Implications of Asymmetry and Valvular Morphotype on Echocardiographic Measurements of the Aortic Root in Bicuspid Aortic Valve.

BACKGROUND: Transthoracic echocardiography (TTE) and magnetic resonance imaging (MRI) have yielded excellent results in aortic root diameter measurement in patients with tricuspid aortic valve. However, accuracy in bicuspid aortic valve (BAV), often associated with aortic root asymmetry, is not fully defined. The aim of this study was to determine the agreement between TTE and MRI in proximal ascending aortic diameters in patients with BAVs. METHODS: Seventy-six consecutive patients with BAVs (mean age, 53 ± 15 years; 65% men) who underwent both TTE and MRI for ascending aortic assessment in a follow-up protocol were included in the study. Maximum aortic root and ascending aortic diameters were compared. RESULTS: For the whole population, TTE slightly underestimated aortic root diameter (difference, -0.8 ± 2.9 mm; P = .02). However, agreement was significantly better in BAV with fusion of the left and right coronary cusps than with fusion of the right coronary and noncoronary cusps, both with (type 1) and without (type 0) raphe (mean difference, 0.1 ± 2.5 vs -2.8 ± 2.8 mm, P < .001, respectively). In raphe BAV, mean absolute differences of maximum diameters between both techniques were significantly greater in asymmetric versus symmetric aortic roots (3.3 ± 2.2 vs 1.6 ± 1.9 mm, P = .002). BAV type and root asymmetry were independent related to measurement disagreement between both modalities. CONCLUSIONS: Although TTE is the technique of choice in the follow-up of patients with BAVs, aortic root diameter measurements may be inaccurate in the presence of root asymmetry and in BAV with fusion of the right coronary and noncoronary cusps. In these cases, cross-sectional imaging, with MRI or computed tomography, to confirm aortic diameters may be advisable.

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.

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

AIMS: 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. METHODS AND RESULTS: This was a prospective, multicentre randomized open label trial in Fontan patients. One group received bosentan for 6 months. The other group did not receive study medication for the first 3 months, followed by bosentan for 6 months. The primary endpoint was exercise capacity, and secondary endpoints were NT-proBNP level, cardiac output, SF-36 (Short Form-36) quality of life (QoL), and NYHA class. Forty-two adults (median age 29 (range 18-56) years, 52% male, 88% NYHA class I-II) from five tertiary referral centres participated in the study. Ten patients were on diuretics. Ten patients were not motivated to finish the study. Analysis of all 32 patients who finished the study at 6 months of treatment showed that mean peak V'O2 (24 vs. 25 mL/kg/min), median SQUASH score (6614 vs. 6390), median NT-proBNP (314 vs. 274 ng/L), and mental QoL (50 vs. 51) remained unchanged as compared with baseline (P = NS, for all). After treatment, NYHA class had improved in 6 (19%), was unchanged in 24 (75%), and declined in 2 (6%) patients. Subgroup analysis on age, ventricular morphology, type of Fontan circulation, or baseline NT-proBNP level did not reveal efficacy of bosentan. Six transient adverse effects were reported. CONCLUSION: An increased NT-proBNP level was present in the majority of Fontan patients. Six months of bosentan treatment was not beneficial. Trial registration NTR1557.

High-sensitivity troponin T is associated with poor outcome in adults with pulmonary arterial hypertension due to congenital heart disease.

