An Investigation Into The Potential Roles Of Vasoactive Intestinal Peptide And Substance P In The Pathophysiology Of Plastic Bronchitis And Protein Losing Enteropathy In Children With Palliated Single Ventricle Physiology

Protein losing enteropathy (PLE) has emerged as an increasingly common complication of single ventricle palliation in children born with cyanotic congenital heart disease. This entity becomes manifest months or years after the modified Fontan operation and is thought to affect 5-15% of all patients with Fontan physiology. Patients with PLE often suffer from symptoms related to severe hypoproteinemia and intestinal malabsorption, including edema, ascites, pleural and pericardial effusions, chronic diarrhea and poor growth. Mortality is strikingly high, with only 50% of patients surviving for more than 5 years following diagnosis. The pathophysiology is poorly understood and several theories are presented as possible mechanisms which includes: 1) chronic low cardiac output and intestinal injury leading to loss of intestinal integrity, 2) chronic intestinal inflammation leading to loss of intestinal integrity, 3) chronic elevated portal venous pressure with intestinal injury leading to loss of intestinal integrity. Treatment is sporadically successful and has included 1) creating a fenestration between the Fontan pathway and pulmonary venous atrium which decreases Fontan pressure and increases cardiac output, 2) chronic use of unfractionated or low molecular weight heparin to reconstitute the intestinal basement membrane, 3) Use of oral steroids to reduce intestinal inflammation, 4) Use of pulmonary vasodilators to reduce Fontan pressure and increase cardiac output 5) implantation of pacemakers to treat sinus node dysfunction and improve cardiac output, 6) heart transplantation. Short of cardiac transplantation, no treatment of PLE, including efforts to change systemic and/or gastrointestinal hemodynamics, is routinely successful. Thus, it appears that the etiology of PLE is more complex than simply "high venous pressure in the gut" as has been previously believed.

A second entity seen in patients after modified Fontan procedure is "plastic bronchitis" (PB). This is a highly morbid clinical picture of persistent production of high mucoprotein-containing airway secretions that causes severe airway obstruction leading to increased work of breathing, V/Q mismatch and progressive respiratory failure leading to death. The etiology of plastic bronchitis is not understood at all and beyond supportive, palliative measures such as lung lavage, there is no current treatment for plastic bronchitis.

VIP and Substance P are both small peptides with significant autocrine and paracrine signaling ability. The role of VIP in controlling gut protein and solute secretion has been understood for approximately 20 years. The clinical entity where this has been best described are in rare "VIP-omas" and some other chromophore secreting gut tumors where massive amounts of VIP are secreted by the tumor and overwhelm the body's normal ability to clear VIP through cleavage by neutral endopeptidases in the pulmonary endothelium.

Until very recently, Substance P was known primarily for its role in peptidogenic signaling in sensory pathways. As described below, an important and previously not understood role for Substance P in the control of human airway mucus secretion has recently been described.

Scientific Basis for Proposed Research: