Fontan-palliated Patients Research Articles

Efficacy and safety of macitentan in Fontan-palliated patients: 52-week randomized, placebo-controlled RUBATO Phase 3 trial and open-label extension

ObjectivesThe efficacy and safety of macitentan, an endothelin receptor antagonist, were assessed in a 52-week, prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessing the efficacy and safety of macitentan in Fontan-palliated adult and adolescent patients (RUBATO-DB) and an open-label extension trial (RUBATO-OL). MethodsPatients aged 12 years and older with New York Heart Association functional class II or III underwent total cavopulmonary connection more than 1 year before screening and showed no signs of Fontan failure/clinical deterioration. In RUBATO-DB, the primary efficacy end point was change in peak oxygen consumption from baseline to week 16; secondary end points were change from baseline over 52 weeks in peak oxygen consumption and change in mean count/minute of daily physical activity via accelerometer from baseline to week 16. Safety was assessed throughout both studies. ResultsIn RUBATO-DB, 137 patients were randomized to macitentan 10 mg (n = 68) or placebo (n = 69); 92.7% completed 52-week double-blind treatment. At week 16, mean ± SD change in peak oxygen consumption was −0.16 ± 2.86 versus −0.67 ± 2.66 mL/kg/minute with macitentan versus placebo (median unbiased treatment difference estimate, 0.62 mL/kg/minute [99% repeated CI, −0.62 to 1.85]; P = .19). No treatment effect was observed in either of the secondary end points. During RUBATO-DB, most common adverse events with macitentan were headache, nasopharyngitis, and pyrexia. Across RUBATO-DB and RUBATO-OL, most common adverse events were COVID-19, headache, and fatigue. RUBATO-OL was prematurely discontinued because RUBATO-DB did not meet its primary or secondary end point. ConclusionsThe primary end point of RUBATO-DB was not met; macitentan did not improve exercise capacity versus placebo in patients with Fontan palliation. Macitentan was generally well tolerated over long-term treatment.

Abstract 15192: The Impact of Fontan Circulatory Failure on Heart Transplant Survival: A 20 Center Study

Introduction: Fontan circulatory failure (FCF) is a chronic state in palliated single ventricle heart disease with high morbidity and mortality including heart failure, multisystem end-organ disease, and need for heart transplant (HT). Specific FCF morbidities have not been rigorously defined limiting study of how FCF morbidities impact pre- and post-HT outcomes. Hypothesis: FCF-specific morbidities affect survival from HT waitlisting (WL) through 1-year post-HT. Methods: This 20-center, retrospective cohort study collected demographic, medical/surgical history, WL data, and peri- and post-HT data in Fontan patients WL since 2008. Using Delphi methodology, investigators defined FCF-specific morbidities and collected data. Appropriate univariate 2-group statistics compared surviving individuals with those who 1) died anytime from WL to 1-year post-HT, 2) died on the WL, 3) died within 1-year post-HT. Multivariable logistic regression determined independent risk factors for mortality between WL and 1-year post-HT. Results: Of 409 WL patients, 24 (5.9%) died on the WL. Of the 316 (77%) who underwent HT, 27 (8.5%) did not survive to 1-year. Univariate risk factors for WL death included higher aortopulmonary collateral burden, > 1 hospitalizations in prior year, younger age, sleep apnea, higher NYHA class, non-enrollment in school or work, and single-parent home. Risk factors for 1-year post-HT mortality included HLHS diagnosis, patent fenestration, anatomic Fontan obstruction, clinical cyanosis (pulse oximetry < 90%), polycythemia, portal variceal disease, psychiatric disease requiring treatment, and higher HLA class II PRA. For the 15% of patients not surviving from WL to 1-year post-HT, independent risk factors for mortality included >1 hospitalization in the year prior to WL (aOR 2.0, p=0.05) and clinical cyanosis (aOR 5.0, p=0.002). Notably, some FCF morbidities did not impact post-WL survival including protein-losing enteropathy, plastic bronchitis, and kidney disease. Conclusions: Fontan-palliated patients continue to have high mortality from WL through HT. Among FCF specific morbidities, cyanosis is associated with worsened survival and needs further study. Continued study of FCF phenotype is possible via this dataset.