OBJECTIVE: Pulmonary arterial hypertension due to congenital heart disease (CHD-PAH) has a poor prognosis. We sought to determine whether the biomarker high-sensitivity troponin T (hsTnT) measured on routine visit at the outpatient clinic is associated with prognosis. PATIENTS: Consecutive adult CHD-PAH (86% Eisenmenger syndrome) patients referred for advanced medical therapy between January 2005 and March 2007 in the Academic Medical Center in Amsterdam. Patients with severe renal impairment were excluded. MAIN OUTCOME MEASURE: The primary outcome was mortality. RESULTS: Of all 31 patients (mean age 45 ± 12 years) with CHD-PAH, eight patients died during a median follow-up of 5.6 (range 1.6 to 6.8) years. A hsTnT level >0.014 µg/L was the 99th percentile cutoff of the normal distribution and therefore defined as elevated. At baseline, elevated levels of hsTnT were found in eight patients (26%). In univariate Cox regression, hsTnT elevated at baseline, NT-pro-BNP and right ventricular function were determinants of death (P < .05 for all). Patients with elevated levels of hsTnT showed a significantly higher mortality rate as compared to patients with normal hsTnT levels (62% vs. 13%, P = .005). CONCLUSION: Levels of hsTnT were abnormal in a substantial proportion of CHD-PAH patients. A significant inverse relationship was found between hsTnT and survival.

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.

Treatment of segmental pulmonary artery hypertension in adults with congenital heart disease.

INTRODUCTION: Pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD) usually has a homogeneous pressure distribution. More rarely, complex CHD patients have segmental PAH. This is often post-surgically. The characteristics of these patients and their responsiveness to specific pulmonary vasodilator therapy have not been described. METHODS: Seven adults with segmental PAH complicating CHD were treated at 3 specialized adult CHD centers between January 2006 and December 2010. Clinical characteristics, six minute walking distances (6 MWD), laboratory tests and images were obtained from medical records and the responses to Bosentan, an endothelin-1 receptor antagonist, were assessed. RESULTS: All patients (mean age 32 (23-42) years, five females) had a primary diagnosis pulmonary atresia (PA), four with major aortopulmonary collateral arteries (MAPCAs). Four segmental PAH patients had a right pulmonary artery stenosis, two a left pulmonary artery stenosis and one a unilateral MAPCA stenosis. All patients were symptomatic (functional class II or III) and bosentan was started empirically. Bosentan treatment led to a significant improvement in functional class compared to baseline (1.7 ± 0.5 versus 2.4 ± 0.5; p<0.01). Mean 6 MWD (available in 6 patients) increased by 62 m (22-150 m) from 386 ± 135 to 448 ± 133 m (p=0.03) after 12 months treatment. Most improvement was seen in patients with low baseline 6 MWD. Higher baseline exercise heart rate was significantly associated with lesser improvement in 6 MWD (r=-0.91 p=0.01). Laboratory results did not change after initiation of bosentan treatment. CONCLUSION: This small retrospective case series suggested a significant improvement of functional class and exercise capacity after bosentan treatment in patients with segmental PAH. These findings warrant a prospective study of the potential benefit of selective pulmonary vasodilator therapy in these complex patients. Therefore, we call on treating physicians to share similar cases.

[Many adults with congenital heart disease are lost to follow up]. / Veel volwassenen met een aangeboren hartaandoening niet meer onder controle.

OBJECTIVE: Identification of adults with congenital heart disease (CHD) who were lost to cardiological follow-up. DESIGN: Cross-sectional study. METHOD: Adults with CHD and not under cardiological follow-up were asked via a nationwide publicity campaign to contact the CONCOR (CONgenital CORvitia) project group. RESULTS: A total of 593 patients with mild (85%) to moderate-severe (15%) CHD were registered via the nationwide campaign. Of these patients, 66% were examined within 1 year by a cardiologist. Additional cardiac follow-up was necessary within 1 year in 22% of these patients. In 16% of the patients, new residual lesions were found; and in three of these patients the pulmonary valve required replacement. CONCLUSION: During this comprehensive nationwide campaign it became clear that a considerable number of adults with CDH fail to receive regular cardiac care. However, after surgical correction of CHD in childhood, residual lesions are common in this population. Threatening residual lesions can be present asymptomatically. Cardiological follow-up is therefore almost always necessary, also in patients without symptoms. Patients with CHD as well as their medical care personnel need to be well informed of this.

