial Remodeling in Children With Atrial Septal Defect Involves Inflammation, Growth, Fibrosis, and Apoptosis

Abstract

Introduction: Myocardial remodeling due to large atrial septum defect (ASD) is macroscopically characterized by dilation of the right-sided cardiac cavities secondary to volume overload, the cellular mechanisms of which are not yet understood. We postulated that inflammation, fibrosis, and cell death are actors of right atrial remodeling secondary to ASD. Patients and Methods: In 12 children with large ASD (median age: 63 months), expression of genes coding for proteins involved in the response to cell stress and-protection, inflammation, growth and angiogenesis, fibrosis, and apoptosis was assessed by RT-PCR in right atrial myocardial biopsies taken during cardiac surgery. The presence of cytokines in myocardial cells was confirmed by immunohistochemistry and effective apoptosis by TUNEL assay. Results: In all patients investigated, a cellular response to early mechanical stress with the initiation of early protective mechanisms, of inflammation (and its control),-growth, and-angiogenesis, of fibrosis and apoptosis was present. The apoptotic index assessed by TUNEL assay averaged 0.3%. Conclusions: In children with large ASD, macroscopic right atrial remodeling relates to cellular mechanisms involving the expression of numerous genes that either still act to protect cells and tissues but that also harm as they initiate and/or sustain inflammation, fibrosis, and cell death by apoptosis. This may contribute to long term morbidity in patients with ASD.

Accelerated Cardiac Aging in Patients With Congenital Heart Disease

“…Changes in the cytokine profile are acknowledged as part of a compensatory response to the hemodynamic stress in a variety of CHD, including septal defects and shunts. Cytokine response to mechanical stress encompasses high levels of necrosis factor (TNF)-a and acute-phase reactants ( 121 , 122 ), which is intended to facilitate a compensatory structural remodeling ( 123 ).…”

Myocardial Expression of Estrogen Receptor-mRNA Is Associated With Lower Markers of Post-operative Organ Damage in Young Patients With Congenital Cardiac Defect

“…Furthermore, the concentrations of mRNA coding for the different proteins tested correlated well with each other, suggesting an interplay between ERs and the mediators of inflammation, growth, fibrosis, and stress response of myocardial cells and therefore the participation of ERs in the complex mechanisms of myocardial remodeling in patients with congenital cardiac disease ( 13 ). In particular, the relationship between the expression of ER-mRNA and BNP-mRNA might indicate a role of hemodynamic overload in the upregulation of ERs as it has been shown in adult patients with aortic stenosis ( 12 ).…”

“…In adults, the expression of ERs is increased in pressure-loaded myocardium ( 12 ), while in children with congenital cardiac disease, hemodynamic overload induces the expression of genes involved in early stress response, inflammation, apoptosis, and fibrosis ( 13 ).…”

Congenital Heart Disease: An Immunological Perspective

“…Children born with an atrial septal defect (ASD) undergo cardiac remodeling to compensate for the flow of blood from the left atrium to right atrium. This leads to the presence of markers for mechanical stress, inflammation, and remodeling ( 28 ), including tumor necrosis factor (TNF)-α ( 27 ). Similar changes in inflammatory cytokines and acute-phase reactants are seen with ventricular septal defects (VSDs) and other left to right shunts ( 6 , 16 ).…”