Respiratory Ciliary Dysfunction and Pulmonary Risks in Congenital Heart Disease Patients
Abstract
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
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510649
Entities
People
- Cecilia Lo
Organizations
- United States Army
- University of Pittsburgh