Rianne H.A.C.M. de Bruin-Bon

Effect of bosentan on exercise capacity and quality of life in adults with pulmonary arterial hypertension associated with congenital heart disease with and without Down's syndrome

Pulmonary arterial hypertension associated with congenital heart disease caused by systemic-to-pulmonary shunting was associated with a high risk of morbidity and mortality. In this retrospective study, the longer term treatment effect of bosentan on exercise capacity and quality of life (QoL) were evaluated in 58 adult patients (>18 years) with pulmonary arterial hypertension associated with congenital heart disease, including patients with Downs syndrome. All patients were evaluated at baseline and during follow-up using laboratory tests, 6-minute walk test, QoL questionnaires, and Doppler echocardiography. Treatment efficacy was analyzed separately for patients without (n = 30) and with Downs syndrome (n = 28). Median follow-up of all patients treated with bosentan was 22 months (range 3 to 36). In patients without Downs syndrome, mean 6-minute walk distance increased from 427 +/- 97 to 461 +/- 104 m (p <0.01) after 6 months of treatment, followed by a gradual return to baseline and disease stabilization. QoL improved significantly during treatment and was maintained during 18 months of follow-up (p <0.05). In patients with Downs syndrome, 6-minute walk distance and QoL were stable during treatment. In conclusion, findings suggested that in patients without Downs syndrome, longer term bosentan treatment resulted in a persistent improvement in QoL and stabilization of exercise capacity.

Impact of bosentan on exercise capacity in adults after the Fontan procedure : a randomized controlled trial

An endothelin‐1 receptor blocker, shown to be effective in patients with pulmonary arterial hypertension, might decrease pulmonary vascular resistance to increase cardiac filling and consequently improve exercise capacity in Fontan patients.

Six-Minute Walk Test in Patients With Down Syndrome: Validity and Reproducibility

OBJECTIVES To examine the validity of the six-minute walk test (6MWT) as a tool to evaluate functional exercise performance in patients with Down syndrome (DS). DESIGN Comparison of the six-minute walk distance (6MWD) in 2 distinct groups of DS patients: with and without severe cardiac disease. To test reproducibility, a group of patients with DS performed the 6MWT twice. SETTING Tertiary referral centers for patients with congenital heart defects and outpatient clinics for people with intellectual disabilities. PARTICIPANTS Adult patients with DS with (n=29) and without (n=52) severe cardiac disease categorized by cardiac echocardiography. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURE Distance walked on the 6MWT. RESULTS The mean 6MWD in the group with severe cardiac disease was 289+/-104 m and in the group without severe cardiac disease 280+/-104 m (P=.70). Older age, female sex, and severe level of intellectual disability were all found to be independently and significantly correlated with a lower 6MWD (r=.67, P<.001). The paired 6MWD was not significantly different (310+/-88 m vs 317+/-85 m; P=.40) in patients who performed the 6MWT twice. The coefficient of variation was 11%. CONCLUSIONS The 6MWD between the 2 groups was not significantly different. However, the walking distance inversely correlated with the level of intellectual disability. Therefore, the 6MWT is not a valid test to examine cardiac restriction in adult patients with DS.

Prolonged beneficial effect of bosentan treatment and 4-year survival rates in adult patients with pulmonary arterial hypertension associated with congenital heart disease

Pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) due to systemic to pulmonary shunting is associated with a high risk of morbidity and mortality. In this study we evaluated 4 years treatment effect of bosentan on exercise capacity and quality of life and survival rates in 64 adult patients with PAH associated with CHD, including patients with Down syndrome (DS). All patients were evaluated at baseline and during follow-up with laboratory tests, 6-minute walk test, quality of life questionnaires, and Doppler echocardiography. In total, 13 patients (20%) died during 4-years of follow-up; 4 patients with DS and 9 patients without DS. Mean follow-up of all patients treated with bosentan was 3.5 ± 1.2 year. We analyzed treatment efficacy separately within patients without DS (n=34) and patients with DS (n=30). Mean 6-minute walking distance (6 MWD) in patients without DS significantly increased at 6 months from 417 ± 108 to 458 ± 104 m (+41 m; p=0.002) and significant improvement continued to exist during at least 2.5 years of follow-up (p=0.003). Moreover, stroke volume increased significantly (p=0.02). In the patients with DS, 6-MWD, stroke volume and quality of life remained stable during treatment. In this study we demonstrate a prolonged beneficial effect of bosentan treatment on exercise capacity, stroke volume and quality of life in patients without DS. However the mortality rate of 20% of patients after 4 years of follow-up remains high.

