Mechanisms in the Pathogenesis of HLHS

Lay Summary: The study funded by Saving Tiny Hearts foundation supported research by Dr. Eghtesady’s group to develop a clinically relevant animal model of Hypoplastic Left Heart Syndrome (or HLHS), a congenital heart disease. We were successful in establishing a rodent model using data from our clinical studies in pregnant mothers of HLHS babies. These studies showed that one third of mothers of HLHS babies have high circulating titers of certain antibodies, some of which specifically react against heart tissue. In particular, we found higher serum titers of cardiac myosin in HLHS mothers compared with mothers of babies with other congenital heart diseases or healthy controls. We studied the effects of cardiac myosin in the animal model. Furthermore, the model allowed us to test our hypothesis that a potential mechanism(s) that induces the pathogenic features of this devastating heart defect are initiated in response to an immune reaction in the pregnant mothers. We found that transplacental passage of anti-cardiac myosin antibodies produced in the mother could induce an HLHS-type phenotype in some of their offspring. These findings suggest a new concept in the pathogenesis of HLHS and were published recently (Cole CR et. al. Congenital heart Disease linked to maternal autoimmunity against cardiac myosin The Journal of Immunology, 2014, 192:4074-4082). Structural congenital heart disease has not previously been linked to autoimmunity although anti-cardiac myosin autoantibodies are linked to several autoimmune disease of the heart, including autoimmune myocarditis. Evidence of an immune-mediated mechanism in the pathogenesis of congenital heart diseases has significant implications for future diagnosis and treatment of these heart defects.