Cardiac Function and Serum Biomarkers throughout Staged Fontan Palliation: A Prospective Observational Study.

Fontan patients undergo multiple cardiothoracic surgeries in childhood. Following these procedures, ventricular function is temporarily decreased, and recovers over months. This is presumably related to cardiopulmonary bypass, but this is incompletely understood. Throughout the Fontan palliation, cardiac function is also affected by volume unloading. We aimed to gain insight into the biological processes related to impaired ventricular function and recovery following Fontan palliations using a panel of biomarkers. Furthermore, we described changes in ventricular function across the Fontan palliation due to volume unloading. We performed a prospective multicenter observational study in patients undergoing partial (PCPC) or total cavo-pulmonary connection (TCPC). Patients underwent assessment-including echocardiography and blood sampling-before surgery (T1), at first follow-up (T2), and 1 year after their procedures (T3). Blood samples were analyzed using a biomarker panel (OLINK CVD-III). Ninety-two biomarkers were expressed as principal components (PC) to limit multiple statistical testing. We included 32 PCPC patients aged 7.2 [5.3-10.3] months, and 28 TCPC patients aged 2.7 [2.2-3.8] years. The single ventricular longitudinal strain (SV GLS) temporarily decreased for PCPC patients at T2 (-15.1 ± 5.6 (T1) to -13.5 ± 5.2 (T2) to -17.3 ± 4.5 (T3), p < 0.047 for all differences), but not following TCPC. The serum biomarkers were expressed as 4 PCs. PC1, including biomarkers of cell-cell adhesion, was not related to any patient characteristic. PC2, including biomarkers of superoxide anion regulation, increased at T2. PC3, including biomarkers of cardiovascular development, related to the stage of Fontan palliation. PC4 was of uncertain biological or clinical significance. No PC was found that related to ventricular performance. The SV GLS was temporarily diminished following PCPC, but not following TCPC. Several biomarkers were related to post-operative stress and adaptation to the PCPC or TCPC circulation, but none were related to the outcome.

Right ventricular-vascular coupling ratio in pediatric pulmonary arterial hypertension: A comparison between cardiac magnetic resonance and right heart catheterization measurements.

BACKGROUND: In pulmonary arterial hypertension (PAH), right ventricular (RV) failure is the main cause of mortality. Non-invasive estimation of ventricular-vascular coupling ratio (VVCR), describing contractile response to afterload, could be a valuable tool for monitoring clinical course in children with PAH. This study aimed to test two hypotheses: VVCR by cardiac magnetic resonance (VVCRCMR) correlates with conventional VVCR by right heart catheterization (VVCRRHC) and both correlate with disease severity. METHODS AND RESULTS: Twenty-seven patients diagnosed with idiopathic and associated PAH without post-tricuspid shunt, who underwent RHC and CMR within 17 days at two specialized centers for pediatric PAH were retrospectively studied. Clinical functional status and hemodynamic data were collected. Median age at time of MRI was 14.3 years (IQR: 11.1-16.8), median PVRi 7.6 WU × m2 (IQR: 4.1-12.2), median mPAP 40 mm Hg (IQR: 28-55) and median WHO-FC 2 (IQR: 2-3). VVCRCMR, defined as stroke volume/end-systolic volume ratio was compared to VVCRRHC by single-beat pressure method using correlation and Bland-Altman plots. VVCRCMR and VVCRRHC showed a strong correlation (r = 0.83, p < 0.001). VVCRCMR and VVCRRHC both correlated with clinical measures of disease severity (pulmonary vascular resistance index [PVRi], mean pulmonary artery pressure [mPAP], mean right atrial pressure [mRAP], and World Health Organization functional class [WHO-FC]; all p ≤ 0.02). CONCLUSIONS: Non-invasively measured VVCRCMR is feasible in pediatric PAH and comparable to invasively assessed VVCRRHC. Both correlate with functional and hemodynamic measures of disease severity. The role of VVCR assessed by CMR and RHC in clinical decision-making and follow-up in pediatric PAH warrants further clinical investigation.

Right ventricular pressure overload alters cardiac lipid composition.