Transient liver elastography in the follow-up of Fontan patients: results of a nation wide survey in Germany.

Fontan-palliated patients are at risk for the development of Fontan-associated liver disease (FALD). Currently, there is no consensus on how to stage FALD. Transient elastography (TE) is a rapid, non-invasive method to assess FALD and liver fibrosis. To assess the availability and conditions of using TE to monitor liver disease in Fontan patients in german centers for pediatric cardiology and to propose the introduction of a standardized national protocol for the monitoring of liver disease, we developed a questionnaire. In total, 95 valid questionnaires were collected. Only 20% of the centers offer the TE investigation directly. Most of the centers transfer the patients to another department or center (40%) or didńt offer TE (40%). In only 2.6% of the centers TE is performed directly by the cardiologist. Most of the centers transfer the patients to a other department. In 29.2% TE is performed only at a certain age of the patients and in 27.7% it is performed if the patients present symptoms of failing Fontan. In only 13.9% of the centers TE is proposed in all the Fontan patients on a routine basis. Most often TE is performed only from the beginning of the adolescence. In the majority of answers it was not known if the patients are fasting for the examination (68%) or not and if the TE examination had to be performed in a specific breathing phase during TE (Inspiration/Expiration, 90%). In the majority, TE is not offered routinely (46.9%). To date in Germany, TE is only used in a few numbers of centers specialized in Fontan follow-up. A standardized protocol to use TE is currently not existing. With regard to the feasibility of the examination, it is evident that TE is a quick, cheap and easy method to distinguish between cases with and without progressive FALD. This makes TE a useful and prognostic tool for screening of liver disease and to failing Fontan circulation. We propose a systematic TE evaluation of possible liver congestion and fibrosis, as a part of the routine follow-up of Fontan patients.

Pulmonary artery banding in sheep: a novel large animal model for congestive hepatopathy.

Congestive hepatopathy is becoming increasingly recognized among Fontan-palliated patients. Elevated central venous pressure is thought to drive the pathologic progression, characterized by sinusoidal dilatation, congestion, and fibrosis. A clinically relevant large animal model for congestive hepatopathy would provide a valuable platform for researching novel biomarkers, treatment, and prevention. Here, we report on a titratable, sheep pulmonary artery banding model for this disease application. Pulmonary artery banding was achieved by progressively inflating the implanted pulmonary artery cuff. Right ventricular catheter was implanted to draw venous blood samples and measure pressure. The pulmonary artery cuff pressure served as a surrogate for the intensity of pulmonary artery banding and was measured weekly. After about 9 wk, animals were euthanized, and the liver was harvested for histopathological assessment. Nine animal subjects received pulmonary artery banding for 64 ± 8 days. Four of the nine subjects exhibited moderate to severe liver injury, and three of those four exhibited bridging fibrosis. Increasing pulmonary artery cuff pressure significantly correlated with declining mixed venous oxygen saturation (P = 3.29 × 10-5), and higher congestive hepatic fibrosis score (P = 0.0238), suggesting that pulmonary artery banding strategy can be titrated to achieve right-sided congestion and liver fibrosis. Blood analyses demonstrated an increase in plasma bile acids, aspartate aminotransferase, and γ-glutamyltransferase among subjects with moderate to severe injury, further corroborating liver tissue findings. Our large animal pulmonary artery banding model recapitulates congestive hepatopathy and provides a basis to bridge the current gaps in scientific and clinical understanding about the disease.NEW & NOTEWORTHY We present here a large animal platform for congestive hepatopathy, a disease growing in clinical prevalence due to the increasing number of Fontan-palliated patients. Further data are needed to develop a better clinical management strategy for this poorly characterized patient population. Previous reports of animal models to study this disease have mostly been in small animals with limited fidelity. We show that congestive hepatopathy can be replicated in a chronic, progressive pulmonary artery banding model in sheep. We also show that the banding strategy can be controlled to titrate the level of liver injury. To date, we do not know of any other large animal model that can achieve this level of control over disease phenotype and clinical relevance.

