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.