'The sedentary heart': physical inactivity is associated with cardiac atrophy in adults with an intellectual disability.

BACKGROUND: The cardiac muscle is well regulated in response to changes in loading conditions. This cardiac plasticity has been studied intensively and is well known in trained athletes. Conversely, the mechanisms leading to the opposite response are less clear. The aim of this study was to investigate left ventricular (LV) dimensions in a physically inactive population of adults with an intellectual disability. METHODS: Adults with an intellectual disability with and without Down syndrome (DS) and healthy controls were included (n=182). Echocardiography was performed in all included subjects and physical activity was measured by means of a questionnaire. RESULTS: Physical activity was lower in adults with an intellectual disability compared to controls (p<0.001). In DS, iLVM was significantly lower compared to controls (64 ± 17 g/m(2) vs. 94 ± 17 g/m(2)p<0.001). Non-DS adults with an intellectual disability had higher iLVM (72 ± 16 g/m(2)) compared to subjects with DS, although not significantly different (p<0.08). LV volumes were significantly smaller in adults with DS compared to both controls and non-DS adults with an intellectual disability (p<0.001). Moderate diastolic dysfunction was found in 57% of the adults with an intellectual disability. In 48 children with DS and 79 controls, mean LV end diastolic diameter was not significantly different during childhood. CONCLUSIONS: LV dimensions are significantly smaller in adults with an intellectual disability compared to controls. These findings appear to be lifestyle related as differences become manifest at adulthood and adults with an intellectual disability generally experience a sedentary lifestyle. Presumably, physical inactivity leads to a condition of cardiac atrophy.

Rationale and design of a trial on the role of bosentan in Fontan patients: improvement of exercise capacity?

BACKGROUND: The Fontan circulation is a palliative procedure performed in patients with complex congenital heart disease (CHD), making transpulmonary blood flow dependent on the systemic venous pressure. In a Fontan circulation a low pulmonary vascular resistance (PVR) is crucial, as is epitomized by the observation that a high PVR is a strong predictor of mortality. Long-term follow-up has shown that PVR may rise many years after the Fontan procedure has been performed, possibly due to micro-emboli from a dilated right atrium or from the venous system. Other mechanisms of increased PVR might be aging, obstructed airways caused by lymphatic dysfunction, lack of pulsatile pulmonary flow causing a release of endothelium-derived vasoactive molecules, and prolonged overexpression of vasoconstrictors such as endothelin-1. Mean plasma level of endothelin-1 has been shown to be significantly higher in Fontan patients compared to healthy controls. In patients with pulmonary arterial hypertension (PAH), therapy with bosentan, an endothelin-1 receptor antagonist, has demonstrated to improve exercise capacity and to reduce the elevated PVR. In addition, reduction of PVR is shown early and late after the Fontan procedure on treatment with exogenous NO, another advanced PAH therapy. However, the long term effect of reducing the PVR by bosentan treatment on exercise capacity in Fontan patients is still unknown. METHODS: We designed a prospective, multicenter, randomized open label trial to study the effect of bosentan in Fontan patients. The primary endpoint will be the change in maximum exercise capacity (peak V'O2). CONCLUSION: We hypothesize that treatment with bosentan, an endothelin-1 receptor antagonist, improves maximum exercise capacity and functional capacity in adult Fontan patients.

WITHDRAWN: Predictors of long-term survival in pulmonary hypertension treated with bosentan.

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Sexuality in adult patients with congenital heart disease and their partners.