The efficacy and safety of macitentan in Fontan-palliated patients: results of the 52-week randomised, placebo-controlled RUBATO trial

Abstract Background The clinical utility and long-term effects of endothelin receptor antagonists (ERAs) in Fontan-palliated patients remain unclear and there are currently no approved therapies. A decline in peak VO2 between consecutive cardiopulmonary exercise tests (CPETs) is highly prognostic for death or transplant in adult Fontan patients, hence its use as a primary endpoint in clinical trials of ERAs in patients with Fontan circulation. Purpose The RUBATO trial aimed to assess the efficacy and safety of macitentan, an endothelin receptor antagonist, in Fontan-palliated patients over 52 weeks. Methods In the multicentre, double-blind, randomised, placebo-controlled, phase 3 RUBATO trial, Fontan-palliated patients were randomised 1:1 to macitentan 10 mg once-daily or placebo for 52 weeks. Eligible patients were aged ≥12 years, in New York Heart Association functional class II or III, had no limitations for CPET (including no pacemakers), had undergone lateral tunnel or extracardiac conduit Fontan (total cavopulmonary connection) >1 year before screening and showed no signs of Fontan failure or clinical deterioration within 3 months before screening. Primary efficacy endpoint was change in peak VO2 from baseline to week 16. Secondary endpoints were change in peak VO2 from baseline over 52 weeks and change in mean count per minute of daily physical activity from baseline to week 16 as measured by an accelerometer. Adverse events were also assessed. Results 137 patients were randomised to macitentan (n=68) or placebo (n=69). 92.7% of patients completed 52 weeks of double-blind treatment: 7 and 3 patients prematurely discontinued study treatment in macitentan and placebo arms, respectively. Patient baseline characteristics are shown in Table 1. At week 16, the mean (SD) change from baseline in peak VO2 was –0.16 (2.86) with macitentan vs –0.67 (2.66) mL/kg/min with placebo (median unbiased estimate of the difference between macitentan and placebo: 0.62 mL/kg/min [99% repeated confidence interval –0.62; 1.85], p=0.1930). No treatment effect was observed in the two secondary endpoints (Table 2): mean (SD) count per minute of daily physical activity decreased from baseline to week 16 by 3.02 (92.44) with macitentan and by 14.34 (117.56) with placebo (p=0.4512). The most common AEs were headache (10.3% vs 8.7% on placebo), nasopharyngitis (5.9% vs 4.3%), and pyrexia (5.9% vs 4.3%). AEs leading to treatment discontinuation were reported in 3 (4.4%) and 1 (1.4%) of macitentan and placebo patients. Conclusion The 52-week RUBATO trial provides an important addition to data on the clinical utility of ERAs in Fontan-palliated patients. The primary efficacy endpoint was not met and no treatment effect was observed for the two secondary endpoints. Macitentan was well tolerated; safety findings were consistent with the known safety profile of macitentan 10 mg. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Actelion Pharmaceuticals Ltd., a Janssen pharmaceutical company of Johnson & Johnson.

Adequate exercise response at artificial altitude in Fontan patients

PurposeFor Fontan-palliated patients, altitude exposure is still a part of discussion since the extent of hypoxic pulmonary vasoconstriction potentially resulting in decreasing cardiac output (Qc), especially during physical exercise, is still unclear. We investigated the effects of normobaric hypoxia (15.2% O2) simulating 2,500 m above sea level on cardiopulmonary and metabolic parameters and the benefit of daily physical activity (PA) on hypoxic exercise capacity.MethodsA total of 21 Fontan patients (14–31 years) and 20 healthy controls performed cardiopulmonary exercise tests on a bicycle ergometer in normoxia and hypoxia until subjective exhaustion, measuring capillary lactate (cLa) every 2 min. In between, participants underwent an activity tracking over 5 days with a triaxial accelerometer.ResultsHypoxic exercise was well tolerated by Fontan patients, and no adverse clinical events were observed. Fontan patients showed reduced physical capacity under both conditions compared to controls (63% normoxia, 62% hypoxia), but the relative impairment due to hypoxia was similar for both (≈10%). Up to workloads of 2 W/kg oxygen uptake (O2) and heart rate (HR) developed similarly in patients and controls. cLa increased faster in relation to workload in Fontan patients, but remained significantly lower at peak workload (normoxia 3.88 ± 1.19 mmol/l vs. 7.05 ± 2.1 mmol/l; hypoxia 4.01 ± 1.12 mmol/l vs. 7.56 ± 1.82 mmol/l). Qc was diminished but could be increased similar to controls. Fontan patients with higher PA levels showed a higher O2peak in hypoxia.ConclusionExercise during short-time artificial altitude exposure seems to be safe for young Fontan patients. Further studies are needed to validate longer exposure under real conditions. O2, HR, and Qc might not be a limiting factor for exercise until workloads of 2 W/kg. Higher daily PA levels might improve physical capacity under altitude conditions.

