Pulmonary arterial hypertension (PAH) is a well-recognized complication of congenital heart disease (CHD), associated with alarmingly high morbidity and mortality.1 PAH-CHD is considered a complex syndrome involving many pathophysiological mechanisms, the components of which can be represented by various biomarkers. There has been a growing interest in biomarkers as prognostic markers in chronic heart disease, given the wide availability and reproducibility, non-invasive nature and low costs. Although a wide variety of biomarkers have been explored in PAH-CHD,2, 3 only natriuretic peptides have been incorporated by the European guidelines.4 The use of multiple biomarkers in combination (the so-called ‘multimarker’ approach) may however be of greater prognostic value than a single biomarker approach. Moreover, little is known about the prognostic value of repeatedly measured biomarkers. Ideally, changes in biomarker levels over time should reflect disease progression more accurately. We therefore evaluated the prognostic value of repeated measurements of several biomarkers in a prospective cohort of patients with PAH-CHD. Pathways and corresponding candidate biomarkers studied were (i) myocardial stress [N-terminal pro brain natriuretic peptide (NT-proBNP)], (ii) myocyte injury [high-sensitive troponin T (hs-TnT)], (iii) cardio-renal dysfunction (cystatin-C) and (iv) extracellular matrix remodelling (galectin-3). This observational dual-centre study included consecutive PAH-CHD adults who were prospectively followed at our institutions with first clinical assessment between January 2004 and January 2016. According to local protocol, patients underwent routine evaluation every 6–12 months at outpatient clinics, including regular assessment of serum biomarkers using commercially available immunoassays. The endpoint was all-cause mortality. Patient deaths and causes of death were site determined and verified by medical records documentation. Biomarker levels were log-transformed and expressed as one standard deviation (SD) increase for hazard ratios (HRs) and 95% confidence intervals (CIs). The association with mortality was assessed using fitted mixed-effect, Cox regression and joint models, adjusted for age, gender and Eisenmenger syndrome (ES). The study cohort consisted of 98 patients (43 ± 16 years, 34% male, 37% Down syndrome), of whom 90% was treatment naive at baseline and started on advanced therapy within 1 month [interquartile range (IQR) 0.4–4.0]. The majority of patients had ES (69%), followed by closed defects (17%), systemic-to-pulmonary shunts (12%), and small defects (1%). Among ES patients, 47% had complex anatomy, 29% post-tricuspid shunts, and 24% pre-tricuspid shunts. During a median follow-up of 6.9 (IQR 4.1–10.7) years, 41 patients (42%) died. Half of ES patients (47%) died at 50 ± 12 years, whereas patients with systemic-to-pulmonary shunts (50%), closed defects (12%) or small defects (100%) died at older age (60 ± 16, 66 ± 16, and 77 years, respectively). Causes of death were validated in 38 (93%) cases, and primarily due to right heart failure (49%) and sudden cardiac death (12%). The average number of repeated measurements per patient during follow-up was nine for NT-proBNP, five for hs-TnT, and four for cystatin-C and galectin-3. Corresponding median levels of repeated measurements were: NT-proBNP 518 ng/L (IQR 223–1433), hs-TnT 11 ng/L (IQR 5–24), cystatin-C 0.97 mg/L (IQR 0.81–1.23), and galectin-3 15 μg/L (IQR 12–18). The correlations among the four biomarkers were weak to moderate (all r < 0.4). All biomarker levels in patients who died progressively increased before time of death compared to those who remained alive during follow-up. Initiation of advanced therapy reduced biomarker levels in short-term, although levels deteriorated again after 1 year.5 After imputation and internal validation with 40 bootstrap samples, baseline levels were associated with an increased risk of death, HRs as follows: NT-proBNP 1.90 (95% CI 1.30–2.78); hs-TnT 1.54 (95% CI 1.14–2.08); cystatin-C 1.69 (95% CI 1.21–2.37); galectin-3 1.58 (95% CI 1.12–2.19). During follow-up, one SD increase in biomarker level represented 250% increase of NT-proBNP, 150% of hs-TnT, and 50% of cystatin-C and galectin-3. Each SD increase in biomarker level was associated with a doubled risk of death at any particular time (all P < 0.001), adjusted HRs as follows: NT-proBNP 2.17 (95% CI 1.64–2.89); hs-TnT 2.34 (95% CI 1.61–3.41); cystatin-C 1.81 (95% CI 1.35–2.43); galectin-3 1.79 (95% CI 1.27–2.74). Risk prediction with repeated measurements was more accurate than with single measurements. Figure 1 illustrates the improved prognostic accuracy for an individual patient with NT-proBNP measurements; 95% CI is significantly broader using only the last single measurement compared with using repeated measurements. Of potential clinical value to physicians, we developed a free online risk stratification tool: https://biomarkers-pah-chd.shinyapps.io/PAH-CHDbiomarkers/. Of the four biomarkers, NT-proBNP, hs-TnT and cystatin-C achieved excellent predictive performance for 10-year mortality (c-index 