Role of cilia and left-right patterning in congenital heart disease

Abstract

A central role for cilia in the pathogenesis of congenital heart disease was uncovered by our large-scale mouse mutagenesis screen for mutations causing congenital heart disease. This is supported by human clinical studies, which showed a high prevalence of ciliary dysfunction and respiratory symptoms and disease in patients with congenital heart disease. Our mouse studies indicate this involves essential roles for both primary and motile cilia in the pathogenesis of congenital heart disease. As laterality defects were also observed with high prevalence among the congenital heart disease mutants, this further suggested an important role for left-right patterning in the pathogenesis of congenital heart disease. This finding is reminiscent of the high prevalence of heterotaxy among human fetuses with congenital heart disease, indicating the fetal mouse screen may provide a window into the unborn human fetal population. Clinically, congenital heart disease patients with ciliary dysfunction were found to have more respiratory symptoms and disease, a finding with significant clinical implications, as congenital heart disease patients undergoing surgical palliation often have respiratory complications with high morbidity. While this is usually attributed to the heart disease, we propose this may involve intrinsic airway clearance deficits from ciliary dysfunction. Thus the presurgical screening of congenital heart disease patients for respiratory ciliary dysfunction may provide opportunities to provide perioperative pulmonary therapy to enhance airway clearance for at-risk patients. Such change in the standard of care may improve outcome, especially for those congenital heart disease patients who must endure multiple rounds of cardiac surgeries.