Sildenafil improves exercise hemodynamics in Fontan patients

Abstract

Background: Reduced preload reserve is a fundamental limitation of the Fontan circulation. Sildenafil may increase exercise capacity in patients with Fontan physiology, but the underlying mechanism is still unclear. Using a novel exercise cardiac magnetic resonance (CMR) methodology, we tested the hypothesis that sildenafil would improve exercise hemodynamics in Fontan patients. Methods: Ten Fontan patients (6 male, age 20±4 years) underwent CMR at rest and during supine exercise on a programmable cycle ergometer before (baseline) and after a single dose of sildenafil (50 mg oral). Systemic ventricular volumes were obtained at rest and during mild (104±11 bpm), moderate (127±16 bpm) and high intensity (147±15 bpm) exercise. Bi-plane cine images were acquired using an ungated, free-breathing real-time CMR sequence (12-18 contiguous 8mm slices) and analyzed using software developed enabling retrospective gating for cardiac phase and respiratory translation. Endocardial borders were delineated using a bi-plane model. Simultaneously, radial and pulmonary artery pressures (PAPs) were measured. Results: Under resting conditions as compared with baseline, sildenafil reduced PAPs (9±3 to 8±3 mmHg, P=0.029) and increased heart rate (72±14 to 82±13 bpm, P<0.0001) and cardiac output (6.8±1.6 to 8.1±2.1 L/min, P=0.006). Total pulmonary resistance (TPR) (1.49±0.86 to 1.13±0.66 mmHg.min/L; P=0.010) and systemic vascular resistance (SVR) (11.05±2.43 to 8.65±1.90 mmHg.min/L; P<0.0001) decreased. During exercise sildenafil resulted in improved hemodynamics. PAPs (mean difference -1.0±0.7 mmHg, P=0.010) and mean arterial pressures (mean difference -7.1±1.5 mmHg, P<0.0001) decreased, whilst cardiac output (mean difference +1.4±0.7 L/min, P=0.001), ejection fraction (mean difference +4.6±2.5%, P=0.003) and stroke volume (mean difference +6.7±4.8 ml, P=0.012) all increased. TPR (mean difference -0.34±0.21 mmHg.min/L, P=0.004) and SVR (mean difference -1.38±0.28 mmHg.min/L, P<0.0001) decreased. The decrease in SVR between exercise stages was similar before and after sildenafil (interaction P=0.137). However, in contrast to the increase in TPR before sildenafil, TPR did not increase between stages after sildenafil (interaction P=0.033). Conclusion: In patients with Fontan physiology, sildenafil improves cardiac output during exercise which is presumably related an improved response of the pulmonary vasculature, especially during exercise. This implies that pulmonary vasodilation is a potential physiological target for improving exercise hemodynamics, the clinical significance of which warrants further study.