Data on relational and sexuality issues in adult patients with congenital heart disease (CHD) are scarce. The present study aimed to evaluate relational and sexual behaviors, satisfaction, and functioning in a representative sample of patients with CHD and their partners. In addition, we aimed to evaluate the relation between sexuality parameters and quality of life. Relational and sexuality issues were assessed using a sexuality questionnaire in 133 patients (52% men, 37 ± 13 years old) with CHD (43 with coarctation of the aorta, 42 with transposition of great arteries, 36 with Marfan syndrome, and 12 with Eisenmenger syndrome), and 74 partners. Quality of life was assessed using the Dutch translation of the Medical Outcomes Study Short Form 36-Item Health Survey. Data were compared to an age- and gender-matched control group (n = 3,642). Seventy-one percent of patients with CHD were involved in a relationship, which was significantly less compared to controls (79%, p < 0.05). Nonetheless, patients perceived their relationship as more satisfactory compared to controls (p < 0.05). Overall, sexual satisfaction was equal in patients compared to controls, although they perceived lower body esteem (p < 0.001), decreased sexual esteem (p < 0.05), and more distress during sex (p < 0.001). Patients reported no more erectile and lubrication problems compared to partners and to controls. We found significant associations between most relational and sexual parameters and quality of life. In conclusion, many aspects of sexuality are affected in adult patients with CHD, whereas their partners remain relatively unaffected. Moreover, sexuality is an important aspect of quality of life in these patients. We advise physicians to be receptive to discuss sexuality issues and provide patients with adequate therapy.

Adult patients with pulmonary arterial hypertension due to congenital heart disease: a review on advanced medical treatment with bosentan.

Pulmonary arterial hypertension (PAH) is a progressive disease with poor survival outcome. PAH is classified by the 2009 updated clinical classification of pulmonary hypertension and a major subgroup is PAH due to congenital heart disease (CHD) with systemic-to-pulmonary shunt. CHD-PAH is a result of systemic-to-pulmonary shunting and chronic increased flow that ultimately results in adaptations of pulmonary vasculature and endothelial dysfunction. The advanced stage is called Eisenmenger syndrome which forms a small percentage (1%) of all CHD patients. Therapies targeted on PAH symptoms are called primary therapy for PAH, but most CHD-PAH patients progress to advanced therapy which is directed at the PAH itself. In CHD-PAH, advanced therapies are extensively investigated for all three major pathways: endothelin-1 receptor antagonists such as bosentan, prostanoids such as epoprostenol and phosphodiesterase 5 inhibitors such as sildenafil. Endpoints in most trials were catheterization hemodynamics, World Health Organization functional class, six-minute walking distance and patient-focused outcomes, based on quality of life questionnaires and Borg dyspnea index. The BREATHE-5 and EARLY study were two important randomized controlled trials showing efficacy of bosentan at short follow-up. Moreover in patients with Eisenmenger syndrome, one recent survival retrospective study with majority of patients on bosentan showed strong survival benefit over conservative therapy. A diversity of prospective cohort and retrospective studies were performed but all with limited data, due to small numbers and heterogeneity of underlying CHD diagnoses. Further larger studies are needed to determine optimal treatment for adults with CHD-PAH. This review focuses on bosentan in CHD-PAH. In particular, we discuss outcome of various clinical trials and compare efficacy and safety of bosentan to other advanced therapies.

Congenital heart defects are under-recognised in adult patients with Down's syndrome.

BACKGROUND: Congenital heart defects (CHD) are common in patients with Down's syndrome; however, patients living in residential centres have not always been screened for CHD in the past. The aim of this study was to investigate the prevalence of CHD in patients with Down's syndrome living in residential centres, and to determine whether cardiac screening should be recommended. METHODS: Between January 2007 and November 2009 Dutch residential centres nationwide were randomly sampled. Medical files of all patients with Down's syndrome were investigated to retrieve documented information on known CHD. Echocardiography was performed on patients with unknown cardiac status. The main outcome measure was the number of newly diagnosed cases of CHD in adult patients with Down's syndrome. RESULTS: Thirty-one centres and 1158 patients were included in the first stage of the study. Overall prevalence of known CHD was 16% (189 defects). Screening was performed in 138 patients without known CHD. In total, 24 new patients (17%) with a CHD were found, of which six patients needed semi-urgent care. Furthermore, 77% of the screened patients had mild to moderate regurgitation in one or more heart valves. Overall prevalence of CHD in adult Down's syndrome patients living in residential centres would be estimated at 33%. CONCLUSIONS: Seventeen per cent of patients with Down's syndrome living in residential centres had undiagnosed CHD, and valvular regurgitation was present in the majority of patients. Cardiac screening is recommended in older Down's syndrome patients, for whom new therapeutic options are available and for prevention of cardiac complications in old age.

