Hemodynamic and Clinical Implications of Impaired Pulmonary Vascular Reserve in the Fontan Circulation

Background: Pulmonary vascular disease, pulmonary endothelial dysfunction, liver fibrosis, renal disease, and exercise intolerance are common in adults with Fontan physiology. Although the pathophysiologic mechanisms linking these phenomena have been studied, certain aspects are not well understood. Objectives: We hypothesized that impaired pulmonary vascular reserve (VR) plays a central role linking these abnormalities, and that patients with abnormal pulmonary VR with exercise would display poorer pulmonary endothelial function, greater liver stiffness, more renal dysfunction and poorer exercise capacity as compared to patients with normal VR. Methods: Symptomatic adults with the Fontan palliation (n=29) underwent invasive cardiopulmonary exercise testing, echocardiography, and assessment of microvascular function. Abnormal pulmonary VR was defined by the slope of increase in pulmonary pressure relative to cardiac output (mPAP/CO slope) with exercise >3mmHg/l/min. Pulmonary endothelial function was assessed using reactive hyperemia index (RHI). End-organ function was assessed using magnetic resonance elastography-derived liver stiffness, glomerular filtration rate (GFR), NT-proBNP, and peak oxygen consumption (VO2). Results: Compared to individuals with normal VR (n=8), those with abnormal VR (n=21) displayed higher central and pulmonary venous pressures, and more severely impaired cardiac output and stroke volume responses to exertion, but similar pulmonary vascular resistance at rest (PVRrest). Patients with abnormal VR displayed more severely impaired RHI, increased liver stiffness, lower GFR, higher NTproBNP, and lower peak VO2. As compared to PVRrest, mPAP/CO slope displayed stronger correlations with RHI (r=−0.63 vs r=−0.31, Meng’s test p=0.009), MRE-derived liver stiffness (r=0.47 vs r=0.29, Meng’s test p=0.07), GFR (r=−0.52 vs r=−0.24, Meng’s test p=0.03), NT-proBNP (r=0.56 vs r=0.17, Meng’s test p=0.02) and peak VO2 (r=−0.63 vs r=−0.26, Meng’s test p=0.02). Conclusions: Pulmonary vascular limitations in Fontan physiology are related to pulmonary endothelial and end-organ dysfunction, suggesting a mechanistic link between these commonly-observed findings, and these abnormalities are more apparent during exercise testing, with little relationship at rest.