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: This study hypothesized that impaired pulmonary vascular reserve (VR) plays a central role linking these abnormalities, and that patients with abnormal pulmonary VR with exercise, compared with patients with normal VR, would display poorer pulmonary endothelial function, greater liver stiffness, more renal dysfunction, and poorer exercise capacity. 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 with exercise >3 mm Hg/l/min. Pulmonary endothelial function was assessed using reactive hyperemia index. End-organ function was assessed using magnetic resonance elastography-derived liver stiffness, glomerular filtration rate, N-terminal pro–B-type natriuretic peptide, and peak oxygen consumption (VO₂). Results: Compared with 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. Patients with abnormal VR displayed more severely impaired reactive hyperemia index, increased liver stiffness, lower glomerular filtration rate, higher N-terminal pro–B-type natriuretic peptide, and lower peak VO₂. As compared to pulmonary vascular resistance at rest, slope of increase in pulmonary pressure relative to cardiac output displayed stronger correlations with reactive hyperemia index (r = −0.63 vs. r = −0.31; Meng test p = 0.009), magnetic resonance elastography–derived liver stiffness (r = 0.47 vs. r = 0.29; Meng test p = 0.07), glomerular filtration rate (r = −0.52 vs. r = −0.24; Meng test p = 0.03), N-terminal pro–B-type natriuretic peptide (r = 0.56 vs. r = 0.17; Meng test p = 0.02), and peak VO₂ (r = −0.63 vs. r = −0.26; Meng 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.