New predictors of mortality in adults with congenital heart disease and pulmonary hypertension: Midterm outcome of a prospective study

BACKGROUND Patients with CHD-PAH have a limited prognosis. In daily practice, combination therapy is often initiated after a clinical event. Although clinical events have been associated with a poor prognosis in idiopathic PAH, data on this association are limited in CHD-PAH. The aim of this study was to determine whether baseline characteristics and clinical events associate with mortality in patients with pulmonary hypertension (PAH) due to congenital heart disease (CHD). METHODS In total 91 consecutive adults (42 ± 14 year) with CHD-PAH were referred for therapy between January 2005 and June 2013. Cox proportional hazard analysis was performed to identify determinants of mortality, including clinical events as time dependent covariates. RESULTS Twenty-four patients (nine with Down) died during the median follow-up of 4.7 (range 0.1-7.9) years. The one and eight year mortality rates were 7.3% and 37.3%, respectively. Clinical events included admission for heart failure (n=9), arrhythmias (n=9), haemoptysis (n=5), change to a worse NYHA class (n=16), vascular events (n=1), syncope (n=1) and need for red blood cell depletion (n=4). In univariate analysis, both baseline characteristics and clinical events were associated with mortality. In multivariate analysis, only baseline NT-pro-BNP serum level ≥ 500 ng/L and TAPSE<15mm at echocardiography were significant determinants of mortality. None of the clinical events remained significant. Patients with both a NT-pro-BNP serum level ≥ 500 ng/L and TAPSE<15mm at echocardiography have a nine fold higher mortality rate than patients without both risk factors. CONCLUSION Prognosis is still poor in contemporary patients with CHD-PAH. Both baseline NT-pro-BNP serum level and right ventricular function are superior to clinical events in prognostication. These two baseline characteristics should have a major impact on therapeutic management in patients with CHD-PAH, such as initiation of combination therapy.

Duration of right ventricular contraction predicts the efficacy of bosentan treatment in patients with pulmonary hypertension.

AIMS In patients with pulmonary hypertension (PH), elevated endothelin-1 levels are associated with prolonged duration of right ventricular (RV) contraction, which induces leftward ventricular septal bowing with impaired left diastolic filling. We hypothesized that baseline RV contraction duration predicts efficacy of endothelin receptor antagonist, bosentan. METHODS AND RESULTS Eighteen PH patients (age 57, range 35-79 years, 33% male) received bosentan. Six minute walk distance (6-MWD) and echocardiography were performed at baseline and after 1 year follow-up. After 1 year of treatment, 6-MWD increased (mean 60 +/- 41 m) in 67% of patients (responders). Baseline RV contraction duration was longer in responders, compared with non-responders (612 +/- 66 vs. 514 +/- 23 ms; P < 0.01). A baseline RV contraction duration >550 ms was associated with improved 6-MWD (sensitivity 83%, specificity 83%; P < 0.01). CONCLUSION An improvement of 6-MWD during bosentan treatment was associated with a decrease in RV contraction duration and could be predicted by a baseline RV contraction duration >550 ms.

Echocardiographic determinants of the clinical condition in patients with a systemic right ventricle.

Background: Ventricular systolic and diastolic function, as measured by echocardiography, are diminished in patients with a systemic right ventricle (RV). As the clinical implications of these finding remained unknown, we aimed to identify echocardiographic parameters of systolic and diastolic ventricular function that are independent determinants of the clinical condition in these patients. Methods: Forty‐six adult patients (61% male; mean age 33 [range 18–69] years) with a systemic RV underwent echocardiography to assess qualitative and quantitative systolic and diastolic function of the systemic RV and the subpulmonary left ventricle (LV). Uni‐ and multivariate linear regression analyses were performed to identify independent echocardiographic determinants for NYHA class, maximal exercise capacity (V’O2peak) and NT‐proBNP levels. Results: We found qualitative assessment of RV and LV function to be significantly associated with NYHA class (RV: β= 0.26; P = 0.05 and LV: β= 0.82; P < 0.01), V’O2peak (RV: β=−10.4; P < 0.05 and LV: β=−18.4; P < 0.05) and NT‐proBNP levels (RV: β= 0.58; P < 0.01 and LV: β= 1.40; P < 0.001). Tricuspid annulus plane systolic excursion (TAPSE) was significantly associated with NYHA class (β=−0.92; P = 0.001), V’O2peak (β= 18.5; P = 0.05), and serum NT‐proBNP levels (β=−1.00; P < 0.05). Associations between quantitative parameters of systolic subpulmonary LV function and clinical parameters were less distinct. We found no associations between RV and LV diastolic function and clinical parameters. Conclusions: Qualitative function of the systemic RV and the subpulmonary LV, and TAPSE, are determinants of clinical condition in patients with a systemic RV. These patients’ clinical condition could not be determined by echocardiographically measured diastolic RV function, and systolic and diastolic LV function. (Echocardiography 2010;27:1247‐1255)

The role of cystatin C as a biomarker for prognosis in pulmonary arterial hypertension due to congenital heart disease

