Assessing the role of phosphodiesterase-5 inhibitors for improvement of myocardial performance in adolescentswith abnormal cardiac physiology following fontan palliation : a meta-analysis

Background The Fontan operation represents a cornerstone in the surgical management of hypoplastic left heart syndrome (HLHS), a complex congenital cardiac anomaly characterized by underdevelopment of the left ventricle, aortic arch, and mitral valve. While this palliation allows survival into adolescence and adulthood, it imposes significant hemodynamic burdens. The physiological constraints manifest clinically as impaired cardiovascular efficiency, exercise intolerance, ventricular dysfunction, and heightened risks of long-term morbidity such as protein-losing enteropathy, arrhythmias, and heart failure. In response to these challenges, recent studies have focused on pharmacotherapeutic strategies to enhance myocardial performance and functional capacity, with particular emphasis on phosphodiesterase-5 (PDE-5) inhibitors such as oral sildenafil and udenafil in adolescent populations following Fontan palliation. Methodology A comprehensive search of major databases like PubMed, Scopus, Embase, Cochrane, and Google Scholar was conducted to retrieve eligible studies. The inverse variance random-effects model was used to generate pooled effects estimates of outcomes as mean difference (MD) and standard mean difference (SMD) with 95% confidence interval. Results 3 RCTs with 464 participants of age 14-16 years showcased that administration of PDE-5 inhibitors such as Sildenafil and Udenenafil in adolescents following Fontan palliation showed no significant difference in peak O2 consumption [MD: 0.17; 95% CI: -0.01, 0.35; p = 0.07] and peak ventilation [SMD: 0.07; 95% CI: -0.12, 0.26; p = 0.46]. However, it significantly improved anaerobic threshold [SMD: 0.22; 95% CI: 0.02, 0.42; p = 0.03] and reduced VE/VCO2 [MD: -0.26; 95% CI: -0.48, -0.03; p = 0.02]. MPI [MD: -0.05; 95% CI: -0.09, -0.00; p = 0.05] shows a statistically negative trend for PDE-5 inhibitors. Conclusion In adolescents post-Fontan palliation, PDE-5 inhibitors (sildenafil/udenafil) demonstrated no significant improvement in peak VO₂ or ventilation. However, they yielded modest but clinically meaningful enhancements in anaerobic threshold and ventilatory efficiency, alongside a borderline reduction in myocardial performance index. These findings suggest PDE-5 inhibitors may optimize submaximal exercise capacity and ventricular-vascular coupling by enhancing pulmonary vasodilation and diastolic function, despite limited peak aerobic impact. Favorable safety profiles support chronic use, though long-term studies are needed to assess functional outcome trajectories.