Hypoplastic left heart syndrome: Rheumatic heart disease of the fetus?

Hypoplastic left heart syndrome (HLHS) accounts for nearly 25% of deaths among neonates with congenital heart disease. The essential feature of HLHS is a small left ventricle (LV) incapable of supporting the circulation. The etiology of HLHS is unknown. A hypothesis is proposed implicating an immune mechanism involving maternal antibodies produced in response to pharyngitis caused by group A β-hemolytic streptococci (GABHS) ("strep throat"). After crossing the placenta, the antibodies injure the developing fetal heart, leading to HLHS either because of direct injury to the LV or secondary to reduced blood flow through affected aortic and mitral valves. Analogy is drawn to rheumatic heart disease (RHD), a known sequela of strep throat. In RHD a misdirected immune response originally intended for GABHS leads to cardiac injury through "molecular mimicry"; the normal heart antigens supposedly mimic the GABHS antigens. A similar pathogenesis is proposed for HLHS and related heart defects. HLHS may represent an extreme form of injury, while a milder insult may present as only mild aortic stenosis or a bicuspid aortic valve, conditions with wide prevalence among the general population. The injury may indeed superimpose on many other congenital heart defects, leading to a variable presentation of these other diseases. Beside remarkable likenesses between HLHS and RHD, the hypothesis is also supported by increasing evidence for the role of deleterious transplacental antibodies in the pathogenesis of other fetal diseases. Implications for other congenital heart diseases and the broader picture of global public health are discussed.