title: Immunohistologic evidence supports apoptosis, IgG deposition, and novel macrophage/fibroblast crosstalk in the pathologic cascade leading to congenital heart block.
abstract: OBJECTIVE
  To assess in vivo the pathologic cascade leading to fibrosis in congenital heart block (CHB). In vitro studies suggest that CHB is initiated via apoptosis, resulting in translocation of SSA/Ro and SSB/La antigens and surface binding by maternal autoantibodies. These opsonized cardiocytes are phagocytosed by macrophages, which secrete factors inducing fibrosis.
  
  
  METHODS
  Immunohistochemistry analysis was performed on formalin-fixed sections of 4 fetal hearts identified in utero as having CHB or isolated myocarditis; mothers had anti-SSA/Ro and anti-SSB/La antibodies.
  
  
  RESULTS
  Apoptosis was most extensive in fetuses dying early and most pronounced in regions containing conduction tissue. Deposition of IgG was observed in hearts from fetuses with CHB/myocarditis, but not in 3 control hearts, and was colocalized with apoptotic cells. Giant cells and macrophages (frequently seen proximal to IgG and apoptotic cells) were present in septal and thickened fibrous subendocardial regions, most apparent in the youngest fetuses. Septal tissue also revealed extensive areas of fibrosis and microcalcification in which a predominant smooth muscle actin (SMA)-positive infiltrate (myofibroblast scarring phenotype) was observed. In contrast, there were no macrophages or SMA-positive cells (other than those lining blood vessels) in septal tissue from control hearts, although rare macrophages were seen in the working myocardium.
  
  
  CONCLUSIONS
  In summary, findings in this unique autopsy material paralleled those in in vitro studies. These data support the notion of exaggerated apoptosis, probably due to ongoing inflammation caused by IgG binding and ingestion by macrophages. Transdifferentiation of cardiac fibroblasts to a scarring phenotype may be a pathologic process initiated by maternal antibodies, and persistence of this phenotype even after birth may relate to the progression of block seen in some infants postpartum.
authors.affiliation: Hospital for Joint Diseases, New York University School of Medicine, New York, New York 10003, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Clancy
authors.forename: Raj P
authors.initials: RP
authors.lastname: Kapur
authors.forename: Yair
authors.initials: Y
authors.lastname: Molad
authors.forename: Anca Dinu
authors.initials: AD
authors.lastname: Askanase
authors.forename: Jill P
authors.initials: JP
authors.lastname: Buyon
mesh_terms: D000328:Adult; D000974:Antibodies, Antinuclear / Q000032:analysis; D017209:Apoptosis / Q000276:immunology*; D001324:Autoantigens; D005260:Female; D005333:Fetus; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology*; D005355:Fibrosis; D006327:Heart Block / Q000151:congenital / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007231:Infant, Newborn; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D009205:Myocarditis / Q000151:congenital / Q000276:immunology / Q000473:pathology*; D011247:Pregnancy; D012261:Ribonucleoproteins / Q000276:immunology; D000097585:SS-B Antigen
chemical_list: D000974:Antibodies, Antinuclear; D001324:Autoantigens; D007074:Immunoglobulin G; D012261:Ribonucleoproteins; D000097585:SS-B Antigen; C035356:SS-A antibodies