Plastic Bronchitis and Protein Losing Enteropathy in Children With Single Ventricle Physiology
Plastic Bronchitis and Protein Losing Enteropathy in Children With Single Ventricle Physiology
The investigators are studying what causes Plastic Bronchitis and Protein Losing Enteropathy.
 The investigators think that these problems are from too much of two small proteins called
 Vasoactive Intestinal Peptide (VIP) and Substance P. VIP and Substance P are important
 proteins in the body that normally tell the body to make small amounts of fluid and they help
 the intestines work. Normally, VIP and Substance P are made in the intestines and then
 destroyed in the lungs after they do their normal work. The investigators think that kids who
 have Plastic Bronchitis and/or Protein Losing Enteropathy who also had the Fontan surgery
 might have too much VIP and Substance P in their bodies. The investigators think this causes
 too much fluid to go in the lungs and too much protein in the intestines.
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:

 The basis for this proposal arises from three, independent streams of research.

 1. First, extensive investigations in patients with increased portal venous pressures,
 usually from cirrhosis, has shown that increased portal venous pressures lead to
 significant increases in the excretion of a wide variety of small peptide signaling
 molecules. Included in these molecules are VIP, 5-HT and Substance P.As patients with
 Fontan physiology always have increased portal and gut venous pressures as a direct
 consequence of their anatomic palliation, it stands to reason that they should likewise
 have increased GI production of these signaling peptides.

 2. Second, clearance of gut-derived signaling peptides such as VIP, Substance P,
 angiotensin, brandykinin and others occurs primarily in the lungs via peptide cleavage
 catalyzed by the neutral endopeptidases, a class of enzymes heavily resident in the
 pulmonary circulation. The role of the neutral endopeptidases is to cleave and thus
 inactivate small peptides and 'protect" the systemic circulation from the plethora of
 vasoactive peptides that come from the systemic circulation. With respect to the
 potential role of VIP and/or Substance P in the etiology of PLE or PB, it is important
 to note that in patients with Fontan physiology current practice is to fenestrate the
 Fontan shunt to allow some portion of the systemic venous blood flow to bypass the
 lungs. Thus, any vasoactive / signaling peptides returning in the lower body systemic
 venous circulation will bypass the pulmonary clearance mechanisms in proportion to the
 degree of fenestration shunt at the moment. This pulmonary clearance bypass physiology
 is relative unique in medicine to older patients with Fontan-palliated congenital heart
 disease and thus may be, in part, the basis that PLE and PB are seen almost uniquely in
 Fontan patient.

 Further implicating derangements in active peptide clearance physiology in the etiology
 of PLE and PB is the fact that the classic member of the neutral endopeptidase class is
 (the misnamed) Angiotensin Converting Enzyme (ACE) , which actually cleaves a number of
 these small peptide signaling molecules including VIP and Substance P. Virtually all
 patients with Fontan physiology are on large doses of ACE-inhibitors to lower systemic
 afterload. Captopril-induced inhibition of VIP and Substance P inactivation would
 significantly increase already elevated systemic levels of these signaling peptides and
 further potentiate the etiology of PLE and PB in Fontan-palliated patients. Variations
 of neutral endopeptidase inhibitor ("ACE inhibitor" ) drug dosage and/or genotype
 variation of ACE which causes dramatically altered activity can in part explain the
 variable incidence of PLE and PB in Fontan physiology patients. In this study, the use
 and dose of ACE inhibitor that each patient is on will be recorded to see if there is a
 correlation between ACE inhibitor dose and measured VIP and Substance P levels. There
 are wide variation of ACE gene genomics that have been described for decades.
 Intriguingly, approximately 10-15% of all persons have a newly described genomic
 variation of the ACE gene which leads to profoundly reduced circulating levels of ACE
 and increased susceptibility to ACE inhibition and 10-15% of patients with Fontans
 develop PB or PLE.

 3. Lastly, very recent work has completely changed our understanding of the control of
 normal, basal mucus and solute secretion in the human airways and gut. Here-to-fore it
 was believed that cholinergic mechanisms controlled airway mucus secretion. This recent
 and still emerging work shows that in fact it is VIP and Substance P which act
 individually and synergistically in the control of both normal basal human airway mucus
 production and in regulating gut secretion. This very new work gives a unifying
 hypothesis to the seemingly disparate entities of PLE and PB: since Substance P and VIP
 control normal basal human airway secretion and stimulated human gut protein secretion,
 increases in pulmonary venous and/or gut arterial levels of these peptides can be the
 basis for PLE and PB. The GI, cardiac and pulmonary physiology and pharmacologic
 treatment of patients with fenestrated Fontans is a perfect setting for this interaction
 to occur.