BACKGROUND Adults with pulmonary arterial hypertension due to congenital heart disease (PAH-CHD) have a poor prognosis. Identifying patients with a high risk for clinical events and death is important because their prognosis can be improved by intensifying their treatment. Cystatin C, a novel cardiac biomarker, correlates with right ventricular dimensions in patients with idiopathic PAH, giving it potential to determine prognosis in PAH-CHD patients. We investigated the predictive value of cystatin C for long-term mortality and clinical events. METHODS Fifty-nine PAH-CHD patients (mean age 42 SD 13 years, 42% male) were included in this prospective observational study, with cystatin C measurements between 2005 and 2015 on the outpatient clinic. Patients were evaluated with a standardized evaluation protocol including laboratory, functional and echocardiographic variables. Clinical events comprised worsening functional classification, worsening heart failure, symptomatic hyperviscosity, haemoptysis and arrhythmia. We used Cox regression to determine predictors for mortality and clinical events. RESULTS Mean follow-up was 4.4years, during which 12 (20%) patients died. Cystatin C (HR 1.3, p<0.001), creatinine (HR 1.2, p<0.001), NT-pro-BNP (HR 2.0, p=0.012), hs-troponin T (HR 1.9, p=0.005), 6-MWD (HR 0.8, p=0.044) and TAPSE (HR 0.8, p<0.001) predicted mortality. Similar results were found for the prediction of clinical events. When adjusted for NT-pro-BNP or glomerular filtration rate in multivariate analysis, cystatin C remained predictive for mortality. CONCLUSIONS Cystatin C, a novel cardiac biomarker, predicts long-term mortality and clinical events in patients with PAH-CHD. Consequently, cystatin C may attribute to clinical decision making regarding treatment intensity.

Rates and determinants of progressive aortic valve dysfunction in aortic coarctation

PURPOSE Aortic valve dysfunction is common in coarctation patients(CoA). Bicuspid aortic valve (BAV) in CoA is associated with aortic valve stenosis (AS), aortic valve regurgitation (AR), and ascending aortic dilatation. The aim of this study was to evaluate the progression of and predictors for aortic valve dysfunction in CoA. METHODS 96 CoA patients prospectively underwent echocardiography twice between 2001 and 2010. AS was defined as an aortic valve gradient ≥ 20 mmHg, AR as none/minor, or moderate/severe. Aortic dilatation as an ascending aortic diameter ≥ 37 mm. RESULTS All patients (median age 28.0 years, range 17-61 years; male 57%) were followed with a median follow-up of 7.0 years. Sixty patients (63%) had BAV. At baseline 10 patients had AS (10%, 9 BAV), 6 patients AR (6%, 3 BAV) and 11 patients aortic dilatation (11%, 11 BAV). At follow-up 15 patients had AS (15%, 13 BAV) and 12 patients AR. (13%, 8 BAV). Median AS progression was 1.1 mmHg/5 years (range - 13-28). Determinants for AS at follow-up were age (ß=0.20, P=0.01), aortic dilatation (ß=4.6, P=0.03), and baseline aortic valve gradient (ß=0.93, P<0.001). BAV was predictive for AR. (ß=0.91, P=0.049). CONCLUSION Progression of AS in adult CoA patients is mild in this young population. Older age, aortic dilatation and the baseline aortic valve gradient are determinants for AS at follow-up. BAV is predictive for AR. These findings point towards a common embryological pathway of both valvular and aortic disease in CoA.

A Potential Diagnostic Approach for Foetal Long-QT Syndrome, Developed and Validated in Children

In patients with Long-QT Syndrome (LQTS), mechanical abnormalities have been described. Recognition of these abnormalities could potentially be used in the diagnosis of LQTS, especially in the foetus where an ECG is not available and DNA-analysis is invasive. We aimed to develop and validate a marker for these mechanical abnormalities in children and to test its feasibility in foetuses as a proof of principle. We measured the myocardial contraction duration using colour Tissue Doppler Imaging (cTDI) in 41 LQTS children and age- and gender-matched controls. Children were chosen to develop and validate the measurement of the myocardial contraction duration, due to the availability of a simultaneously recorded ECG. Feasibility of this measurement in foetuses was tested in an additional pilot study among seven LQTS foetuses and eight controls. LQTS children had a longer myocardial contraction duration compared to controls, while there was no statistical difference in heart rate. Measuring the myocardial contraction duration in children had a high inter- and intra-observer validity and reliably correlated with the QT-interval. There was an area under the curve (AUC) of 0.71, and the optimal cut-off value showed an especially high specificity in diagnosing LQTS. Measuring the myocardial contraction duration was possible in all foetuses and had a high inter- and intra-observer validity (ICC = 0.71 and ICC = 0.88, respectively). LQTS foetuses seemed to have a longer myocardial contraction duration compared to controls. Therefore, a prolonged contraction duration may be a potential marker for the prenatal diagnosis of LQTS in the future. Further studies are required to support the measurement of the myocardial contraction duration as a diagnostic approach for foetal LQTS.