The Influence of Respiration on Blood Flow in the Fontan Circulation: Insights for Imaging-Based Clinical Evaluation of the Total Cavopulmonary Connection.

Congenital heart disease is the most common birth defect and functionally univentricular heart defects represent the most severe end of this spectrum. The Fontan circulation provides an unique solution for single ventricle patients, by connecting both caval veins directly to the pulmonary arteries. As a result, the pulmonary circulation in Fontan palliated patients is characterized by a passive, low-energy circulation that depends on increased systemic venous pressure to drive blood toward the lungs. The absence of a subpulmonary ventricle led to the widely believed concept that respiration, by sucking blood to the pulmonary circulation during inspiration, is of great importance as a driving force for antegrade blood flow in Fontan patients. However, recent studies show that respiration influences pulsatility, but has a limited effect on net forward flow in the Fontan circulation. Importantly, since MRI examination is recommended every 2 years in Fontan patients, clinicians should be aware that most conventional MRI flow sequences do not capture the pulsatility of the blood flow as a result of the respiration. In this review, the unique flow dynamics influenced by the cardiac and respiratory cycle at multiple locations within the Fontan circulation is discussed. The impact of (not) incorporating respiration in different MRI flow sequences on the interpretation of clinical flow parameters will be covered. Finally, the influence of incorporating respiration in advanced computational fluid dynamic modeling will be outlined.

Impact of Protein-Losing Enteropathy on Inflammatory Biomarkers and Vascular Dysfunction in Fontan Circulation

Fontan palliation has improved survival for single ventricle patients, but long-term complications persist including cardiovascular dysfunction, neurohormonal abnormalities, and protein-losing enteropathy (PLE). Although chronic inflammation contributes to morbidity, an association between inflammation and vascular dysfunction has not been studied. We assessed inflammation and vascular function in 31 Fontan-palliated patients (52% male, median age 14.3 years), including 10 PLE+. Fontan circulation was associated with altered inflammatory cytokines (TNF-α: mean 2.5 ± 1.4 vs. 0.7 ± 0.2 pg/ml, p < 0.0001; sTNFR2: 371 ± 108 vs. 2694 ± 884 pg/ml, p < 0.0001) and vascular dysfunction [log-transformed reactive hyperemia index (lnRHI) 0.28 ± 0.19 vs. 0.47 ± 0.26, p < 0.01; augmentation index (AI) -2.9 ± 13.8 vs. -16.3 ± 12.0, p = 0.001; circulating endothelial progenitor cells (cEPCs) 5.0 ± 8.1 vs. 22.8 ± 15.9, p = 0.0002)]. Furthermore, PLE+ patients showed greater inflammation (IFN-γ 6.3 ± 2.2 vs. 11.5 ± 7.9 pg/ml, p = 0.01; sTNFR1: 1181 ± 420 vs. 771 ± 350 pg/ml, p = 0.01) and decreased arterial compliance (AI: 5.4 ± 17.1 vs. -6.8 ± 10.2, p = 0.02) than PLE- patients. Circulating EPCs, but not inflammatory cytokines, were inversely associated with arterial stiffness in Fontan patients. In conclusion, chronic inflammation and vascular dysfunction are observed after Fontan operation, with greater inflammation and arterial stiffness in Fontan patients with active PLE. However, there is no clear association between inflammatory cytokines and vascular dysfunction, suggesting these pathophysiologic processes are not mechanistically linked.