INTRODUCTION: Right ventricular (RV) failure due to pressure load is an important determinant of clinical outcome in pulmonary hypertension, congenital heart disease and left ventricular failure. The last decades it has become clear that metabolic dysregulation is associated with the development of RV-failure. However, underlying mechanisms remain to be unraveled. Recently, disruption of intracardiac lipid content has been suggested as potential inducer of RV failure. In the present study, we used a rat model of RV-dysfunction and aimed to obtain insight in temporal changes in RV-function, -remodelling and -metabolism and relate this to RV lipid content. METHODS AND RESULTS: Male Wistar WU rats were subjected to pulmonary artery banding (n = 25) or sham surgery (n = 14) and cellular, hemodynamic and metabolic assessments took place after 2, 5 and 12 weeks. In this model RV dysfunction and remodelling occurred, including early upregulation of oxidative stress markers. After 12 weeks of pressure load, lipidomics revealed significant decreases of myocardial diglycerides and cardiolipins, driven by (poly-)unsaturated forms. The decrease of cardiolipins was driven by its most abundant form, tetralinoleoylcardiolipin. Mitochondrial capacity for fatty acid oxidation preserved, while the capacity for glucose oxidation increased. CONCLUSION: RV dysfunction due to pressure load, is associated with decreased intracardiac unsaturated lipids, especially tetralinoleoylcardiolipin. This was accompanied with preserved mitochondrial capacity regarding fatty acids oxidation, with increased capacity for glucose oxidation, and early activation of oxidative stress. We suggest that early interventions should be directed towards preservation of lipid availability as possible mean in order to prevent RV failure.

Necrotizing Enterocolitis Associated with Congenital Heart Disease: a Different Entity?

BACKGROUND: Necrotizing enterocolitis (NEC) predominantly occurs in preterm infants (PT-NEC). In term neonates, NEC occurs more frequently when a congenital heart disease is present (CHDNEC). Our aim was to evaluate differences and similarities in disease characteristics of PT-NEC versus CHD-NEC. METHODS: In this retrospective case-control study we identified all CHD infants who developed NEC Bell's stage ≥2 in our center from 2004 to 2014. We randomly selected (1:2 ratio) PT-NEC infants from the same period. Biochemical and clinical variables were retrieved from patient files. RESULTS: We found 18 CHD-NEC infants and selected 36 PT-NEC infants (gestational age 28.3 [25-35.6] weeks vs. 38.6 [31.7-40.7] weeks). Postnatal age at onset was significantly lower in CHD-NEC patients (4 [2-24] vs. 11 [4-41] days, p < 0.001). Lowest pH levels were lower (7.21 [7.01-7.47] vs. 7.27 [6.68-7.39], p = 0.02), and highest CRP levels were higher (112.5 mg/L [5.0-425.0] vs. 66.0 [5.2-189.0], p = 0.05) in PT-NEC vs. CHD-NEC. Anatomic localisation of the disease differed: the colon was significantly more often involved in CHD-NEC versus PT-NEC (86% vs. 33%, p = 0.03). Mortality caused by NEC was not different (22% vs. 11%, p = 0.47). CONCLUSION: While outcome of NEC in both groups is similar, the predominant NEC localisation differed between CHD-NEC and PT-NEC patients. This suggests that both variants of the disease have a different underlying pathophysiological mechanism that predisposes different intestinal regions to develop NEC. TYPE OF STUDY: Retrospective Case-Control Study. LEVEL OF EVIDENCE: Level III.

Maternal-fetal cholesterol transport in the second half of mouse pregnancy does not involve LDL receptor-related protein 2.

AIM: LDL receptor-related protein type 2 (LRP2) is highly expressed on both yolk sac and placenta. Mutations in the corresponding gene are associated with severe birth defects in humans, known as Donnai-Barrow syndrome. We here characterized the contribution of LRP2 and maternal plasma cholesterol availability to maternal-fetal cholesterol transport and fetal cholesterol levels in utero in mice. METHODS: Lrp2+/- mice were mated heterozygously to yield fetuses of all three genotypes. Half of the dams received a 0.5% probucol-enriched diet during gestation to decrease maternal HDL cholesterol. At E13.5, the dams received an injection of D7-labelled cholesterol and were provided with 1-13 C acetate-supplemented drinking water. At E16.5, fetal tissues were collected and maternal cholesterol transport and fetal synthesis quantified by isotope enrichments in fetal tissues by GC-MS. RESULTS: The Lrp2 genotype did not influence maternal-fetal cholesterol transport and fetal cholesterol. However, lowering of maternal plasma cholesterol levels by probucol significantly reduced maternal-fetal cholesterol transport. In the fetal liver, this was associated with increased cholesterol synthesis rates. No indications were found for an interaction between the Lrp2 genotype and maternal probucol treatment. CONCLUSION: Maternal-fetal cholesterol transport and endogenous fetal cholesterol synthesis depend on maternal cholesterol concentrations but do not involve LRP2 in the second half of murine pregnancy. Our results suggest that the mouse fetus can compensate for decreased maternal cholesterol levels. It remains a relevant question how the delicate system of cholesterol transport and synthesis is regulated in the human fetus and placenta.