0.81–0.92), whereas galectin-3 did not (c-index 0.60). In combination, the three strongest biomarkers, however, did not further improve discriminatory abilities (c-index 0.85). We evaluated the prognostic value of a range of repeated biomarkers, individually and collectively, in patients with PAH-CHD. Our patient cohort had a high mortality rate, with 42% deceased by the end of follow-up. All repeated biomarkers individually were powerful predictors of mortality risk: patients with one SD increase had more than doubled the risk of death compared to those with no or less elevation. This is consistent with what has been found in previous studies in acquired heart failure6, 7 that have shown that serial measures provide superior prognostic power over a single biomarker measurement. Previous studies have suggested using absolute cut-off values.6 From a clinical point of view, this approach may however neglect, at least to some extent, changes within a subject and not serve individual patients optimally. Based on our findings, we recommend to make use of relative changes (e.g. 100% increase) derived from our study rather than absolute (e.g. > 400 ng/L) change criterion, as this could help to initiate a more tailored approach. Altogether, it highlights the importance of serial measures in chronic diseases, in which multiple underlying pathophysiological mechanisms are ongoing dynamic processes that cannot be captured by a single biomarker measure at one point in time. Similar to data from acquired heart failure studies, NT-proBNP and hs-TnT were the most powerful prognostic biomarkers in our cohort. Contrary to studies in acquired heart failure,8 we did not find a prognostic gain of using multiple repeated biomarkers compared to individual repeated biomarkers. The following limitations of our study should be considered. It is a dual-centre study with relatively small sample size. There is potential for information bias given that the number of measurements was not equal for all biomarkers. The study focused on a panel of four biomarkers. Therefore, additional studies will be necessary to evaluate other markers of different pathways in PAH-CHD and validate our results in clinically distinct cohorts. Further research should certainly determine the optimal frequency of measurements required and investigate whether individual changes in biomarkers over time can also reflect response to therapy. This will enable further optimization of individual follow-up strategies and timely initiation of therapeutic management. In conclusion, repeated biomarker measurements were associated with an approximately two-fold higher mortality risk per SD increase and were more powerful predictors of mortality than single measurements. A multimarker approach provided no incremental prognostic value beyond the repeated measurements of individual biomarkers. Therefore, our findings support the concept of regular assessment of at least one biomarker, e.g. NT-proBNP, to help identify patients with PAH-CHD at greatest risk. The work described in this study was carried out in the context of the Parelsnoer Institute (PSI). PSI is part of and funded by the Dutch Federation of University Medical Centres and has received initial funding from the Dutch Government (from 2007 to 2011). This study was supported by an unrestricted research grant from Actelion Pharmaceuticals Ltd. Conflict of interest: none declared.

Background: The purpose of this prospective randomised controlled trial was to assesswhether home-based, self-selected exercise training is safe, results in high compliance and improves exercise capacity in symptomatic adults with congenital heart disease (CHD). Methods: Forty adults with moderate or severe CHD (40 +/- 12 years, 56% male, New York Heart Association [NYHA] II/III 37/3) were randomly assigned, stratified by CHD complexity, either to home-based exercise training or usual care. The exercise training protocol consisted of three exercise sessions per week for six consecutive months. Patients were free to choose any sports of their preference. Results: Thirty-four patients (each randomisation group n=17) completed the protocol and were analysed. The majority was involved in high-dynamic sports (76%); none had to discontinue the training programme due to exercise-related adverse events. More than 70% adhered to the exercise programme at or above the target training level. Peak VO2 increased significantly in the exercise group by + 1.7 +/- 2.7 ml.kg.min(-1) (qp=0.025), whereas it remained unchanged in the control group by +0.8 +/- 2.2 ml.kg.min-1 (p=0.184). No significant changes were found in serum N-Terminal pro-brain natriuretic peptide levels or quality of life in either randomisation group or between groups. Conclusions: In symptomatic adults with moderate or severe CHD, home-based exercise training of their preference appeared safe, with good compliance and favourable effects on exercise capacity. Our results demonstrate that it is appropriate to stimulate our patients to regularly perform moderate to vigorous physical activities, in absence of medical restrictions. (c) 2018 Elsevier B.V. All rights reserved.