 Taken in totality, these three streams of independent research give a strong basis for the
 hypothesis that the palliative physiology and pharmacologic treatment of Fontan patients
 leads to increased levels of VIP, Substance P or both, and they may be causal in the
 pathophysiology of PB and PLE.

 Rationale for Current Study Design and Subject Recruitment:

 Consistent with our Aims and Hypotheses, four patient groups will be studied: i)Fontan
 Physiology Patients with PLE and PB Patients ii) Fontan Physiology Patients without PLE and
 PB iii) Patients with Glenn Physiology Congenital Heart Disease and iv) Patients with 2
 ventricle physiology and an atrial septal defect who will serve as a Control group.
 Measurement of mixed venous and arterial levels of substance P and VIP in these 4 groups of
 subjects will allow us to determine the effects of elevated portal venous pressure on the
 production and clearance of substance P and VIP and well as the effects of altered
 hepatic-pulmonary blood flow on the clearance of substance P and VIP. This should allow us to
 determine if 1) systemic arterial levels of substance P and VIP levels are elevated in Fontan
 patients when compared to controls, and if elevated, 2) whether this is due to increased
 hepatic production, reduced pulmonary clearance or both. The rationale for the inclusion of
 each patient group is summarized below.

 Subjects with Fontan physiology (Group I and II) have a unique physiology where both the
 superior vena cava (SVC) and inferior vena cava (IVC) are connected directly to the pulmonary
 arteries thereby bypassing the heart. This palliation scheme allows for separation of the
 pulmonary and systemic circulations in patients with univentricular hearts and essentially
 eliminates cyanosis. These patients have non-pulsitile pulmonary artery flow with elevated
 central venous and portal venous pressures. Therefore, it is suspected that these patients
 will have increased production of substance P and VIP. In addition, a fenestration (or hole),
 is created between the Fontan conduit and the atrium at the time of Fontan surgery in order
 to lower central venous pressure and increase cardiac output by creating a right to left
 intracardiac shunt. It is suspected that these patients will have elevated systemic venous
 and arterial levels of vasoactive peptides as a result of 1) increased hepatic/gut
 production, 2) decreased pulmonary vascular clearance, and/or 3) intracardiac right to left
 shunting. Studying these subjects will allow us to determine how systemic venous and systemic
 arterial levels of Substance P and VIP are altered by the Fontan circulation. By comparing
 systemic arterial and venous levels of vasoactive peptides among control, Glenn physiology
 and Fontan physiology groups we hope to measure differences in vasoactive peptide levels that
 could be responsible for the development of PLE and PB in Fontan physiology patients.

 Subjects with Glenn physiology (Group III) have a unique physiology where hepatic venous and
 lower body venous blood returns to the heart and enters the systemic ventricle and is
 recirculated to the body after combining with the pulmonary venous blood. There is no direct
 connection thru the heart for hepatic venous blood to enter the pulmonary arteries.
 Therefore, it is suspected that these patients will likely have elevated systemic arterial
 circulating levels of Substance P and VIP due to intracardiac right to left shunting and
 reduced pulmonary clearance. However, since these patients typically have normal portal
 venous pressures, they are not thought to have increased production of these vasoactive
 peptides. In addition, these patients historically are not at risk for developing PLE and PB.
 Studying these subjects will allow us to determine how systemic venous and systemic arterial
 levels of Substance P and VIP are altered by the Glenn circulation. By comparing systemic
 arterial and venous levels of vasoactive peptides among control, Glenn physiology and Fontan
 physiology groups we hope to measure differences in vasoactive peptide levels that could be
 responsible for the development of PLE and PB in Fontan physiology patients.

 Control group subjects (Group IV) will have normal hepatic-pulmonary blood flow and normal
 portal venous pressures. An atrial septal defect allows for left to right shunting of blood
 thru the heart but does not typically result in elevated pulmonary artery or right
 ventricular pressures. These subjects will have normal flow of hepatic venous blood into the
 pulmonary capillary bed. Therefore they should have normal hepatic production and pulmonary
 clearance of substance P and VIP.
Inclusion Criteria:

 -  Fontan physiology patients with PB or PLE

 -  Fontan physiology patients without PB or PLE

 -  Glenn physiology patients

 -  2 ventricle patients with Atrial Septal Defect

 -  Patient has scheduled cardiac catheterization (of right and left heart)

 -  Age is greater than 6 months

 -  Weight is greater than 10kg

 Exclusion Criteria:

 -  Known Inflammatory Bowel Disease

 -  Hepatitis

 -  Congenital/ acquired liver disease

 -  Nephropathy

 -  Acute/ chronic renal dysfunction

 -  Active pulmonary hemorrhage

 -  Malignancy