Structural defects involving the heart, also known as congenital heart defects (CHD), are the most common type of birth defects, seen in nearly 1% of live births. Some of the most complex and lethal CHD are associated with individuals who also have defects in the normal left-right asymmetric positioning of organs in the body. This stems from the fact that the heart is actually left-right asymmetric, and this asymmetry is essential for efficient oxygenation of blood. Interestingly, the specification of left-right asymmetry during embryonic development requires cilia, which are small hair-like protrusions projecting from the cell surface that can be motile or non-motile. In the early developing embryo, motile cilia are found in a region known as the embryonic node. The motile cilia at the node are required for normal left-right patterning, including the heart. Motile cilia also line the airway and through their coordinated beating action, play an essential role in maintaining lung health by allowing efficient removal of viruses, bacteria, and mucus from the airway. The connection between cilia, airway clearance, and left-right patterning is further indicated by the finding that patients with primary ciliary dyskinesia (PCD), a disease in which the airway cilia are immotile or have abnormal motion, can exhibit left-right patterning defects. PCD diagnosis can be made by obtaining tissue lining the nose and examining beating of the nasal cilia under the microscope. A second method is to measure the concentration of a gas, nitric oxide (nNO), in the nasal sinuses, as NO production requires motile cilia in the airway. Hence, PCD individuals typically have very low nNO.

We previously showed CHD patients with left-right patterning defects, also known as heterotaxy, have airway cilia motility defects. This likely reflects the common role of motile cilia in mediating left-right patterning and in cilia motility. We observed 42% of CHD patients with heterotaxy have airway ciliary dysfunction (CD) characterized by low nasal nitric oxide and abnormal ciliary motion. We recently expanded these studies to non-heterotaxy CHD patients and found a similar high prevalence of CD. We further showed CHD patients with or without heterotaxy both exhibited increased respiratory symptoms and disease.

Significantly, among CHD patients undergoing cardiac surgeries, more respiratory complications were observed in patients with airway CD. These findings provide the basis for the current study, which is designed to test the hypothesis that respiratory CD dysfunction in CHD patients can impair lung function, causing increased postsurgical respiratory complications and worse outcomes. In our proposed study, we will recruit patients with CHD undergoing cardiac surgery at Children's Hospital of Pittsburgh and Children's National Medical Center. This includes infants and children between 1 month to 6 years of age with heterotaxy or severe CHD of the single ventricle type, CHD types with very high mortality. We will measure nNO levels and also obtain nasal cells for microscopy to determine if there is CD. We will also assess lung function using three types of sophisticated measurements: mucus clearance scans, lung clearance index measurement, and pulmonary function test. Using these measures of lung function, we will be able to determine whether CD can compromise lung function.

To determine if CD can cause postsurgical respiratory problems and other acute health issues, we will collect data on various post-surgical parameters, such as length of intubation (how long a ventilator is required to support patient breathing), number of re-intubations, tracheostomies (placement of tube in the airways when prolonged ventilation is required), need for extracorporeal membrane oxygenation (a complex way to provide oxygen without a ventilator), length of intensive care unit stay, total hospitalization days, and rehospitalization. We will also track use of respiratory medications, respiratory infections, and other postsurgical adverse events, and assess the overall outcomes related to the lungs. We will also assess the overall health status and quality of life of the patients using clinically validated scales in longer term follow-up studies. This will include data collection at 1 month, 6 months, and 9 months after surgery to allow evaluation of possible changes in the functional status of the patient. Together, these studies will provide insight into the acute and long-term effects of CD and impaired lung function on postsurgical outcome in CHD patients. Overall, we expect to recruit approximately 100 patients for this study, which exceeds the 67 patients required to be 90% confident that we will be able to detect a modest difference in outcomes between patients with and without CD. These studies will be carried out by a large team of clinicians, scientists, engineer, and statistician to ensure the success of this study.

The results of this study will allow us to determine whether CD can impair lung function and cause more postsurgical complications and worsen outcome in CHD patients. Such findings would suggest there could be significant benefit with screening of CHD patients for airway CD prior to surgery and introducing pulmonary therapy to help reduce postsurgical respiratory complications. This could benefit not only infants and children with CHD, but this can help reduce healthcare costs for the Military Health System. One study showed an average bill of over $500,000 in the first 2 years for patients with a severe CHD known as hypoplastic left-heart syndrome. Hence, clinical outcomes research that can reduce postsurgical complications will have benefit not only for the patients and their families, but this can also help lessen the economic burden on the Military Health System.