Gut, Inflammation and Nutrition in Adult Patients After Fontan Operation (GIN-Fontan Study)

Clinical studies in patients with acquired heart disease and heart failure have shown that elevated systemic venous pressure is associated with significant venous congestion of the gastrointestinal tract and impairment of its protective and absorptive functions. The consequence of an impaired intestinal barrier is the entry of toxins (lipopolysaccharide or endotoxin), intestinal bacteria, or their metabolites into the bloodstream. In patients with decompensated heart failure, significantly higher levels of endotoxin were recorded, which were shown to decrease following treatment with diuretics. The translocation of bacterial toxins and metabolites across has been proven to trigger a systemic inflammatory response, which is considered a major factor in the progression of heart failure. Additionally, intestinal barrier dysfunction and systemic inflammatory response can lead to malnutrition and the development of cachexia, which is a poor prognostic factor in patients with heart failure.

Adult patients after Fontan operation represent a specific group of patients with congenital heart disease that is characterized by with long-term systemic venous pressure elevation. The Fontan procedure is a multistage palliative surgical intervention performed in patients with complex congenital heart defects where a bi-ventricular repair is not possible. In patients after Fontan operation, systemic venous blood from both inferior and superior venae cavae is surgically redirected into the pulmonary artery. The systemic venous circulation thus functions without an active pump (the right ventricle), so the flow to the pulmonary artery is passive. The pathophysiological consequence of establishing Fontan circulation is an elevated systemic venous pressure. Based on invasive hemodynamic studies the systemic venous pressure in patients after Fontan operation averages around 14 mmHg, which is approximately 3-4 times higher than normal systemic venous pressure (3-5 mmHg).

Patients after the Fontan operation experience numerous systemic complications and have a known reduced life expectancy. The most well-known and studied gastrointestinal consequences are liver damage with hepatopathy and the development of cirrhosis (Fontan-associated liver disease, FALD) and protein-losing enteropathy (PLE). Protein-losing enteropathy is recorded in 3-18% of patients after Fontan operation, and its occurrence is associated with elevated systemic venous pressure, disturbances in lymphatic circulation, and systemic inflammation.

The impact of the Fontan operation and its hemodynamic consequences on the protective and absorptive functions of the gastrointestinal tract in patients without signs of protein-losing enteropathy is unknown. Pathophysiologically, adult patients after Fontan operation have several factors that may contribute to impaired intestinal function. In addition to intestinal congestion due to elevated systemic venous pressure, reduced cardiac output may further contribute to impairment by leading to hypoperfusion and intestinal ischemia. Some patients after Fontan operation also have a surgical connection ("fenestration") that leads to a right-to-left cardiac shunt, hypoxemia, and cyanosis, which may further worsen intestinal blood flow.

Studies on intestinal barrier dysfunction in adult patients after Fontan operation who do not have protein-losing enteropathy are not available. A previous study on a group of patients with various congenital heart defects demonstrated intestinal barrier dysfunction with higher serum levels of bacterial endotoxin compared to healthy controls. These levels were higher in patients with concomitant signs of heart failure. Furthermore, patients with congenital heart defects had significantly elevated biomarkers of the systemic inflammatory response (tumour necrosis factor-alpha (TNFα) and interleukin-6 (IL-6)). Dysbiosis of intestinal bacteria, characterized by a pathologically altered composition of the gut microbiota, and a systemic inflammatory response with elevated levels of TNFα and IL-6, have also previously been demonstrated in patients after Fontan operation.