Abstract P114: Evidence of Transplacental Antibody Transfer in Proposed Animal Model for Hypoplastic Left Heart Syndrome

Abstract

Background: The pathogenesis of Hypoplastic Left Heart Syndrome (HLHS), a congenital heart disease with significant morbidity and mortality, remains unknown. We previously proposed a hypothesis wherein HLHS represents a type of rheumatic heart disease in the fetus; trans-placental passage of maternal anti-strep or anti-cardiac myosin (CM) antibodies are postulated to play a key role in the pathogenesis of disease. This is a first report of an animal model that we have developed to assess our hypothesis. Methods: Female Lewis rats (∼ 8 weeks old) were immunized with either streptococcal antigen M type 5 S. pyogenes (PepM5; n=6), rat CM (n=8) or saline (controls; n=5) with three booster injections administered at 2-week intervals. Serum titers of acquired PepM5 or CM antibodies were determined by ELISA assays every 7–14 days. No boosters were administered during gestation. Trans-uterine echocardiography was performed near term (E19-21) to determine fetal number and viability then cesarean section was performed under anesthesia to deliver the progeny. Maternal and fetal serum and hearts were harvested for analysis. Results: All rats immunized with PepM5 had elevated serum anti-PepM5 antibody titers (>1:12800) and two of these animals also had elevated anti-CM titers (1:800). The offspring of these PepM5 immunized animals had elevated anti-PepM5 antibody titers (≥1:6400), but no CM elevation. Rats immunized with CM had a variable response ranging from anti-CM titers of 1:1600 to >1:12800; there were two non-responders. Their fetuses had anti-CM titers that ranged from 1:100 to 1:800. None of the controls had detectable serum titers. Fetal CM titers of ≥1:200 correlate with maternal peak CM titers of ≥1:6400 and/or maternal harvest titers of ≥1:800. Thus far, 6 of the CM treated fetuses have evidence of left-sided morphologic abnormalities along a variable spectrum; all of these fetuses had CM titers of ≥1:200. Conclusion: We have documented maternal antibody response and trans-placental antibody transfer from maternal rats immunized with CM or PepM5 prior to pregnancy. Anti-CM antibody does not cross the placental as readily as PepM5. Preliminary histologic findings demonstrate probable HLHS phenotype, which appears to correlate with fetal antibody titer.