Mechanisms in the Pathogenesis of HLHS

Principal Investigator(s):

  • Dr. Pirooz Eghtesady
  • Washington University


Project Abstract:

Each year, congenital heart disease affects 1 out of 100 children born in the United States. Among these, hypoplastic left heart syndrome (or HLHS) is perhaps the most severe and devastating. Parents of these otherwise normal infants have the difficult task of choosing between “compassionate care” (i.e., doing nothing) or heart transplantation or multiple, palliative open-heart surgeries. These have an overall associated 40%-58% mortality, high costs (~$200,000/child with HLHS in 2003) and potentially result in substantial developmental delay.  Although tremendous resources are devoted to its medical management, what causes HLHS is unknown. In addition, by analyzing cases of HLHS in the Pediatric Hospital Information Systems database (1996–2006) from 24 children’s hospitals across the United States we found an increase in prevalence of HLHS over that decade. The long-term goal of the proposed research would have great significance and relevance to public health by preventing and/or defining alternative or improved treatments for babies with HLHS.

At present it is unclear what causes the development of HLHS in babies during pregnancy. We propose that HLHS is an expression of a form of rheumatic heart disease in the fetus. Rheumatic heart disease is serious consequence of pharyngeal group A ß-hemolytic streptococcal infection, most commonly in the form of “strep throat”, and is the leading cause of acquired heart disease. We believe that in a similar way, in HLHS, maternal antibodies produced in response to prior and recurrent strep infection cross the placenta and damage the fetal heart. These steps occur only in those moms/babies who are genetically susceptible (see Figure below).

The main steps in our proposed theory are: Step (1) strep throat infections of the mother; Step (2) transfer of antibodies to the baby during pregnancy leads to Step (3) ONLY in susceptible individuals only there is development of the heart defect characteristic of HLHS – small left side structures of the baby’s heart.

Our preliminary data support our theory and show not only a strong association between HLHS and prior maternal strep infection, but also elevated blood levels of certain antibodies in these same mothers, which are normally found in patients with rheumatic heart disease. These antibodies specifically recognize and react against heart tissue. Injury to the unborn baby caused by the mother’s antibodies has been reported for other newborn diseases, including one in which the heart rhythm is disturbed (congenital heart block). The goal of this study is to develop a clinically relevant animal model of HLHS based on our novel theory that there is a potential association between pharyngeal streptococcal infection or “strep throat” in mothers and the development of HLHS in their babies. Lack of an animal model has limited progress in HLHS research. We plan to develop a model of HLHS in rats. For these experiments, we will “vaccinate” female rats with strep and study their offspring to see if they develop HLHS (and the same harmful antibodies described before). Development of an animal model of HLHS is essential to furthering the efforts to improve its understanding as well as potentially identify therapeutic targets, and may provide important clues useful for treating HLHS in humans.