Colin Chan

Introduction. Congenital heart block (CHB) is an autoimmune disorder with high fetal morbidity and mortality.¹ CHB is caused by placental transcytosis of maternal IgG antibodies that act against ribonucleic complex Ro and La leading to pathogenic inflammation in fetal hearts culminating in complete heart block.^2,3 Most children require a pacemaker and are at constant risk for sudden death related to asystole or pause-dependent torsades de pointes.¹ While majority cases of CHB are associated with maternal anti Ro/La antibodies, CHB only occurs in about 2-5% of positive IgG mothers. As such, it is thought that while the maternal autoantibodies are necessary, they are not sufficient to cause CHB on its own.^2-4 Type I Interferons (IFN), through its activation of sialic acid-binding immunoglobin-type lectins (SIGLEC1) type macrophages, have been proposed as a possible mediator of CHB inflammation due to its well-established role in similar autoimmune diseases in systemic erythematous lupus and primary Sjogren’s syndrome.¹ Methods. Type I IFN-α and SIGLEC1 signature were monitored in blood of women with CHB children and positive Ro/La autoantibodies and compared to women without CHB children but positive Ro/La autoantibodies.¹ Transcriptomes of electively terminated CHB hearts tissue was analyzed to compare gene expression levels.⁵ Macrophages from CHB hearts were analyzed to compare IFN-α and SIGLEC1 levels to control macrophages.⁶ A clinical trial using hydroxychloroquine, a known inhibitor of macrophage toll-like receptor, was used to treat CHB recurrency.⁷ Results. Maternal blood with positive Ro/La autoantibodies and CHB children had higher levels of IFN-α and SIGLEC1 compared to control.¹ In cardiac tissue of electively terminated CHB hearts, transcriptomes showed high levels of IFN type genes and lower levels of anti-fibrotic genes.⁵ Within the macrophage transcriptomes, both IFN-α and SIGLEC1 showed significantly higher expressions in macrophages from CHB hearts.⁶ Hydroxychloroquine trials showed reduction of CHB recurrency by more than 50% in mothers who took the treatment throughout the entire pregnancy. Conclusion. Type I IFN plays a critical role in activating SIGLEC1 positive macrophages to induce fibrosis of fetal cardiac tissue in CHB. When SIGLEC1 positive macrophages interact with the maternal IgG Ro/La immune complexes through its TLRs, additional pro-inflammatory cytokines in addition to more type I IFN are secreted causing recruitment of additional mononuclear cells leading to ultimate fibrosis of fetal cardiac tissue^1,5,6 Treatments such as hydroxychloroquine that target the IFN pathway have shown promise and continued research into this area of therapeutics could reduce CHB prevalence.

1.  Lisney AR, Szelinski F, Reiter K, Burmester GR, Rose T, Dörner T. High maternal expression of SIGLEC1 on monocytes as a surrogate marker of a type I interferon signature is a risk factor for the development of autoimmune congenital heart block. Ann Rheum Dis. 2017;76(8):1476-1480. doi:10.1136/annrheumdis-2016-210927
2. Steinberg L. Congenital Heart Block. Cardiac Electrophysiology Clinics. 2021;13(4):691-702. doi:10.1016/j.ccep.2021.07.006
3. Wainwright B, Bhan R, Trad C, et al. Autoimmune-mediated congenital heart block. Best Practice & Research Clinical Obstetrics & Gynaecology. 2020;64:41-51. doi:10.1016/j.bpobgyn.2019.09.001
4. Manolis AA, Manolis TA, Melita H, Manolis AS. Congenital heart block: Pace earlier (Childhood) than later (Adulthood). Trends in Cardiovascular Medicine. 2020;30(5):275-286. doi:10.1016/j.tcm.2019.06.006
5. Clancy RM, Markham AJ, Jackson T, Rasmussen SE, Blumenberg M, Buyon JP. Cardiac fibroblast transcriptome analyses support a role for interferogenic, profibrotic, and inflammatory genes in anti-SSA/Ro-associated congenital heart block. American Journal of Physiology-Heart and Circulatory Physiology. 2017;313(3):H631-H640. doi:10.1152/ajpheart.00256.2017
6. Clancy RM, Halushka M, Rasmussen SE, Lhakhang T, Chang M, Buyon JP. Siglec-1 Macrophages and the Contribution of IFN to the Development of Autoimmune Congenital Heart Block. JI. 2019;202(1):48-55. doi:10.4049/jimmunol.1800357
7. Izmirly P, Kim M, Friedman DM, et al. Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti-SSA/Ro-Positive Mothers. Journal of the American College of Cardiology. 2020;76(3):292-302. doi:10.1016/j.jacc.2020.05.045