Treatment strategies for protein-losing enteropathy in Fontan-palliated patients.

Protein-losing enteropathy is an infrequent but severe condition occurring after Fontan procedure. The multifactorial pathogenesis remains unclear and no single proposed treatment strategy has proven universally successful. Therefore, we sought to describe different treatment strategies and their effect on clinical outcome and mortality. We performed a retrospective observational study. From the total cohort of 439 Fontan patients treated in our institution during the study period 1986-2019, 30 patients (6.8%) with protein-losing enteropathy were identified. Perioperative, clinical, echocardiographic, laboratory, and invasive haemodynamic findings and treatment details were analysed. Median follow-up after disease onset was 13.1 years [interquartile range 10.6]. Twenty-five patients received surgical or interventional treatment for haemodynamic restrictions. Medical treatment, predominantly pulmonary vasodilator and/or systemic anti-inflammatory therapy with budesonide, was initiated in 28 patients. In 15 patients, a stable remission could be achieved by medical or surgical procedures (n = 3 each), by combined multimodal therapy (n = 8), or ultimately by cardiac transplantation (n = 1). Phrenic palsy, bradyarrhythmia, Fontan pathway stenosis, and absence of a fenestration were significantly associated with development of protein-losing enteropathy (p = 0.001-0.48). Ten patients (33.3%) died during follow-up; 5-year survival estimate was 96.1%. In unadjusted analysis, medical therapy with budesonide and pulmonary vasodilator therapy in combination was associated with improved survival. Protein-losing enteropathy is a serious condition limiting survival after the Fontan procedure. Comprehensive assessment and individual treatment strategies are mandatory to achieve best possible outcome. Nevertheless, relapse is frequent and long-term mortality substantial. Cardiac transplantation should be considered early as treatment option.

Severity of Fontan-Associated Liver Disease Correlates with Fontan Hemodynamics

Fontan-palliated patients are at risk for the development of Fontan-associated liver disease (FALD). In this study, we performed a detailed hemodynamic and hepatic assessment to analyze the incidence and spectrum of FALD and its association with patients' hemodynamics. From 2017 to 2019, 145 patients underwent a detailed, age-adjusted hepatic examination including laboratory analysis (FibroTest®, n = 101), liver ultrasound (n = 117) and transient elastography (FibroScan®, n = 61). The median patient age was 16.0 years [IQR 14.2], and the median duration of the Fontan circulation was 10.3 years [IQR 14.7]. Hemodynamic assessment was performed using echocardiography, cardiopulmonary exercise capacity testing and cardiac catheterization. Liver ultrasound revealed hepatic parenchymal changes in 83 patients (70.9%). Severe liver cirrhosis was detectable in 20 patients (17.1%). Median liver stiffness measured by FibroScan® was 27.7 kPa [IQR 14.5], and the median Fibrotest® score was 0.5 [IQR 0.3], corresponding to fibrosis stage ≥ 2. Liver stiffness values and Fibrotest® scores correlated significantly with Fontan duration (P1 = 0.013, P2 = 0.012). Exercise performance was significantly impaired in patients with severe liver cirrhosis (P = 0.003). Pulmonary artery pressure and end-diastolic pressure were highly elevated in cirrhotic patients (P1 = 0.008, P2 = 0.003). Multivariable risk factor analysis revealed Fontan duration to be a major risk factor for the development of FALD (P < 0.001, OR 0.77, CI 0.68–0.87). In the majority of patients, hepatic abnormalities suggestive of FALD were detectable by liver ultrasound, transient elastography and laboratory analysis. The severity of FALD correlated significantly with Fontan duration and impaired Fontan hemodynamics. A detailed hepatic assessment is indispensable for long-term surveillance of Fontan patients.

Physical activity and heart rate monitoring in Fontan patients - Should we recommend activities in higher intensities?

