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Background: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. Methods: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. Results: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (–0.2%) in the placebo group ( P =0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus –9±193 [–0.9%] mL/min, P =0.012), ventilatory equivalents of carbon dioxide (–0.8 versus –0.06, P =0.014), and work rate (+3.8 versus +0.34 W, P =0.021). There was no an improvement in myocardial performance index (–0.02 vs 0.01, P =0.030), but no change in reactive hyperemia index, or serum brain-type natriuretic peptide level. Conclusions: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02741115.

Introduction: In the Pediatric Heart Network double-blind Fontan Udenafil Exercise Longitudinal (FUEL) trial, treatment with udenafil (Mezzion Pharma Co Ltd) for 6 months was associated with modest improvements in exercise capacity and ventricular performance (NCT02741115). Measures of vascular function, which have been related to Fontan exercise capacity, were also obtained but have not been explored in detail. Methods: Endothelial function (Framingham reactive hyperemia index, FRHI; area under the curve to max occlusion, AUC Max ) and arterial stiffness (augmentation index, AI) were assessed with peripheral arterial tonometry. The primary outcome was the effect of udenafil vs. placebo on vascular function. Secondary outcomes included baseline, and 26-week change from baseline, measures of vascular function in subgroups of the udenafil arm, stratified by exercise response. Exercise response was defined by longitudinal change in peak oxygen consumption and categorized by 1) any positive change vs. other and 2) tertile of change. Results: Paired measures of vascular function were analyzed in 164 (82%) and 167 (84%) udenafil and placebo participants, respectively. There were no baseline differences between groups, including the use of vasoactive medications. Overall, there were no differences in change in measures of vascular function between treatment groups. In subgroup analysis, exercise responders demonstrated better baseline endothelial function (FRHI: 0.39 ± 0.37 vs. 0.29 ± 0.31, p=0.056; AUC Max : 6.53 ± 2.91 vs. 5.63 ± 2.21, p=0.023) and suggestion of a 26-week reduction in arterial stiffness (AI: -1.42 ± 10.3 vs. 1.69 ± 11.7, p=0.075). Analysis by tertile of exercise response showed that AI was significantly improved in the top tertile of exercise responders (-3.27 ± 8.4 vs. 2.62 ± 12.4 vs. 0.35 ± 11.1, p=0.022) compared with the lower tertiles. Conclusions: In the FUEL trial, treatment with udenafil was not associated with significant changes in measures of vascular function. Udenafil-treated participants with evidence of exercise responsiveness to therapy manifest better baseline endothelial function and a significant improvement in arterial stiffness. Vascular function may play a role in PDE-5 responsiveness in Fontan circulation.

Background— Patients after the Fontan procedure are at risk for suboptimal functional health status, and associations with laboratory measures are important for planning interventions and outcome measures for clinical trials. Methods and Results— Parents completed the generic Child Health Questionnaire for 511 Fontan Cross-Sectional Study patients 6 to 18 years of age (61% male). Associations of Child Health Questionnaire Physical and Psychosocial Functioning Summary Scores (FSS) with standardized measurements from prospective exercise testing, echocardiography, magnetic resonance imaging, and measurement of brain natriuretic peptide were determined by regression analyses. For exercise variables for maximal effort patients only, the final model showed that higher Physical FSS was associated only with higher maximum work rate, accounting for 9% of variation in Physical FSS. For echocardiography, lower Tei index (particularly for patients with extracardiac lateral tunnel connections), lower indexed end-systolic volume, and the absence of atrioventricular valve regurgitation for patients having Fontan procedure at age Conclusions— In relatively healthy Fontan patients, laboratory measures account for a small proportion of the variation in functional health status and therefore may not be optimal surrogate end points for trials of therapeutic interventions.

Background— Aging is a risk factor for coronary and peripheral artery disease. Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, is expressed in ischemic tissue and is known to modulate angiogenesis. Little is known about the role of TNF-α receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling. Methods and Results— We studied neovascularization in the hindlimb ischemia model in young and old TNFR2/p75 knockout (p75KO) and wild-type age-matched controls. Between days 7 to 10 after hindlimb surgery, 100% of old p75KOs experienced autoamputation of the operated limbs, whereas none of the age-matched wild-type mice exhibited hindlimb necrosis. Poor blood flow recovery in p75KO mice was associated with increased endothelial cell apoptosis, decreased capillary density, and significant reductions in the expression of vascular endothelial growth factor and basic fibroblast growth factor-2 mRNA transcripts in ischemic tissue and in circulating endothelial progenitor cells. The number of circulating bone marrow–derived endothelial progenitor cells was significantly reduced in p75KO mice. Transplantation of wild-type bone marrow mononuclear cells into irradiated old p75KO mice 1 month before hindlimb surgery prevented limb loss. Conclusions— Our present study suggests that ischemia-induced endothelial progenitor cell–mediated neovascularization is dependent, at least in part, on p75 TNF receptor expressed in bone marrow–derived cells. Specifically, endothelial cell/endothelial progenitor cell survival, vascular endothelial growth factor expression, endothelial progenitor cell mobilization from bone marrow, endothelial progenitor cell differentiation, and ultimately ischemia-induced collateral vessel development are dependent on signaling through TNFR2/p75. Furthermore, because TNFR2/p75 becomes an age-related limiting factor in postischemic recovery, it may be a potential gene target for therapeutic interventions in adult vascular diseases.

Background— We compared the therapeutic potential of purified mobilized human CD34 + cells with that of mobilized total mononuclear cells (tMNCs) for the preservation/recovery of myocardial tissue integrity and function after myocardial infarction (MI). Methods and Results— CD34 + cells were purified from peripheral blood tMNCs of healthy volunteers by magnetic cell sorting after a 5-day administration of granulocyte colony-stimulating factor. Phosphate-buffered saline (PBS), 5×10 5 CD34 + cells/kg, 5×10 5 tMNCs/kg (low-dose MNCs [loMNCs]), or a higher dose of tMNCs (hiMNCs) containing 5×10 5 CD34 + cells/kg was transplanted intramyocardially 10 minutes after the induction of MI in athymic nude rats. Hematoxylin and eosin staining revealed that moderate to severe hemorrhagic MI on day 3 was more frequent in the hiMNC group than in the PBS and CD34 + cell groups. Immunostaining for human-specific CD45 revealed abundant distribution of hematopoietic/inflammatory cells derived from transplanted cells in the ischemic myocardium of the hiMNC group. Capillary density on day 28 was significantly greater in the CD34 + cell group (721.1±19.9 per 1 mm 2 ) than in the PBS, loMNC, and hiMNC groups (384.7±11.0, 372.5±14.1, and 497.5±24.0 per 1 mm 2 ) ( P + cell group (15.6±0.9%) than in the PBS, loMNC, and hiMNC groups (26.3±1.2%, 27.5±1.8%, and 22.2±1.8%) ( P + cell group (30.3±0.9%) than in the PBS, loMNC, and hiMNC groups (22.7±1.5%, 23.4±1.1%, and 24.9±1.7%; P + cell group (21.8±0.5) than in the PBS, loMNC, and hiMNC groups (25.4±0.4, 24.9±0.4, and 24.1±0.6; P Conclusions— CD34 + cells exhibit superior efficacy for preserving myocardial integrity and function after MI than unselected circulating MNCs.