Pathophysiology of autoimmune-associated congenital heart block

Congenital heart block (CHB), detected at or before birth, in a structurally normal heart, is strongly associated with autoantibodies to SSA/Ro-SSB/La ribonucleoproteins. The historical hallmark of CHB is complete atrioventricular block (AVB) which is irreversible. CHB occurs in 2% of primigravid mothers with anti-Ro/La antibodies, and in 20% of women who had a previous CHB offspring. Although not consistent, emerging clinical research expanded the spectrum of CHB to include lesser degrees of AVB, sinus bradycardia, QT prolongation, and late onset cardiomyopathy. Despite over a century since the discovery of CHB, the wide spectrum of CHB manifestation has posed a challenge in the elucidation of the true underlying pathogenesis and thus effective therapy. This review focuses on the recent knowledge and some hypotheses proposed for CHB pathogenesis, mainly the apoptosis and the Ca channel hypotheses. Experimentally, the first challenge in establishing the association between anti-Ro/La antibodies and CHB was overcome by the development of in vivo animal models for CHB. The incidence of conduction abnormalities in these models was fairly similar to that clinically, indicating that anti-Ro/La antibodies are essential but not sufficient for the disease expression. Subsequent in vitro experiments demonstrated that maternal anti-Ro/La antibodies directly cross react and inhibit Ca channels. This inhibition of Ca channels provides a logical explanation for the AVB, sinus bradycardia and perhaps even the cardiomyopathy because Ca channels play a vital role in the action potential genesis and conduction at the atrioventricular node and sinus node; and in excitation-contraction coupling of the developing heart, respectively. Because Ro/La antigens are intracellularly located, apoptosis was proposed as a process that helps Ro/La antigens translocate to the fetal cell surface membrane where they will be accessible to circulating maternal antibodies. In this regard, extensive evidence showed that in experimentally induced apoptotis in human fetal ventricular myocytes, the intracellular Ro/La antigens translocate to the sarcolemma, interact with anti-Ro/La antibodies, divert normal clearance of apoptotic cardiac myocytes by healthy cardiac myocytes toward clearance by professional macrophages with the release of the inflammatory and/or fibrosing cytokines which leads to fibrosis and permanent CHB. Despite the significant progress made in the last decade in the understanding of the CHB pathogenesis, the wide spectrum of CHB expression point to the multifactorial nature of CHB pathogenesis and to the need for continuous and joint international efforts to dissect the complex pathways involved in CHB.