ObjectiveExercise capacity is impaired in Fontan palliated patients. The change in daily activity behaviour with an increase in sedentary lifestyle results in low physical activity levels. This might have a greater impact on patients with chronic heart disease in contrast to healthy controls. For a better understanding, we compared data from cardiopulmonary exercise testing (CPET) with heart rates and physical activity in daily life.Methods21 Fontan patients and 20 age, sex and BMI matched controls underwent CPET and 5 days of daily life activity tracking with a triaxial accelerometer (wGT3x-BT, Actigraph) including heart rate monitoring with an optical heart rate sensor.Results27% of our Fontan teenagers and 71% of the Fontan adults reached the specific WHO recommendations for moderate to vigorous physical activity (MVPA) during everyday life (EDL), without differences to controls. There was a strong correlation between MVPA and for all Fontan patients (p = 0.0035, Pearson r = 0.788). Daily MVPA correlated to peak oxygen uptake and lactate production. Up to workloads of 2 W/kg and in daily life heart rates in Fontan patients were similar to controls.ConclusionsDaily MVPA is alarmingly low without any differences between Fontan patients and controls. Heart rate behaviour was similar and does not seem to be a limiting factor for physical activity in daily life. Higher intensity activities should be implemented regularly in EDL for Fontan patients. Proof is needed as to whether sports in moderate or possibly even in vigorous activity (e.g. high-intensity interval training) improve exercise capacity the most.

Tissue oxygen saturation assessment of microvascular perfusion in adults with Fontan palliation and comparator groups using vascular optical spectrophotometry: a pilot study

Objective: The Fontan operation greatly improves survival for single ventricle congenital heart disease patients but creates a physiology that leads to long-term multi-organ dysfunction. A non-invasive screening tool that can identify impending decline is sought. The objective of this pilot study was to assess the microcirculation in Fontan-palliated patients by measuring tissue oxygen saturation (StO2) in superficial and deeper tissues. Approach: Three patient cohorts were studied: Fontan group (n = 8) and two patient control groups, liver disease group (n = 8) and tetralogy of Fallot group (n = 9). 22 healthy controls were also examined. Superficial and deeper StO2 was measured at the forearm, thenar eminence, index and ring fingers of both arms using the LEA O2C spectrophotometry device. Main results: Superficial StO2 was reduced in Fontan patients compared to healthy controls (p = 0.002) and tetralogy patients (p = 0.016), but not compared to the liver group (p = 0.313). Deeper StO2 was similar between groups (p = 0.112). The gap between deeper and superficial StO2 was raised in Fontan patients compared to healthy controls (p = 0.001) and tetralogy patients (p = 0.037), but not compared to the liver group (p = 0.504). There was no clinically relevant difference in StO2 between the left and right arms, and the variation in StO2 according to measurement site was similar between the four groups. Significance: Vascular optical spectrophotometry is a feasible non-invasive measure of micro-circulatory function that can easily be performed in the clinic setting and may have utility in patients with Fontan circulations. Further, we provide important normal range data in the healthy control population which can be used to design future studies.

(305) - Dopamine as Rescue Therapy for Refractory Protein-Losing Enteropathy in Fontan-Palliated Patients

(305) - Dopamine as Rescue Therapy for Refractory Protein-Losing Enteropathy in Fontan-Palliated Patients

Sildenafil and Ventriculo-Arterial Coupling in Fontan-Palliated Patients: A Noninvasive Echocardiographic Assessment

