Predictors of protein losing enteropathy after Fontan completion: An 8-year retrospective study at Sheikh Khalifa Medical City.

BACKGROUND: The Fontan procedure is the final stage of a three-stage palliation process in patients born with a univentricular heart as part of hypoplastic left heart syndrome (HLHS) or other pathologies with a univentricular heart. As essential as this procedure has proven to be for such cases, the Fontan physiology diminishes cardiac output and expands systemic venous pressure, which then leads to venous congestion that can be complicated by protein-losing enteropathy (PLE). This retrospective study aimed to identify the predictors of such complications in all patients who underwent completion of the Fontan procedure at our center (Sheikh Khalifa Medical City/SKMC) in the past eight years. METHODS: This study examined the medical records of patients who underwent completion of Fontan repair at our center since the inauguration of the cardiac surgery program of SKMC in the United Arab Emirates (UAE) - 01 Jan 2012 to 31 Dec 2020. Exclusion criteria included the absence of any of the undermentioned data in patient files. Patients were divided into two groups: those who developed PLE and those who did not. For each group, the following data were collected: demographics data (current age and age at completion of Fontan), clinical and laboratory data (oxygen saturation, serum albumin), echocardiographic data (classification of original cardiac diagnosis, degree of atrio-ventricular valve regurgitation, ventricular functions), hemodynamic data (mean pressures of superior vena cava and pulmonary arteries before Fontan completion), operative data (type of initial palliation, type of Fontan, presence of fenestrations and its size) and the need for any cardiac intervention prior to Fontan completion, such as atrio-ventricular valve repair, peripheral pulmonary stenting and arch balloon dilatation. RESULTS: Of the 48 included patients,13 (25%) developed PLE. Multivariate regression analysis proved that the best predictors of PLE were superior vena cava mean pressure (P = 0.012) and the degree of atrio-ventricular valve regurgitation (P = 0.013). An oxygen saturation <83% prior to Fontan completion was 92% sensitive in predicting PLE after Fontan completion. CONCLUSION: This is a single-center study of the predictors of PLE after Fontan procedure and, as expected from similar studies, SVC pressure higher than 11 mmHg and moderate-to-severe atrio-ventricular valve regurgitation were predictors of Fontan failure. The higher prevalence of PLE in our cohort, as well as lower cut-offs of SVC pressure that can predict complications, may be related to the predominance of hypoplastic left heart in the operated patients, which has been the main referral center for cardiac surgeries in UAE in the last decade.

Taste Receptor Activation in Tracheal Brush Cells by Denatonium Modulates ENaC Channels via Ca2+, cAMP and ACh.

Mucociliary clearance is a primary defence mechanism of the airways consisting of two components, ciliary beating and transepithelial ion transport (ISC). Specialised chemosensory cholinergic epithelial cells, named brush cells (BC), are involved in regulating various physiological and immunological processes. However, it remains unclear if BC influence ISC. In murine tracheae, denatonium, a taste receptor agonist, reduced basal ISC in a concentration-dependent manner (EC50 397 µM). The inhibition of bitter taste signalling components with gallein (Gßγ subunits), U73122 (phospholipase C), 2-APB (IP3-receptors) or with TPPO (Trpm5, transient receptor potential-melastatin 5 channel) reduced the denatonium effect. Supportively, the ISC was also diminished in Trpm5-/- mice. Mecamylamine (nicotinic acetylcholine receptor, nAChR, inhibitor) and amiloride (epithelial sodium channel, ENaC, antagonist) decreased the denatonium effect. Additionally, the inhibition of Gα subunits (pertussis toxin) reduced the denatonium effect, while an inhibition of phosphodiesterase (IBMX) increased and of adenylate cyclase (forskolin) reversed the denatonium effect. The cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTRinh172 and the KCNQ1 potassium channel antagonist chromanol 293B both reduced the denatonium effect. Thus, denatonium reduces ISC via the canonical bitter taste signalling cascade leading to the Trpm5-dependent nAChR-mediated inhibition of ENaC as well as Gα signalling leading to a reduction in cAMP-dependent ISC. Therefore, BC activation contributes to the regulation of fluid homeostasis.

Bitter taste signaling in tracheal epithelial brush cells elicits innate immune responses to bacterial infection.

Constant exposure of the airways to inhaled pathogens requires efficient early immune responses protecting against infections. How bacteria on the epithelial surface are detected and first-line protective mechanisms are initiated are not well understood. We have recently shown that tracheal brush cells (BCs) express functional taste receptors. Here we report that bitter taste signaling in murine BCs induces neurogenic inflammation. We demonstrate that BC signaling stimulates adjacent sensory nerve endings in the trachea to release the neuropeptides CGRP and substance P that mediate plasma extravasation, neutrophil recruitment, and diapedesis. Moreover, we show that bitter tasting quorum-sensing molecules from Pseudomonas aeruginosa activate tracheal BCs. BC signaling depends on the key taste transduction gene Trpm5, triggers secretion of immune mediators, among them the most abundant member of the complement system, and is needed to combat P. aeruginosa infections. Our data provide functional insight into first-line defense mechanisms against bacterial infections of the lung.