Endothelial Function and Arterial Stiffness Relate to Functional Outcomes in Adolescent and Young Adult Fontan Survivors

Goldstein, Bryan H.; Urbina, Elaine M.; Khoury, Philip R.; Gao, Zhiqian; Amos, Michelle A.; Mays, Wayne A.; Redington, Andrew N.; Marino, Bradley S.

doi:10.1161/jaha.116.004258

Cited by 22 publications

(12 citation statements)

References 35 publications

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“…Data from these tests are collected at each site and sent to a core lab for interpretation. The primary outcome for vascular function is the log-transformed reactive hyperemia index, which is obtained by comparing blood flow before and after limb ischemia, adjusted for the control arm, and has been shown to correlate with functional capacity and quality of life(8). An additional outcome measure of vascular function is the augmentation index, which is a measure of arterial stiffness.…”

Section: Study Design and Methodsmentioning

confidence: 99%

“…This creates a circulation characterized by elevated central venous pressure and chronically low cardiac output. Over time, these inherent characteristics of Fontan physiology result in a predictable, persistent deterioration of cardiovascular efficiency marked by a progressive decline in exercise performance as well as impaired ventricular and vascular function(3–8). Medical therapies that can favorably alter the deficiencies of the Fontan circulation might help to slow the decline associated with Fontan physiology and lead to improved outcomes over a lifetime(9).…”

Section: The Fontan Circulationmentioning

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: The Fontan Circulationmentioning

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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“…Fontan circulation shares pathophysiologic features with heart failure, including hemodynamic derangement, manifested as increased CVP and decreased CO, 16 neurohormone activation, 17 , 18 inflammation, 19 endothelial activation, 20 and increased oxidative stress. 19 These features of heart failure can result in an important catabolic drive that is capable of contributing to the growth retardation and ultimately to sarcopenia and/or cachexia, which are often observed in failed Fontan patients.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of Short Stature and Growth Hormone Deficiency and Factors Associated With Short Stature After Fontan Surgery

et al. 2020

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Background: Fontan circulation is characterized by many features commonly observed in heart failure that may affect physical growth regardless of pituitary gland dysfunction status. The aims of the present study were to investigate the prevalence of short stature and growth hormone deficiency (GHD) and determine the factors associated with short stature after Fontan surgery. Methods and Results: On retrospective evaluation of 47 patients after Fontan surgery, a very high prevalence of short stature was observed (38.3%). In the short stature group, 5 patients were diagnosed with GHD (10.6% of patients after Fontan Surgery), which is much higher than the frequency of 1/10,000 in the general population. Central venous pressure (CVP) was significantly higher (14.6±4.5 vs. 12.2±1.9 mmHg, P<0.05) and the blood pressure and arterial oxygen saturation were significantly lower in the short stature group. Laboratory data also indicated volume retention and congestion in the short stature group. Mean change in stature from catheterization 1 year after Fontan surgery to the most recent visit was significantly lower in the short stature group (−1.1±1.1 SD vs. 0.0±0.8 SD, P<0.05) and significantly negatively correlated with CVP (r=−0.42, P<0.05). Conclusions: Volume retention and congestion, the prominent features of Fontan circulation, affect physical growth partly due to pituitary gland dysfunction, highlighting the need for the screening for and treatment of this condition after Fontan surgery.

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“…A recent study estimated an overweight/obesity prevalence of 30% among single ventricular patients 5 years after undergoing a Fontan (79). Importantly, increased adiposity is independently associated with worse endothelial function and worse functional outcomes after the Fontan operation (80,81). Understanding the relationship between vascular function and functional outcomes and the specific role of obesity is an important next step.…”

Section: Congenital Heart Disease and Cardiopulmonary Bypassmentioning

confidence: 99%

Childhood Obesity, Endothelial Cell Activation, and Critical Illness

Radman¹,

McGuire²,

Zimmerman³

2020

Front. Pediatr.

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Pediatric obesity is increasing in prevalence and is frequently an antecedent to adult obesity and adult obesity-associated morbidities such as atherosclerosis, type II diabetes, and chronic metabolic syndrome. Endothelial cell activation, one aspect of inflammation, is present in the early stages of atherosclerosis, often prior to the onset of symptoms. Endothelial activation is a pathological condition in which vasoconstricting, pro-thrombotic, and proliferative mediators predominate protective vasodilating, anti-thrombogenic, and anti-mitogenic mediators. Many studies report poor outcomes among obese children with systemic endothelial activation. Likewise, the link between childhood obesity and poor outcomes in critical illness is well-established. However, the link between obesity and severity of endothelial activation specifically in the setting of critical illness is largely unstudied. Although endothelial cell activation is believed to worsen disease in critically ill children, the nature and extent of this response is poorly understood due to the difficulty in measuring endothelial cell dysfunction and destruction. Based on the data available for the obese, asymptomatic population and the obese, critically ill population, the authors posit that obesity, and obesity-associated chronic inflammation, including oxidative stress and insulin resistance, may contribute to endothelial activation and associated worse outcomes among critically ill children. A research agenda to examine this hypothesis is suggested.

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Endothelial Function and Arterial Stiffness Relate to Functional Outcomes in Adolescent and Young Adult Fontan Survivors

Abstract: Background--Fontan survivors demonstrate diminished vascular function and functional outcomes, but the relationships between these measures have not been established.

Cited by 22 publications

References 35 publications

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

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

Prevalence of Short Stature and Growth Hormone Deficiency and Factors Associated With Short Stature After Fontan Surgery

Childhood Obesity, Endothelial Cell Activation, and Critical Illness

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