The fundamental role of pulmonary vascular resistance in the Fontan circulation is obvious. Medications decreasing this resistance may have an impact on the fate of this population. Hence, we assessed noninvasively the effect of oral sildenafil on the ventriculo-arterial coupling in patients with Fontan circulation. In a single-center, prospective case series study, 23 patients with fenestrated extracardiac total cavopulmonary connection age 12-31 years were enrolled in this study. Clinical characteristics and echocardiographic examination were performed before and after a 1 week course of sildenafil at 0.5 mg/kg every 8 h. Sildenafil had no effect on heart rate and blood pressure. However, oxygen saturation was significantly increased with sildenafil (87.6 ± 4.3 vs. 90.1 ± 3.6; P < 0.0001). The calculated noninvasive ventricular end-systolic elastance (Ees) was greater after sildenafil compared with the pre-sildenafil values (1.59 ± 0.17 vs. 1.72 ± 0.27 mm Hg/ml; P = 0.001). Moreover, significant decreases in arterial elastance (Ea) (1.62 ± 0.53 vs. 1.36 ± 0.43 mm Hg/ml; P < 0.0001), ventricular end-diastolic elastance (Eed) (0.05 ± 0.021 vs. 0.04 ± 0.013; P = 0.002), and, finally, ventriculo-arterial coupling index (0.99 ± 0.26 vs. 0.76 ± 0.15; P < 0.0001) were found after sildenafil administration. The intolerable side effects that led to stopping the sildenafil occurred only in one (4 %) patient. Sildenafil has increased ventricular systolic elastance and improved ventriculo-arterial coupling in patients palliated with Fontan circulation. Short-term sildenafil was well tolerated in most of the patients with only minor side effects.

Impact of Vitamin C on Endothelial Function and Exercise Capacity in Patients with a Fontan Circulation

To evaluate the impact of antioxidant therapy on functional health status in Fontan-palliated patients. Design. Prospective, randomized, double-blind, placebo-controlled trial. Fifty-three generally asymptomatic Fontan patients. Patients were randomized to receive either high-dose ascorbic acid (vitamin C) or placebo for 4 weeks. Peripheral vascular function, as measured with endothelium-dependent digital pulse amplitude testing (EndoPAT), and exercise capacity were assessed before and after study drug treatment. Primary outcome measures included the EndoPAT index and peripheral arterial tonometry (PAT) ratio, both validated markers of vascular function. Secondary outcome measures included peak oxygen consumption and work. Twenty-three vitamin C- and 21 placebo-assigned subjects completed the protocol (83%). Median age and time from Fontan completion were 15 (interquartile range [IQR] 11.7-18.2) and 11.9 years (IQR 9.0-15.7), respectively. Right ventricular morphology was dominant in 30 (57%). Outcome measures were similar between groups at baseline. Among all subjects, vitamin C therapy was not associated with a statistical improvement in either primary or secondary outcome measures. In subjects with abnormal vascular function at baseline, compared with placebo, vitamin C therapy more frequently resulted in normalization of the EndoPAT index (45% vs. 17%) and PAT ratio (38% vs. 13%). Short-term therapy with vitamin C does not alter endothelial function or exercise capacity in an asymptomatic Fontan population overall. Vitamin C may provide benefit to a subset of Fontan patients with abnormal vascular function.

Oral Budesonide Treatment for Protein-Losing Enteropathy in Fontan-Palliated Patients

Protein-losing enteropathy (PLE) is a rare complication of Fontan palliation associated with significant morbidity and mortality. It is characterized by the loss of serum proteins into the intestinal lumen, and its pathophysiology likely involves enteral inflammation. Budesonide, an oral steroid, is an attractive treatment option because of its potent enteral activity and minimal systemic side effects. A single-center, retrospective review of Fontan-palliated PLE patients treated with oral budesonide for 6 months or longer was performed. The patient characteristics reviewed were demographics, anatomic diagnosis, budesonide treatment (dose and duration), other medications and therapeutic interventions, hospitalizations, serum albumin levels, medical complications, and patient status at the time of follow-up assessment. The study enrolled 10 patients representing 228 patient-months of on-therapy follow-up evaluation. Serum albumin levels increased after initiation of budesonide for 90% of the patients, and clinical evidence of fluid overload improved for 60% of them. Symptomatic improvement was reported in 80% of the cases. During the treatment period, 50% of the patients met the primary end point of death or cardiac transplantation. In this series of PLE patients, oral budesonide therapy was associated with significant symptomatic improvement and sustained increases in serum albumin. However, budesonide therapy may not alter the long-term outcome for patients with advanced PLE.

