Effect of inhaled iloprost on the exercise function of Fontan patients: A demonstration of concept

Rhodes, Jonathan; Tikkanen, Ana Úbeda; Clair, Mathieu; Fernandes, Susan M.; Graham, Dionne A.; Milliren, Carly E.; Daly, Kevin P.; Mullen, Mary P.; Landzberg, Michael J.

doi:10.1016/j.ijcard.2013.03.014

Cited by 83 publications

(65 citation statements)

References 30 publications

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“…Giardini et al 8 showed an improvement in peak oxygen consumption after a single oral dose of sildenafil, whereas Goldberg et al 9,10 observed an improvement in ventilatory efficiency and ventricular performance after a 6-week period of sildenafil therapy. Rhodes et al 35 noted a similar beneficial effect of inhaled iloprost on exercise capacity. The hemodynamic mechanisms for the improvement remained unclear.…”

Section: Effect Of Sildenafil On Exercise Hemodynamicsmentioning

confidence: 85%

Sildenafil Improves Exercise Hemodynamics in Fontan Patients

Bruaene

Gerche

Claessen

et al. 2014

Circ: Cardiovascular Imaging

126

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Sildenafil targets the endothelial NO pathway by inhibiting phosphodiesterase-5, increasing cGMP, and inducing pulmonary vasodilation.7 Giardini et al 8 demonstrated an improvement in peak oxygen consumption and CI after a single oral Background-Patients with Fontan circulation have reduced exercise capacity. The absence of a presystemic pump may limit flow through the pulmonary circulation, restricting ventricular filling and cardiac output. We evaluated exercise hemodynamics and the effect of sildenafil on exercise hemodynamics in Fontan patients. Methods and Results-Ten Fontan patients (6 men, 20±4 years) underwent cardiac magnetic resonance imaging at rest and during supine bicycle exercise before and after sildenafil. Systemic ventricular volumes were obtained at rest and during low-(34±15 W), moderate-(69±29 W), and high-intensity (97±36 W) exercise using an ungated, free-breathing cardiac magnetic resonance sequence and analyzed correcting for cardiac phase and respiratory translation. Radial and pulmonary artery pressures and cGMP were measured. Before sildenafil, cardiac index increased throughout exercise (4.0±0.9, 5.9±1.1, 7.0±1.6, 7.4±1.7 L/(min·m 2 ); P<0.0001) with 106±49% increase in heart rate. Stroke volume index (P=0.015) and end-diastolic volume index (P=0.001) decreased during exercise. End-systolic volume index remained unchanged (P=0.8). Total pulmonary resistance index (P=0.005) increased, whereas systemic vascular resistance index decreased during exercise (P<0.0001). Sildenafil increased cardiac index (P<0.0001) and stroke volume index (P=0.003), especially at high-intensity exercise (interaction P=0.004 and P=0.003, respectively). Systemic vascular resistance index was reduced (P<0.0001-interaction P=0.1), whereas total pulmonary resistance index was reduced at rest and reduced further during exercise (P=0.008-interaction P=0.029). cGMP remained unchanged before sildenafil (P=0.9), whereas it increased significantly after sildenafil (P=0.019). Conclusions-In Fontan patients, sildenafil improved cardiac index during exercise with a decrease in total pulmonary resistance index and an increase in stroke volume index. This implies that pulmonary vasculature represents a physiological limitation, which can be attenuated by sildenafil, the clinical significance of which warrants further study. (Circ Cardiovasc Imaging. 2014;7:265-273.)

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Section: Effect Of Sildenafil On Exercise Hemodynamicsmentioning

confidence: 85%

Sildenafil Improves Exercise Hemodynamics in Fontan Patients

Bruaene

Gerche

Claessen

et al. 2014

Circ: Cardiovascular Imaging

126

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“…. 23 From these observations with pulmonary vasodilators, it was anticipated that subgroup analyses in our study could pinpoint measures such as baseline peak…”

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confidence: 97%

Bosentan Improves Exercise Capacity in Adolescents and Adults After Fontan Operation

et al. 2014

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Background— The Fontan procedure has improved survival in children with functionally univentricular hearts. With time, however, complications such as reduced exercise capacity are seen more frequently. Exercise intolerance is multifactorial, but pulmonary vascular resistance probably plays a crucial role. Elevated pulmonary vascular resistance has been associated with raised levels of endothelin-1, which are common both before and after Fontan operations. Treatment with endothelin-1 receptor antagonists could theoretically improve cardiopulmonary hemodynamics and exercise capacity. The aim of this study was therefore to examine the efficacy and safety of bosentan in Fontan patients. Methods and Results— Seventy-five adolescents and adults were randomized 1:1 to 14 weeks of treatment with bosentan or placebo. Cardiopulmonary exercise test, functional class, blood samples, and quality-of-life questionnaires were evaluated at baseline and at the end of treatment. Sixty-nine patients (92%) completed the study. Peak oxygen consumption increased 2.0 mL·kg −1 ·min −1 (from 28.7 to 30.7 mL·kg −1 ·min −1 ) in the bosentan group compared with 0.6 mL·kg −1 ·min −1 (from 28.4 to 29.0 mL·kg −1 ·min −1 ) in the placebo group ( P =0.02). Cardiopulmonary exercise test time increased by 0.48 minute (from 6.79 to 7.27 minutes) versus 0.08 minute (from 6.94 to 7.02 minutes; P =0.04). Nine bosentan-treated patients improved 1 functional class, whereas none improved in the placebo group ( P =0.0085). Side effects were mild and occurred equally in both groups. No serious adverse effects were seen, and no patients had liver enzyme levels above the 3-fold upper limit. Conclusions— Bosentan improves exercise capacity, exercise time, and functional class in Fontan patients without serious adverse events or hepatotoxicity. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01292551.

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“…A number of studies have demonstrated acute improvements in exercise performance, ejection fraction, and cardiac output, while the only reported randomized clinical trial showed improvements in some sub-groups during sub-maximal exercise, but did not detect an improvement in maximal oxygen consumption 10–14 . More recently, investigators have evaluated the effect of Bosentan and inhaled prostacyclin on measures of exercise performance 23–25 . The results of these studies were also mixed; one demonstrating a possible benefit and the other demonstrating no evidence of benefit.…”

Section: Discussionmentioning

confidence: 99%

Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation

Goldberg

Zak

Goldstein

et al. 2017

American Heart Journal

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Background The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes. Objectives This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan. Methods A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five. Results The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts. Conclusions Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial.

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Effect of inhaled iloprost on the exercise function of Fontan patients: A demonstration of concept

Cited by 83 publications

References 30 publications

Sildenafil Improves Exercise Hemodynamics in Fontan Patients

Sildenafil Improves Exercise Hemodynamics in Fontan Patients

Bosentan Improves Exercise Capacity in Adolescents and Adults After Fontan Operation

Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation

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