The pathogenesis of congenital heart block (CHB) remains unclear. The occurrence rate of neonatal CHB is low, even in murine models of lupus erythematosus. The assessment of heart block in murine maternal lupus models by measuring atrioventricular conduction in neonatal offspring is potentially confounded by fetal wastage. We therefore sought to develop a murine CHB model with a superior immune response and to use embryonic Doppler echocardiography to observe conduction system damage in the fetus. Mature 8-wk-old female C3H/HeJ mice (n ϭ 43) were immunized with 60 kD Ro, 48 kD La, or recombinant calreticulin autoantigens. ELISA confirmed that significant serum autoantibodies developed in all three immunized groups when compared with controls. Starting at 13 d of gestation, a significantly lower fetal heart rate (HR) and a higher percentage of fetal bradycardia/atrioventricular block (AVB, nonadvanced second degree) were observed in all immunized groups, compared with controls. There was 9 -18% nonadvanced second-degree AVB in immunized groups and 0% in controls at Ͻ18 d of gestation. Neonatal electrocardiograms demonstrated only 1°AVB in immunized groups. Maternal immunization with 60 kD Ro, 48 kD La, or recombinant calreticulin autoantigens resulted in AVB in a significant percentage of fetuses, however, lesser degrees of AVB were seen at birth. Significant fetal bradycardia and AVB may be missed by assessment only at birth in murine models of CHB due to fetal wastage. (Pediatr Res 57: 557-562, 2005) Abbreviations AVB, atrioventricular block CHB, congenital heart block HR, heart rate A century has passed since the first description of CHB in the medical literature (1). The disease is defined as the demonstration of the establishment of heart block "in a young patient by graphic records" and "there must be evidence of the existence of the slow pulse at an early age and absence of a history of any infection which might cause the condition after birth" (2). The ECG criteria specify that atrial and ventricular activity are completely dissociated, the ventricular rate is slower, and no captured beats are present. This definition remains as the standard for the diagnosis of CHB.The pathogenesis of CHB remains unclear. The association of the disease with maternal autoantibodies has been recognized since 1977 (3,4). Immune-mediated damage to the fetal conduction system by maternal autoantibodies crossing the placenta in early to mid-gestation has been proposed (5,6) but not confirmed as the mechanism of injury in CHB. Serological studies have demonstrated an association with anti-Ro and anti-La antibodies that is sensitive but not specific for the development of CHB (5,7-10). It has also been suggested that there is an association between anti-calreticulin antibodies and CHB (11).Research into the pathogenesis of CHB has been hindered by its low incidence in infants (1 in 14,000 births) (12) and by the absence of a naturally occurring animal model. Therefore, experimental models have been developed, including neonatal ...