Usefulness of Peripheral Vascular Function to Predict Functional Health Status in Patients With Fontan Circulation

After the Fontan operation, patients are at a substantial risk of the development of impaired functional health status. Few early markers of suboptimal outcomes have been identified. We sought to assess the association between peripheral vascular function and functional health status in Fontan-palliated patients. Asymptomatic Fontan patients (n = 51) and age- and gender-matched healthy controls (n = 22) underwent endothelial pulse amplitude testing using a noninvasive fingertip peripheral arterial tonometry (PAT) device. Raw data were transformed into the PAT ratio, an established marker of vascular function. Cardiopulmonary exercise testing was performed using the Bruce protocol. In the Fontan cohort, 94% of patients were New York Heart Association functional class I and 88% had a B-type natriuretic peptide level of <50 pg/ml. The baseline pulse amplitude, a measure that reflects the arterial tone at rest, was greater in the Fontan patients than in the controls (median 2.74, interquartile range 1.96 to 4.13 vs median 1.86, interquartile range 1.14 to 2.79, p = 0.03). The PAT ratio, a measure of reactive hyperemia, was lower in Fontan patients (median 0.17, interquartile range -0.04 to 0.44, vs median 0.50, interquartile range 0.27 to 0.74, p = 0.002). The key parameters of exercise performance, including peak oxygen consumption (median 28.8 ml/kg/min, interquartile range 25.6 to 33.2 vs median 45.5 ml/kg/min, interquartile range 41.7 to 49.9, p <0.0001) and peak work (median 192 W, interquartile range 150 to 246 vs median 330, interquartile range 209 to 402 W, p <0.0001), were lower in Fontan patients than in the controls. The PAT ratio correlated with the peak oxygen consumption (r = 0.28, p = 0.02) and peak work (r = 0.26, p = 0.03). In conclusion, in an asymptomatic Fontan population, there is evidence of reduced basal peripheral arterial tone and vasodilator response, suggesting dysfunction of the endothelium-derived nitric oxide pathway. Vasodilator function appears to correlate with exercise performance.

Heart failure and ventricular dysfunction in patients with single or systemic right ventricles.

Previous studies suggested a high incidence of congestive heart failure in patients with single and/or systemic right ventricles. The corresponding risk in an adult population is unknown. A cohort of 188 consecutive adult patients with single or systemic right ventricles was prospectively assessed with gated radionuclide angiography (n=135) or 2D echocardiography (n=188) and followed up clinically. Clinical assessment showed 82.4% of the patients were in New York Heart Association class I or II, 13.3% were in class III, and 4.3% were in class IV. Heart failure occurred in 22.2% of patients with transposition of the great arteries and a Mustard procedure, 32.3% of patients with congenitally corrected transposition of the great arteries, and 40% of Fontan-palliated patients. Symptomatic patients had significantly lower anaerobic thresholds (10.3 +/- 2.8 versus 13.2 +/- 4.8 mL center dot kg(-1) center dot min(-1), P=0.006) and peak (center dot)VO(2) (15.2 +/- 4.8 versus 20.3 +/- 6.8 mL center dot kg(-1) center dot min(-1), P<0.00029). Systemic ventricular ejection fraction in symptomatic versus asymptomatic patients at rest was 34.8 +/- 15.7% versus 46.7 +/- 13.4% (P=0.00001). Mortality was 47.1% among symptomatic patients and 5% among asymptomatic patients at 15.7 years of postoperative follow-up. Seven of 12 patients with potentially correctable surgical lesions died or persisted in heart failure despite surgery. Best predictors for mortality were New York Heart Association class, systemic ejection fraction, and age at operation. Patients with single or systemic right ventricles have significant risk for heart failure accompanied by high mortality. This study suggests the importance of identifying this group of patients who are at risk for heart failure and considering strategies to preserve ventricular function.

Flow-Pressure Relationship in Fontan-Palliated Patients

Simultaneous pressure and Doppler flow patterns were recorded in the inferior vena cava (IVC) and main pulmonary artery (PA) of 6 subjects in whom nonvalved atriopulmonary anastomosis had been performed. All patients were asymptomatic without any pressure gradient at the level of the anastomosis