NT-proBNP and exercise capacity in adult patients with congenital heart disease and a prosthetic valve: a multicentre PROSTAVA study.

OBJECTIVES: N-terminal B­type natriuretic peptide (NT-proBNP) is an important biomarker for the detection of heart failure. Adults with congenital heart disease (ACHD) and a prosthetic heart valve are at risk for heart failure. This study aimed to determine the value of NT-proBNP in ACHD patients with a prosthetic valve and investigate its relationship with cardiac function and exercise capacity. METHODS: In this multi-centre cross-sectional observational study, data regarding medical history, echocardiography, exercise testing (VO2peak) and laboratory blood evaluation (including NT-proBNP) were collected in ACHD patients with a single prosthetic valve (either homografts, heterografts or mechanical valves). RESULTS: A total of 306 ACHD patients with pulmonary valve replacement (PVR, n = 139), aortic valve replacement (n = 141), mitral valve replacement (n = 21) or tricuspid valve replacement (n = 5) were investigated. The majority of patients (77 %) were in NYHA class I or II. Elevated NT-proBNP levels (cut-off ≥125 pg/ml) were found in 50 % of the patients, with the highest levels in patients with mitral valve replacements. In this study population, NT-proBNP levels were associated with gender (p = 0.029) and VO2max (p < 0.001). In PVR patients, NT-proBNP levels were associated with lower VO2peak, also after adjustment for age, gender and age at valve replacement in a multivariate model (p = 0.015). CONCLUSIONS: In patients with ACHD and a prosthetic valve, elevated NT-proBNP levels are frequently observed despite preserved NYHA class. In PVR patients, a higher NT-proBNP level was associated with a lower VO2peak. These results may be of importance in the ongoing discussion about the timing of valve replacement in patients with CHD.

KinCor, a national registry for paediatric patients with congenital and other types of heart disease in the Netherlands: aims, design and interim results.

OBJECTIVE: Studies in children with heart disease have been hampered by a lack of easily identifiable patient groups. Currently, there are few prospective population-based registries covering the entire spectrum of heart disease in children. KinCor is a Dutch national registry for children with heart diseases. This paper presents the aims, design and interim results of the KinCor project. METHODS: All children presenting at a Dutch university medical centre with a diagnosis of heart disease from 2012 onwards were eligible for registration in the KinCor database. Data entry is through a web-based portal. Entry codes have been synchronised with the European Paediatric Cardiac Coding system, allowing coupling with similar databases for adults, such as CONCOR. RESULTS: Between June 2012 and July 2015, 8421 patients were registered (76 % of those eligible). Median age of the patients was 9.8 years, 44.7 % were female; 6782 patients had morphological congenital heart disease. The most prevalent morphological congenital heart defects were ventricular septal defects (18 %), Tetralogy of Fallot (10 %) and transposition of great arteries (9 %). For 42 % of the patients additional diagnoses were registered. Sixty percent of patients had undergone at least one intervention (catheter intervention or surgery). CONCLUSION: The KinCor database has developed into a large registry of data of children with all types of heart disease and continues to grow. This database will provide the opportunity for epidemiological research projects on congenital and other types of heart disease in children. Entry codes are shared with the CONCOR database, which may provide a unique dataset.

Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension).

