Autoimmune associated congenital heart block: integration of clinical and research clues in the management of the maternal / foetal dyad at risk

Abstract

One of the strongest associations with autoantibodies directed to components of the SSA/Ro-SSB/La ribonucleoprotein complex is the development of congenital heart block (CHB) in an offspring, an alarming prospect facing 2% of primigravid mothers with these reactivities. This risk is 10-fold higher in women who have had a previously affected child with CHB. Anti-Ro/La antibodies are necessary but insufficient to cause disease. In vitro and in vivo experiments suggest that the pathogenesis involves exaggerated apoptosis, macrophage/myfibroblast crosstalk, TGFbeta expression and extensive fibrosis in the conducting system and in some cases surrounding myocardium. A disturbing observation is the rapidity of disease progression, with advanced heart block and life-threatening cardiomyopathy observed <2 weeks from normal sinus rhythm. Once 3rd degree (complete) block is identified, reversal has never been achieved, despite dexamethasone. Current strategies include the evaluation of an early echocardiographic marker of injury, such as a prolonged PR interval and the use of IVIG as a preventative measure for pregnancies of mothers with previously affected children.

Fig. 1

Histological evidence of increased apoptosis in conduction tissue from a foetus with congenital heart block (CHB). Shown are longitudinal sections through septum of a 22-week-old foetus with CHB. Apoptotic cells were identified by TUNEL fluorescein isothiocyanate staining (Left, upper) or TUNEL peroxidase (Left, lower). Apoptotic cells (brown nuclei) are interspersed with nonapoptotic cells (purple nuclei). For the 22 week foetus and a matched healthy heart, values (right) on the Y axis are the mean apoptotic index (AI), expressed as AI = (TUNEL-positive nuclei/total nuclei) × 100, where the total number of nuclei is the number of nonapoptotic nuclei plus the number of apoptotic (TUNEL-positive) nuclei. One hundred cells were counted in 3–5 fields for each cardiac section. RV, right ventricle; LV, left ventricle; CHB, congenital heart block. Reprinted from Rheum Dis Clin North Am, Vol. 30, Robert M. Clancy & Jill P. Buyon, More to death than dying: apoptosis in the pathogenesis of SSA/Ro-SSB/La-associated congenital heart block, pages 589–602, 2004, with permission from Elsevier.

Fig. 2

Proposed pathologic cascade from inflammation to fibrosis whereby maternal antibodies initiate events that lead to a persistent myofibroblast, a phenotype that is associated with scarring.

Fig. 3

Outcome versus history of pregnancy for the PR Interval and Dexamethasone Evaluation (PRIDE) study (98 patients). The study was initiated to test the hypothesis that the mechanical PR interval serves as a biomarker to detect early injury in CHB.