Palliative treatment with the Fontan procedure has greatly improved survival for children with functionally univentricular heart. Since Fontan performed the first successful operation, the procedure has evolved and is now performed as Total Cavo-Pulmonary Connection (TCPC). An increasing prevalence and longer life expectancy of TCPC patients have raised new challenges. The survivors are often suffering complications such as arrhythmias, myocardial dysfunction, thromboembolic events, neuropsychological deficit, protein-losing enteropathy and reduced exercise capacity. Several causes for the reduced exercise capacity may be present e.g. impaired function of the single ventricle, valve dysfunction and chronotropic impairment, and perhaps also increased pulmonary vascular resistance. Thus, plasma endothelin-1 has been shown to correlate with increased pulmonary vascular resistance and the risk of failing Fontan circulation. This has raised the question of the role for pulmonary vasodilation therapy, especially endothelin receptor antagonist in the management of TCPC patients. The TEMPO trial aims to investigate whether Bosentan, an endothelin receptor antagonist, can be administered safely and improve exercise capacity in TCPC patients. The trial design is randomized, double-blind and placebo-controlled. Bosentan/placebo is administered for 14 weeks with control visits every four weeks. The primary endpoint is change in maximal oxygen consumption as assessed on bicycle ergometer test. Secondary endpoints include changes in pulmonary blood flow during exercise test, pro brain natriuretic peptide and quality of life. We hypothesize that treatment with Bosentan, an endothelin receptor antagonist, can be administered safely and improve exercise capacity in TCPC patients. clinicaltrials.gov NCT01292551
Abstract Aims The decisions about placing an ICD in a child are more difficult than in an adult due to longer expected lifespan and the complication risk. Young patients gain the most years from ICDs, despite higher risk of device-related complications. The secondary prevention ICD indication is clear, and device is implanted regardless of potential complications. For primary prevention, risk of sudden cardiac death and complications need to be evaluated. We aimed to compare outcomes for primary and secondary prevention ICDs. Methods and results Retrospective nationwide cohort study including paediatric patients identified from the Danish ICD registry with ICD implanted at an age ≤ 15 from 1982–21. Demographics, complications (composite of device-related infections or lead-failure requiring re-operation, mortality because of arrhythmia, or unknown cause), and mortality were retrieved from medical charts. Endpoint was appropriate therapy (shock or anti-tachycardia pacing for ventricular tachycardia or fibrillation). Of 72 receiving an ICD, the majority had channelopathies (n = 34) or structural heart diseases (n = 28). ICDs were implanted in 23 patients for primary prevention and 49 for secondary prevention, at median ages of 13.8 and 11.6 years (P-value 0.01), respectively. Median follow-up was 9.0 (interquartile ranges: 4.7–13.5) years. The 10-year cumulative incidence of first appropriate therapy was 70%, with complication and inappropriate therapy rates at 41% and 15%, respectively. No difference was observed between prevention groups for all outcomes. Six patients died during follow-up. Conclusion In children, two-thirds are secondary prevention ICDs. Children have higher appropriate therapy and complication rates than adults, while the inappropriate therapy rate was low.
Fontan-type operations in patients with functionally univentricular hearts have been performed for almost 40 years. Since the first description of the Fontan operation, short- and medium-term operative survival has been good in the current era due to careful patient selection, modifications in surgical techniques, and advances in postoperative care. However, a number of serious long-term complications affect most patients. Nonetheless, the prevalence of univentriucular patients is increasing as the number of late survivors increases. Caregivers will therefore be evermore faced with the challenge of recognizing and managing the Fontan related complications and patients with failing Fontan physiology. This review discusses the current surgical management of patients with functionally univentricular heart (UVH) and long-term sequelae of the univentricular circulation based on literature on outcome after the Fontan procedure.
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.
Patients with cyanotic congenital heart disease (CCHD) may have a low burden of atherosclerosis. Endothelial dysfunction is an early stage of atherosclerosis and endothelial function is previously studied in smaller CCHD groups with different techniques and variable results. We aimed to examine endothelial function and carotid atherosclerosis in a larger group of CCHD patients.This multicentre study assessed endothelial function in adults with CCHD and controls by measuring the dilatory response of the brachial artery to post-ischemic hyperaemia (endothelium-dependent flow-mediated-vasodilatation (FMD)), and to nitroglycerin (endothelium-independent nitroglycerin-induced dilatation (NID)). Flow was measured at baseline and after ischaemia (reactive hyperaemia). Carotid-intima-media-thickness (CIMT), prevalence of carotid plaque and plaque thickness (cPT-max) were evaluated ultrasonographically. Lipoproteins, inflammatory and vascular markers, including sphingosine-1-phosphate (S1P) were measured.Forty-five patients with CCHD (median age 50 years) and 45 matched controls (median age 52 years) were included. The patients presented with lower reactive hyperaemia (409 ± 114% vs. 611 ± 248%, p < 0.0001), however preserved FMD response compared to controls (106.5 ± 8.3% vs. 106.4 ± 6.1%, p = 0.95). In contrast, NID was lower in the patients (110.5 ± 6.1% vs. 115.1 ± 7.4%, p = 0.053). There was no difference in CIMT, carotid plaque or cPT-max. The patients presented with lower high-density-lipoprotein cholesterol, and higher level of inflammatory markers and S1P.Adults with CCHD had preserved FMD in the brachial artery, but impaired NID response and lower reactive hyperaemia than controls. The preserved FMD and the comparable prevalence of carotid atherosclerosis indicate that CCHD patients have the same risk of atherosclerosis as controls.
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