BACKGROUND: The TOPP Registry has been designed to provide epidemiologic, diagnostic, clinical, and outcome data on children with pulmonary hypertension (PH) confirmed by heart catheterisation (HC). This study aims to identify important characteristics of the haemodynamic profile at diagnosis and HC complications of paediatric patients presenting with PH. METHODS AND RESULTS: HC data sets underwent a blinded review for confirmation of PH (defined as mean pulmonary arterial pressure ≥ 25 mmHg, pulmonary capillary wedge pressure ≤ 12 mmHg and pulmonary vascular resistance index [PVRI] of >3 WU × m(2)). Of 568 patients enrolled, 472 who fulfilled the inclusion criteria and had sufficient data from HC were analysed. A total of 908 diagnostic and follow-up HCs were performed and complications occurred in 5.9% of all HCs including five (0.6%) deaths. General anaesthesia (GA) was used in 53%, and conscious sedation in 47%. Complications at diagnosis were more likely to occur if GA was used (p=0.04) and with higher functional class (p=0.02). Mean cardiac index (CI) was within normal limits at diagnosis when analysed for the entire group (3.7 L/min/m(2); 95% confidence interval 3.4-4.1), as was right atrial pressure despite a severely increased PVRI (16.6 WU × m(2,) 95% confidence interval 15.6-17.76). However, 24% of the patients had a CI of <2.5L/min/m(2) at diagnosis. A progressive increase in PVRI and decrease in CI was observed with age (p<0.001). CONCLUSION: In TOPP, haemodynamic assessment was remarkable for preserved CI in the majority of patients despite severely elevated PVRI. HC-related complication incidence was 5.9%, and was associated with GA and higher functional class.

Impact of introduction of 20-week ultrasound scan on prevalence and fetal and neonatal outcomes in cases of selected severe congenital heart defects in The Netherlands.

OBJECTIVES: To evaluate in a population-based cohort the effect of the introduction of the 20-week ultrasound scan in 2007 on the time of diagnosis, pregnancy outcome and total prevalence and liveborn prevalence of cases with selected congenital heart defects (CHDs) in The Netherlands. METHODS: We included children and fetuses diagnosed with selected severe CHD, born in the 11-year period from 2001 to 2011. Two groups of CHD were defined: those associated with an abnormal four-chamber view at ultrasound (Group 1), and those associated with a normal four-chamber view at ultrasound (Group 2). The time of diagnosis, pregnancy outcome and total liveborn prevalence were compared for both groups over two 5-year periods, before and after the introduction of the 20-week ultrasound scan. Trends in total and liveborn prevalence were examined over 2001 to 2011. RESULTS: Information was collected on 269 children and fetuses. After the introduction of the 20-week ultrasound scan, the prenatal detection rate of CHDs increased in both groups (Group 1, 34.6% in 2001-2005 vs 84.8% in 2007-2011 (P < 0.001); Group 2, 14.3% in 2001-2005 vs 29.6% in 2007-2011 (P = 0.037)). The rate of termination of pregnancy (TOP) increased significantly only for Group 1 (15.4% vs 51.5% (P < 0.001)). The total prevalence of CHD in Group 1 increased over time from 2.9 per 10 000 births in 2001 to 6.4 per 10 000 births in 2011 (P = 0.016). The liveborn prevalence did not show a trend over time. For Group 2, no trends in total or liveborn prevalence could be detected over time. CONCLUSIONS: Since the implementation of the routine 20-week ultrasound scan in The Netherlands, prenatal detection rate of selected severe CHDs increased significantly. Improved prenatal detection was accompanied by a more than three-fold increase in TOP, although only in those CHDs with an abnormal four-chamber view at prenatal ultrasound.

Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a commonly fatal pulmonary vascular disease that is often diagnosed late and is characterised by a progressive rise in pulmonary vascular resistance resulting from typical vascular remodelling. Recent data suggest that vascular damage plays an important role in the development of radiation-induced pulmonary toxicity. Therefore, the authors investigated whether irradiation of the lung also induces pulmonary hypertension. METHODS: Different sub-volumes of the rat lung were irradiated with protons known to induce different levels of pulmonary vascular damage. RESULTS: Early loss of endothelial cells and vascular oedema were observed in the irradiation field and in shielded parts of the lung, even before the onset of clinical symptoms. 8 weeks after irradiation, irradiated volume-dependent vascular remodelling was observed, correlating perfectly with pulmonary artery pressure, right ventricle hypertrophy and pulmonary dysfunction. CONCLUSIONS: The findings indicate that partial lung irradiation induces pulmonary vascular remodelling resulting from acute pulmonary endothelial cell loss and consequential pulmonary hypertension. Moreover, the close resemblance of the observed vascular remodelling with vascular lesions in PAH makes partial lung irradiation a promising new model for studying PAH.

Patient characteristics in persistent pulmonary hypertension of the newborn.

