CILIA AND CONGENITAL HEART DISEASE: WHAT IS THE CONNECTION?


Maliha Zahid, M.D., Ph.D., University of Pittsburgh, Pittsburgh, PA, USA

Motile cilia at the embryonic node and in the respiratory tract are required for left-right patterning and for muco-ciliary clearance from the respiratory tract, respectively. The heart is one of the most asymmetric organs in the body in order to support two separate circulation systems, the pulmonary and systemic circulation, in parallel. Hence defects in ciliary function could contribute to abnormal heart development resulting in congenital heart disease (CHD) as well as increased respiratory complications. This dual role is exemplified by patients with primary ciliary dyskinesia (PCD) in which patients have abnormal respiratory ciliary function leading to severe respiratory complications over time as well as ~50% of patients having complete reversal of visceral organ situs or situs inversus totalis.

Heterotaxy is characterized by randomized variation of left-right patterning in thoraco-abdominal visceral situs. We have shown that patients with heterotaxy and CHD have a high prevalence of ciliary motion abnormalities as demonstrated by abnormally low nasal nitric oxide (nNO) levels as well as high-speed video-microscopy of ciliated nasal epithelial tissue. These patients had increased respiratory symptoms reminiscent of PCD patients as well as were enriched for mutations in genes typically associated with PCD. We have also extended this work with studies on patients with transposition of the great arteries (TGA), both D- and L-TGA, and show that these patients, similar to heterotaxy patients, have a high prevalence of abnormal ciliary motion, borderline or PCD level abnormal nNO levels, increased respiratory symptoms as compared to TGA patients without ciliary motion abnormalities, and are enriched for novel or rare coding variants in the genes typically associated with PCD.

Our studies support a possible underlying mechanism leading to development of CHD involving mutations in genes relating to cilia structure or function. Screening patient with CHD for ciliary dysfunction might allow for prophylactic treatment of such patients in order to decrease their risk of post-operative infection and complications, which typically have been attributed to their CHD in the past.