Fibrosis-Related Gene Expression in Single Ventricle Heart Disease

J Pediatr. 2017 Dec:191:82-90.e2. doi: 10.1016/j.jpeds.2017.08.055. Epub 2017 Oct 16.


Objective: To evaluate fibrosis and fibrosis-related gene expression in the myocardium of pediatric subjects with single ventricle with right ventricular failure.

Study design: Real-time quantitative polymerase chain reaction was performed on explanted right ventricular myocardium of pediatric subjects with single ventricle disease and controls with nonfailing heart disease. Subjects were divided into 3 groups: single ventricle failing (right ventricular failure before or after stage I palliation), single ventricle nonfailing (infants listed for primary transplantation with normal right ventricular function), and stage III (Fontan or right ventricular failure after stage III). To evaluate subjects of similar age and right ventricular volume loading, single ventricle disease with failure was compared with single ventricle without failure and stage III was compared with nonfailing right ventricular disease. Histologic fibrosis was assessed in all hearts. Mann-Whitney tests were performed to identify differences in gene expression.

Results: Collagen (Col1α, Col3) expression is decreased in single ventricle congenital heart disease with failure compared with nonfailing single ventricle congenital heart disease (P = .019 and P = .035, respectively), and is equivalent in stage III compared with nonfailing right ventricular heart disease. Tissue inhibitors of metalloproteinase (TIMP-1, TIMP-3, and TIMP-4) are downregulated in stage III compared with nonfailing right ventricular heart disease (P = .0047, P = .013 and P = .013, respectively). Matrix metalloproteinases (MMP-2, MMP-9) are similar between nonfailing single ventricular heart disease and failing single ventricular heart disease, and between stage III heart disease and nonfailing right ventricular heart disease. There is no difference in the prevalence of right ventricular fibrosis by histology in subjects with single ventricular failure heart disease with right ventricular failure (18%) compared with those with normal right ventricular function (38%).

Conclusions: Fibrosis is not a primary contributor to right ventricular failure in infants and young children with single ventricular heart disease. Additional studies are required to understand whether antifibrotic therapies are beneficial in this population.

Keywords: collagen; congenital heart disease; hypoplastic left heart syndrome; matrix metalloproteinases (MMPs); pediatric heart failure; tissue inhibitors of metalloproteinases (TIMPs).

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Child
  • Child, Preschool
  • Down-Regulation*
  • Female
  • Fibrosis
  • Genetic Markers
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / pathology*
  • Heart Failure / congenital
  • Heart Failure / genetics
  • Heart Failure / pathology
  • Heart Ventricles / abnormalities*
  • Heart Ventricles / pathology*
  • Humans
  • Hypoplastic Left Heart Syndrome / genetics
  • Hypoplastic Left Heart Syndrome / pathology
  • Infant
  • Infant, Newborn
  • Male
  • Myocardium / pathology*
  • Real-Time Polymerase Chain Reaction


  • Genetic Markers