Objective. To assess the impact of PPHN on mortality, morbidity, and behavioural skills. Methods. A retrospective observational study of 143 newborns with PPHN, over an 11-year period, using objective health-status data from medical records and family doctors, and subjective health status data from a standardized Child Behaviour Checklist. Results. The majority of patients were males, treated with inhaled nitric oxide had maladaptation/maldevelopment as pathophysiological mechanism and a gestational age >37 weeks. In term newborns, types of pathophysiological mechanism (P < .001) and Oxygen Index (P = .02) were independent predicting risk factors for PPHN-related mortality. Analysis of preexisting disease and outcome categories in term newborns showed only a significant correlation between the use of iNO and respiratory complaints (P = .03), not confirmed by multivariate analysis and regression analysis. Conclusions. PPHN is a serious, often fatal condition. The incidence of PPHN in preterm newborns is high. In term survivors, PPHN had no additional role in morbidity/outcome.

Treatment options for paediatric pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a serious, progressive condition, which can present idiopathically or secondary to conditions such as systemic sclerosis or congenital heart disease. The condition exists in both adult and paediatric forms, which possess several similar characteristics. Adult and paediatric PAH can, however, be distinguished based on underlying pathology and the presence of age-specific conditions, some of which are related to poor lung development in children. Improved knowledge of vascular biology has led to the development of several PAH-specific therapies, which have demonstrated clinical benefits in adults, including improved exercise capacity and prolonged survival. Treatment data in paediatric PAH are scarce. Although limited, the existing data indicate that current treatments for paediatric PAH are well tolerated and effective, at least in the short- and medium-term. Nevertheless, the current guidelines for clinicians, which recommend use of the adult treatment algorithm in paediatric patients, appear justified when judged according to the available evidence. However, further randomised, controlled trials are necessary to increase the evidence base for treatment of paediatric PAH, especially in relation to age-specific conditions. At present, early initiation of treatment and combination pharmacological therapy may offer the most promising courses of action to improve outcomes in paediatric PAH.

Management of pulmonary arterial hypertension in children.

In this review we discuss the new anti- Pulmonary Arterial Hypertension [PAH] drugs and the available data on their use in paediatric PAH. Treatment of patients with PAH, children and adults, is aimed at a reduction of symptoms, survival and improvement of haemodynamics as well as exercise capacity. PAH may reflect significant different disease conditions in infants and children when compared to PAH in adults. In contrast to adult PAH, characterized mainly by idiopathic PAH and PAH associated with connective tissue disease, more than half of the cases of PAH in children are associated with congenital heart disease. Therefore, efficacy of PAH drugs in these diseases can not be extrapolated from that in adults with PAH.

Bosentan in pulmonary arterial hypertension: a comparison between congenital heart disease and chronic pulmonary embolism.

Background. In patients with pulmonary hypertension, it is unknown whether the treatment effect of bosentan is dependent on the duration of pulmonary vessel changes. Therefore, we studied the response to bosentan in patients with life-long pulmonary vessel changes (pulmonary arterial hypertension (PAH) due to congenital heart disease (CHD)) and in patients with subacutely induced pulmonary vessel changes (chronic thromboembolic pulmonary hypertension (CTEPH)).Methods. In this open-label study, 18 patients with PAH due to CHD and 16 patients with CTEPH were treated with bosentan for at least one year. All patients were evaluated at baseline and during follow-up by means of the six-minute walk distance (6-MWD) and laboratory tests.Results. Improvement of 6-MWD was comparable in patients with PAH due to CHD (444+/-112 m to 471+/-100 m, p=0.02), and in CTEPH (376+/-152 m to 423+/-141 m, p=0.03) after three months of treatment. After this improvement, 6-MWD stabilised in both groups.Conclusion. Although duration of pulmonary vessel changes is strikingly different in patients with PAH due to CHD and CTEPH, the effect of one year of bosentan treatment was comparable. The main treatment effect appears to be disease stabilisation and decreasing the rate of deterioration. (Neth Heart J 2009;17:334-8.).

Effects of erythropoietin on advanced pulmonary vascular remodelling.