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.

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 Down's 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 Down's syndrome (n = 28). Median follow-up of all patients treated with bosentan was 22 months (range 3 to 36). In patients without Down's 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 Down's syndrome, 6-minute walk distance and QoL were stable during treatment. In conclusion, findings suggested that in patients without Down's syndrome, longer term bosentan treatment resulted in a persistent improvement in QoL and stabilization of exercise capacity.

Down patients with Eisenmenger syndrome: is bosentan treatment an option?

BACKGROUND: Favorable results of treatment with bosentan in patients with Eisenmenger syndrome are available. However, data in Down patients are lacking. In this study, we evaluate the therapeutic role of bosentan treatment in Down patients with Eisenmenger syndrome. METHODS: In this open-label study, 24 Down patients (>18 years) with Eisenmenger syndrome (17 males) were treated with bosentan. Their mean age was 38 years (range 19-55 years). All Down patients were evaluated at baseline and during follow-up with laboratory tests, six-minute walk test (6-MWT), Doppler echocardiography, and quality of life questionnaires. RESULTS: The median follow-up of Down patients treated with bosentan was 11.5 months (range 3-23 months). Induction of oral bosentan therapy was well tolerated among all 24 Down patients. Bosentan treatment was generally well tolerated. No serious adverse drug reactions were noted. Median 6-MWT increased from 296 m (range 40-424 m) to 325 m (range 84-459 m, p<0.05) after 12 weeks. After 26 and 52 weeks of treatment with bosentan, median 6-MWT distance was 276 m (range 140-462 m, n=15, p=0.6) and 287 m (range 131-409 m, n=7, p=0.3), respectively. Quality of life questionnaire scores remained stable during treatment. CONCLUSION: Also patients with Down syndrome may benefit from bosentan treatment when they have Eisenmenger syndrome. Medical treatment appears to be safe and the treatment effects do not deviate from those observed in Eisenmenger patients without Down syndrome.

Increased prevalence of migraine in Marfan syndrome.

OBJECTIVE: A high prevalence of migraine has been described in various forms of congenital heart disease, with and without shunt. In this study we investigated the prevalence of migraine in patients with Marfan syndrome (MFS). METHODS: All 457 adult patients with MFS from the participating centres and 194 controls received a validated questionnaire about headache. Migraine was diagnosed according to the International Headache Society criteria, by three independent neurologists, blinded to patient files. RESULTS: Response rate was 68% and 56% in Marfan patients and controls, respectively. Forty percent of the 309 responding MFS patients (mean age 40+/-14 years; 51% females) and 28% of the 102 controls (mean age 43+/-15 years; 58% females), suffered from migraine (p=0.03). The prevalence of migraine with aura (MA) was 22% in MFS patients and 14% in controls (p=0.06). We found MFS to be an independent risk factor for having overall migraine (OR 1.7; 95%CI 1.1-2.8), also after adjustment for age and gender (OR 1.9; 95%CI 1.1-3.1; p=0.02) and for MA after adjustment for gender (OR 2.0; 95%CI 1.1-3.7; p=0.04). In patient with MFS, previous aortic root surgery appeared to be an independent risk factor for having MA (OR 2.2; 95%CI; 1.2.-4.0, p=0.01) adjusted for gender. CONCLUSION: MFS is an independent risk factor for having overall migraine and MA. Moreover, we found that a history of aortic root surgery seems to be associated with an increased risk of MA.