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

Goldberg, David J.; Zak, Victor; Goldstein, Bryan H.; Chen, Shan; Hamstra, Michelle S.; Radojewski, Elizabeth; Maunsell, Eileen; Mital, Seema; Menon, Shaji C.; Schumacher, K.; Payne, R. Mark; Stylianou, Mario; Kaltman, Jonathan R.; deVries, Tina; Yeager, James L.; Paridon, Stephen M.

doi:10.1016/j.ahj.2017.02.030

Cited by 19 publications

(8 citation statements)

References 27 publications

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“…Among PDE-5 inhibitors, udenafil is the only medication to have undergone phase I/II testing in patients with Fontan physiology(37). This trial, conducted in the PHN (NCT02201342), tested five different dosing strategies in cohorts of six subjects each.…”

Section: Study Design and Methodsmentioning

confidence: 99%

“…These images are sent to a core lab with specific expertise in functional measurements. The primary echocardiographic endpoint is the myocardial performance index, a measure of global ventricular function that has been noted to improve with use of PDE-5 inhibitors in the Fontan population in previous studies(26,37). Secondary endpoints include tricuspid/mitral annular planar systolic excursion, a measure that has been linked to exercise performance(39), and the systolic to diastolic ratio, a measure that has been linked to ventricular end-diastolic pressure and to mortality in adults with Fontan physiology(40–42).…”

Section: Study Design and Methodsmentioning

confidence: 99%

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Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial

Goldberg

Zak

Goldstein

et al. 2018

American Heart Journal

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The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double-blind, placebo-controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co, Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation.

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Section: Study Design and Methodsmentioning

confidence: 99%

Section: Study Design and Methodsmentioning

confidence: 99%

Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial

Goldberg

Zak

Goldstein

et al. 2018

American Heart Journal

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“…There is mounting preclinical and clinical evidence regarding the potentially beneficial cardiac effects of PDE5i, however, their use in children with heart disease remains primarily focused on modulating pulmonary blood flow. While PDE5i therapy in failing SV patients has been associated with improved hemodynamics, exercise tolerance and cardiac function 10,12,43 , the direct effects of PDE5i on the SV myocardium are unknown. Given the significant increase of PDE5 mRNA 20 , protein and activity in SV RV and the presence of PDE5 in SV cardiomyocytes, these findings suggest that in addition to effects on the pulmonary vasculature, PDE5i may directly target the myocardium.…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase-5 Is Elevated in Failing Single Ventricle Myocardium and Affects Cardiomyocyte Remodeling In Vitro

Garcia

Karimpour-Fard²,

Nunley³

et al. 2018

Circ: Heart Failure

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Background: Single ventricle congenital heart disease (SV) is fatal without intervention and eventual heart failure (HF) is a major cause of morbidity and mortality. While there are no proven medical therapies for the treatment or prevention of HF in the SV population, phosphodiesterase-5 inhibitors (PDE5i), such as sildenafil, are increasingly utilized. While the pulmonary vasculature is the primary target of PDE5i therapy in patients with SV, the effects of PDE5i on the SV myocardium remain largely unknown. We sought to determine PDE5 expression and activity in the single right ventricle (RV) of SV patients relative to non-failing (NF) controls, and to determine if PDE5 impacts cardiomyocyte remodeling using a novel serum based in vitro model. Methods and Results: PDE5 expression (n=9 NF, n=7 SV), activity (n=8 NF, n=9 SV) and localization (n=3 SV) were determined in explanted human RV myocardium. PDE5 is expressed in SV cardiomyocytes and PDE5 protein expression and activity are increased in SV RV compared to NF RV. Isolated neonatal rat ventricular myocytes (NRVMs) were treated for 72 hours with NF or SV patient serum ± sildenafil. RT-qPCR (n=5 NF, n=12 SV) and RNAseq (n=3 NF, n=3 SV) were performed on serum-treated NRVMs and demonstrated that treatment with SV sera results in pathological gene expression changes which are attenuated with PDE5i. Conclusions: PDE5 is increased in failing SV myocardium and pathologic gene expression changes in SV serum-treated NRVMs are abrogated by PDE5i. These results suggest that PDE5 represents an intriguing myocardial therapeutic target in this population.

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“…Several studies have evaluated the effects of PDE-5inhibitors (45,(64)(65)(66)(67)(68)(69)(70), endothelin receptor antagonists (71)(72)(73)(74)(75)(76)(77) and prostacyclin analogues (78) in Fontan patients. So far, there is no published data on the use of riociguat, a stimulator of the soluble guanylate cyclase, in Fontan patients.…”

Section: Pulmonary Vasodilator Therapy In Fontan Patientsmentioning

confidence: 99%

Pulmonary vascular disease in Fontan circulation—is there a rationale for pulmonary vasodilator therapies?

Becker¹,

Uebing²,

Hansen³

2021

Cardiovasc Diagn Ther

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The Fontan circulation is a palliative concept for patients with univentricular hearts. The central veins are connected directly to the pulmonary arteries (cavo-pulmonary connection) to separate the pulmonary and the systemic circulation. There is no sub-pulmonary ventricle that generates pressure to drive blood through the pulmonary arteries. Pulmonary blood flow is determined by central venous pressure (CVP) and pulmonary vascular resistance (PVR). The capability of the Fontan circulation to compensate for alterations in PVR is limited, as CVP can only be increased within narrow ranges without adverse clinical consequences. Consequently, systemic ventricular preload and cardiac output are dependent on a healthy lung with low PVR. Failure of the Fontan circulation is relatively common. In addition to ventricular dysfunction, maladaptive pulmonary vascular remodeling resulting in increased pulmonary resistance may play a key role. The pathophysiology of the maladaptive vascular processes remains largely unclear and diagnosis of an increased PVR is challenging in Fontan circulation as accurate measurement of pulmonary arterial blood flow is difficult. In the absence of a sub-pulmonary ventricle, pulmonary artery pressure will almost never reach the threshold conventionally used to define pulmonary arterial hypertension. There is a need for markers of pulmonary vascular disease complementary to invasive hemodynamic data in Fontan patients. In order to treat or prevent failure of the Fontan circulation, pathophysiological considerations support the use of pulmonary vasodilators to augment pulmonary blood flow and systemic ventricular preload and lower CVP. However, to date the available trial data have neither yielded enough evidence to support routine use of pulmonary vasodilators in every Fontan patient nor have they been helpful in defining subgroups of patients that might benefit from such therapies. This review discusses potential pathomechanisms of pulmonary vascular disease; it summarizes the current knowledge of the effects and efficacy of pulmonary vasodilator therapy in Fontan patients and tries to outline areas of potential future research on the diagnosis and treatment of pulmonary vascular disease and Fontan failure.

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

Cited by 19 publications

References 27 publications

Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial

Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial

Phosphodiesterase-5 Is Elevated in Failing Single Ventricle Myocardium and Affects Cardiomyocyte Remodeling In Vitro

Pulmonary vascular disease in Fontan circulation—is there a rationale for pulmonary vasodilator therapies?

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