Erythropoietin (EPO) mobilises endothelial progenitor cells and promotes neovascularisation in heart failure. The present authors studied the effects of EPO on pulmonary vascular and cardiac remodelling in a model for flow-associated pulmonary arterial hypertension (PAH). PAH was induced in adult male Wistar rats by the injection of monocrotaline combined with an abdominal aortocaval shunt 1 week later (PAH or experimental group). Immediately afterwards, rats were randomised into those who received treatment with EPO (PAH+EPO group) and controls. Pulmonary and systemic haemodynamics, and right ventricular and pulmonary vascular remodelling were evaluated 3 weeks later. Vascular occlusion of the intra-acinar pulmonary vessels (13.4+/-0.7 versus 16.7+/-1.3% in PAH+EPO and PAH, respectively) and medial wall thickness of the pre-acinar arteries (wall-to-lumen ratio 0.13+/-0.01 versus 0.17+/-0.01 in PAH+EPO and PAH, respectively) decreased after treatment with EPO. Moreover, right ventricular capillary density was increased by therapy (2,322+/-61 versus 2,100+/-63 capillaries x mm(-2) in PAH+EPO and PAH, respectively). Increased mean pulmonary arterial pressure and decreased right ventricular contractility in the model were not altered by EPO treatment. In this rat model of flow-associated pulmonary arterial hypertension, erythropoietin treatment beneficially affected pulmonary vascular and cardiac remodelling. These histopathological effects were not accompanied by significantly improved haemodynamics.

Pulmonary arterial hypertension in congenital heart disease: an epidemiologic perspective from a Dutch registry.

BACKGROUND: Pulmonary arterial hypertension (PAH) associated with congenital heart disease is usually the result of a large systemic-to-pulmonary shunt, and often leads to right ventricular failure and early death. The purpose of this study was to determine the prevalence of PAH among adult patients included in a national registry of congenital heart disease and to assess the relation between patient characteristics and PAH. METHODS: Patients with PAH associated with a septal defect were identified from the registry. Gender, age, underlying diagnosis, previous closure, age at repair and NYHA classification were recorded. PAH was defined as a systolic pulmonary arterial pressure (sPAP) greater than 40 mm Hg, estimated by means of echocardiographical evaluation. RESULTS: The prevalence of PAH among all 5970 registered adult patients with congenital heart disease was 4.2%. Of 1824 patients with a septal defect in the registry, 112 patients (6.1%) had PAH. Median age of these patients was 38 years (range 18-81 years) and 40% were male. Of these patients, 58% had the Eisenmenger syndrome. Among the patients with a previously closed septal defect, 30 had PAH (3%). Ventricular septal defect (VSD) was the most frequent underlying defect (42%) among patients with PAH and a septal defect. Female sex (Odds ratio=1.5, p=0.001) and sPAP (Odds ratio=0.04, p<0.001) were independently associated with a decreased functional class. CONCLUSION: PAH is common in adult patients with congenital heart disease. In our registry the prevalence of PAH in septal defects is around 6%. More than half of these patients have the Eisenmenger syndrome, which accounts for 1% of the total population in the CONCOR registry. Whether the prevalence of PAH will decrease in the future as a result of early detection and intervention remains to be awaited.

Applicability of bosentan in Dutch patients with Eisenmenger syndrome: preliminary results on safety and exercise capacity.

BACKGROUND: The purpose of this study was to investigate the applicability of bosentan treatment in a broad selection of patients with Eisenmenger syndrome. METHODS: Dutch patients with Eisenmenger syndrome in New York Heart Association functional class III, 9 (41%) male and 13 (59%) female, including 11 patients with Down syndrome (50%), aged 20 to 61 years (median 37 years), were screened for an open-label, standardised treatment protocol. Patients underwent clinical examinations, six-minute walk test (6-MWT), resting oxygen saturation measurements, cardiac MRI, Doppler echocardiography, lung function tests and exercise capacity testing by peak oxygen consumption at baseline. At 12 weeks of treatment 6-MWT and at 26 weeks 6-MWT and Doppler echocardiography were repeated. RESULTS: Median follow-up of the patients who started bosentan treatment was five months (range 0.5 to 9.6 months). Oxygen saturation at baseline was 83% (range 76 to 91%) and did not decrease during treatment. Compared with baseline, 6-MWT increased after 12 weeks from 333±93 m to 384±89 m. None of the patients discontinued medication and no liver function abnormalities were observed. Of all Doppler echocardiographic and MRI parameters measured for right ventricular function, tricuspid annular peak systolic velocities using tissue Doppler imaging (TDI-S) was the only independent predictor for six-minute walk test (ß=0.8, p=0.001). CONCLUSION: Bosentan may be safely applied in patients with Eisenmenger syndrome combined with complex congenital heart disease or with Down syndrome. Our preliminary results suggest that exercise tolerance improves during the first months of bosentan treatment.