Eghtesady Lab Research

Hypoplastic Left Heart Syndrome (HLHS) has the highest mortality amongst congenital heart diseases yet mechanisms leading to the pathogenesis of HLHS remain largely unknown. HLHS does not follow simple Mendelian genetics but exhibits rather “complex inheritance” with contributions from both genetic and environmental factors. A variety of causative factors have been implicated in the pathogenesis of HLHS, including abnormal intrauterine blood flow patterns, hereditary factors, intrauterine infection, and myocarditis or immunologic injury. A major focus of our research is to define mechanisms in the pathogenesis of HLHS. 

In some congenital heart diseases (e.g., congenital heart block), trans-placental passage of maternal IgG has been reported to affect the fetus.  In clinical studies we find high titers of anti-cardiac myosin (CM) autoantibodies in sera from mothers of babies with HLHS. Because cardiac myosin (CM) is a dominant autoantigen in autoimmune heart disease, we hypothesized that exposure of the developing fetal heart to maternal anti-CM antibodies might induce structural heart defects. Our overall hypothesis is that autoimmune mechanisms may play a role in development of HLHS.

Animal models of HLHS

            Limited access to tissues from patients with HLHS is a major obstacle to studies of this disease. Furthermore, a lack of animal models that recapitulate clinical HLHS has hindered investigations into the development of this complex disease.  Studies in rodents to identify genes that control heart development show that “some” LV hypoplasia can be induced during embryogenesis in certain knockout mouse models.  While many candidate genes may participate in developing the phenotype of LV hypoplasia, it is not clear which are critical for the appearance of the HLHS phenotype seen clinically. Furthermore, there is a fundamental difference in the development of LV hypoplasia during cardiac development or embryogenesis in previous animal models compared with that in humans.  Clinically, echocardiography and autopsy studies show LV hypoplasia is usually observed at 19-23 weeks gestation, subsequent to the formation of an apparently normal, 4-chambered heart (~8 weeks gestation). It is for these reasons that we propose alternate approaches to those used previously in developing an animal model of HLHS.

Using Lewis rats, an established model of CM-induced autoimmune heart disease, we tested our hypothesis that autoimmune mechanisms mediate the characteristic heart defects of HLHS in the developing fetus. In this model, we found that maternal immunization with CM induced an HLHS-like phenotype in susceptible offspring, following trans-placental passage of anti-heart antibodies, supporting our hypothesis.  Autoimmunity against the heart is a new concept in the pathogenesis of HLHS. Studies are ongoing to determine potential mechanisms in the development of HLHS in this model. In addition, a role for viral agents as causative pathogens is under investigation.

Dr Eghtesady is also involved in a number of clinical projects.