Abstract 3500: Rescue and Worsening of Electrocardiographic Abnormalities in Two Experimental Transgenic Murine Models of Congenital Heart Block

Congenital Heart Block (CHB) is a passively acquired autoimmune disease associated with the transfer of maternal autoantibodies anti-SSA/Ro -SSB/La through the placenta causing AV block and sinus bradycardia. We previously established a murine model for CHB in which pups born to wild type (WT) mothers immunized with Ro and/or La recombinant proteins developed conduction abnormalities similar to those seen in the clinical settings and inhibited L-type Ca channels (LTCC) responsible for electrogenesis at the AV and SA node. Here, we hypothesized that overexpression of cardiac LTCC should prevent or reduce the electrocardiographic abnormalities seen in the pups, whereas LTCC knockout should exhibit severe conduction abnormalities and increased mortality. Transgenic (TG) mice overexpressing LTCC and LTCC knockouts were immunized with Ro and La antigens. Following the immunization and boosters, a high antibody titer was demonstrated both in mothers and pups. ECG parameters were measured from pups born to immunized and to WT mothers. Ca channel overexpressing pups had significantly lesser sinus bradycardia and AV block compared to their non-TG (NTG) litter mates and WT pups. Sinus bradycardia was seen in 10% (n= 90) of TG pups v.s. 19.7% in WT (n=76, p<0.05) vs. 22% NTG littermates (n=109, p<0.05) and AV block in 8.8% of TG (n=90) v.s. 25% in WT (n= 76, p<0.05) v.s. 27.5% in NTG (n=109, p<0.05). On the other hand, Ca channel knockout pups had a significantly higher sinus bradycardia and a higher percentage of AV bock; 100% in knockout pups (n=16, p<0.05), 42.3% in heterozygotes (n=52, p<0.05), and 18.2% in NTG (n=33, p<0.05). No electrocardiographic abnormalities were observed in control WT pups (nonimmunized). Cardiac specific overexpression of LTCC significantly rescues the incidence of AV block and sinus bradycardia in pups exposed to circulating maternal anti-Ro/La autoantibodies. Whereas exposure of LTCC knockout pups to anti-Ro/La autoantibodies significantly worsened the conduction abnormalities. This finding support the hypothesis that maternal antibodies’ inhibition of LTCC contributes to the development of CHB. Altogether the results are relevant for future novel therapies for CHB.