Neointimal hyperplasia in systemic-to-pulmonary shunts of children with complex cyanotic congenital heart disease

Abstract

OBJECTIVES Neointimal hyperplasia might affect systemic-to-pulmonary shunt failure in infants with complex cyanotic congenital heart disease. The aim of this study was to elucidate histopathologic changes of polytetrafluorethylene shunts and to determine whether increased neointimal formation is associated with early interventions comprising balloon dilatation, stent implantation and shunt revision. Further, we intended to identify clinical factors associated with increased neointimal proliferation. METHODS Removed shunts were processed for histopathological analysis. Slides were stained with Hematoxylin/Eosin and Richardson. Immunohistochemistry was performed with anti-alpha-smooth muscle-actin and anti-CD68. Non-parametric analysis and univariable regressions were performed to identify clinical factors associated with neointimal hyperplasia and shunt stenosis. RESULTS Fifty-seven shunts (39 modified Blalock-Taussig anastomosis, 8 right-ventricle to pulmonary-artery anastomosis, 10 central shunts) were analyzed. Area of neointimal proliferation within the shunt was in median 0.75 mm2 [Interquartile range, 0.3 –1.57 mm2] and relative shunt stenosis in median 16.7% [Interquartile range, 6.7–30.8%]. Neointimal hyperplasia and shunt stenosis correlated with each other and were significantly greater in the group that required early interventions and shunt revision. Univariable linear regression identified smaller shunt size and lower acetylsalicylic acid dosage as factors to be associated with greater neointimal proliferation and shunt stenosis. CONCLUSIONS In infants with complex cyanotic congenital heart disease, neointimal hyperplasia in systemic-to-pulmonary shunts is associated with early interventions comprising balloon dilatation, stent implantation and shunt revision. Smaller shunt size and lower aspirin dosage are associated with increased neointimal proliferation.

EGFR and MMP-9 are associated with neointimal hyperplasia in systemic-to-pulmonary shunts in children with complex cyanotic heart disease

“…Neointimal hyperplasia in systemic-to-pulmonary (SP) shunts has recently been associated with interstage morbidity in children with complex and congenital heart defects (Kottmann et al 2022). Understanding the complex pathophysiology of neointimal formation could identify potential drug targets to reduce cardiovascular interventions in SP shunts in this critical ill population.…”

“…Interstage mortality of these infants remains high and is directly in uenced by the patency of these grafts, which are at risk of obstruction due to neointimal formation or thrombosis (Agarwal et al 2017;Fenton et al 2003;Monagle 2005;Vitanova et al 2019). Neointimal hyperplasia is associated with interstage morbidity in children with complex and congenital heart disease (Kottmann et al 2022) and is caused by the foreign body response, which involves the in ltration of immune cells, the formation of granulation tissue and the generation of a brous capsule around foreign material. The resulting pathological vascular remodeling and tissue deposition within the shunt lead to gradual shunt dysfunction (Lee and Ul Haq 2015).…”

EGFR and MMP-9 are associated with neointimal hyperplasia in systemic-to-pulmonary shunts in children with complex cyanotic heart disease

“…Two categories of clusters were formed based on the shunt stenosis caused by neointimal hyperplasia (Group 1 = 0–39.9% lumen stenosis ( n = 26); Group 2 = ≥ 40% lumen stenosis ( n = 5)). A cut-off of 40% was chosen based on a preliminary analysis suggesting clinical relevance in that a shunt stenosis of greater than 40% was associated with an increased risk for cardiac interventions, such as balloon dilatation or shunt stenting (Kottmann et al 2022 ). PLINK calculated the SNPs that significantly differed in the two groups ( p -value < 0.01, Chi’s Square).…”

“…Interstage mortality of these infants remains high and is directly influenced by the patency of these grafts, which are at risk of obstruction due to neointimal formation or thrombosis (Agarwal et al 2017 ; Fenton et al 2003 ; Monagle 2005 ; Vitanova et al 2019 ). Neointimal hyperplasia is associated with interstage morbidity in children with complex and congenital heart disease (Kottmann et al 2022 ) and is caused by the foreign body response, which involves the infiltration of immune cells, the formation of granulation tissue, and the generation of a fibrous capsule around foreign material. The resulting pathological vascular remodeling and tissue deposition within the shunt lead to gradual shunt dysfunction (Lee and Ul Haq 2015 ).…”

“…Since the pathophysiology of neointimal hyperplasia in SP shunts of infants with complex congenital heart disease remains largely unknown, we aimed to identify the role of EGFR and MMP-9 in the formation of neointima in SP shunts. Previous research has suggested that acetylsalicylic acid (ASS) might play a role in neointimal growth (Kottmann et al 2022 ). Therefore, we also examined the possible association between ASA and expression of the two proteins.…”