Introduction: The number of grown-up congenital heart disease (GUCH) patients is steadily increasing. Unfortunately, the majority of these patients suffer from late sequelae, with heart failure being the most common cause of death. Exercise training is beneficial and safe in patients with acquired heart failure, as well as in asymptomatic GUCH patients. However, its effect remains unknown in symptomatic GUCH patients. This could cause reticence on positive sports advice, with possible counterproductive effects. Areas covered: A review of current literature was performed to evaluate the effect of exercise training in symptomatic (NYHA >= 2) GUCH patients. The search yielded a mere three studies including symptomatic patients, and another six studies including also patients in NYHA 1 without making clear distinction between the NYHA subgroups. Expert commentary: Suboptimal trial designs, low patient numbers, and homogeneity of investigated cardiac anomalies make this review insufficient to draw definite conclusions. However, all studies describe overall positive effects of exercise training in symptomatic GUCH patients in terms of exercise capacity and quality of life. There were no safety concerns. Larger-scaled, randomized controlled trials are needed to obtain certainty.

BACKGROUND:Adult patients with pulmonary arterial hypertension due to congenital heart disease (PAH-CHD) suffer from high mortality. This underlines the importance of adequate risk stratification to guide treatment decisions. Several baseline parameters are associated with mortality, however, their prognostic value may weaken after years of follow-up. Therefore we investigated the prognostic value of serial changes in standard clinical parameters in PAH-CHD. METHODS:In this prospective observational cohort study we included consecutive PAH-CHD adults, between 2005 and 2016. Control visits to the outpatient clinic were standardized, including functional, biochemical and echocardiographic tests, according to the guidelines. The prognostic value of serial changes was determined with time-dependent Cox regression. RESULTS:Ninety-two patients with PAH-CHD were included (age 43±15years, 34% male, 38% Down, 73% Eisenmenger). During a median follow-up of 6.0 (IQR 3.7-9.3) years, 35 (38%) patients died. Serial changes in World Health Organization functional classification (WHO-FC, HR 18.34 for onset class IV), six-minute walk distance (6-MWD, HR 0.65 per 50m), oxygen saturation at peak exercise (peak SaO2, HR 0.74 per 5%), NTproBNP (HR 2.25 per 1000ng/l) and echocardiographic right ventricular function (TAPSE, HR 0.80 per 0.5cm) significantly predicted mortality. Moreover, serial changes in these parameters were more potent predictors compared to baseline parameters, based on reduction in -2 log likelihood. CONCLUSIONS:Serial changes in standard clinical parameters have more prognostic value compared to baseline parameters in PAH-CHD. Our results emphasize the importance of screening for serial changes since periodical assessment could guide treatment decisions to delay disease progression.

Pulmonary arterial hypertension (PAH) due to congenital heart disease (CHD) is a progressive disorder characterized by chronic elevation of pulmonary vascular resistance, leading to significant impairment in exercise capacity, right heart failure and ultimately death. In absence of a cure for PAH-CHD, patients are treated with pulmonary vasodilators to improve symptoms and prognosis. Bosentan, the most widely applied pulmonary vasodilator, improves exercise capacity and quality of life of patients with PAH-CHD [ 1 Galiè N. Humbert M. Vachiery J.-L. Gibbs S. Lang I. Torbicki A. Simonneau G. Peacock A. Vonk Noordegraaf A. Beghetti M. Ghofrani A. Gomez Sanchez M.A. Hansmann G. Klepetko W. Lancellotti P. Matucci M. McDonagh T. Pierard L.A. Trindade P.T. Zompatori M. Hoeper M. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur. Heart J. 2016; 37: 67-119 Crossref PubMed Scopus (4018) Google Scholar , 2 Blok I.M. van Riel A.C.M.J. Mulder B.J.M. Bouma B.J. Management of patients with pulmonary arterial hypertension due to congenital heart disease: recent advances and future directions. Expert. Rev. Cardiovasc. Ther. 2015; 13: 1-16 Crossref PubMed Scopus (4) Google Scholar ]. However, prognosis remains impaired [ [3] Alonso-Gonzalez R. Lopez-Guarch C.J. Subirana-Domenech M.T. Ruíz J.M.O. González I.O. Cubero J.S. del Cerro M.J. Salvador M.L. Dos Subira L. Gallego P. Escribano-Subias P. Pulmonary hypertension and congenital heart disease: an insight from the REHAP National Registry. Int. J. Cardiol. 2015; 184: 717-723 Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar ]. Macitentan, a new pulmonary vasodilator analogous to bosentan with enhanced receptor binding [ [4] Gatfield J. Mueller Grandjean C. Sasse T. Clozel M. Nayler O. Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PLoS One. 2012; 7e47662https://doi.org/10.1371/journal.pone.0047662 Crossref PubMed Scopus (143) Google Scholar ], improved mortality and morbidity in a placebo controlled trial in a wide spectrum of PAH [ [5] Pulido T. Adzerikho I. Channick R.N. Delcroix M. Galiè N. Ghofrani H.-A. Jansa P. Jing Z.-C. Le Brun F.-O. Mehta S. Mittelholzer C.M. Perchenet L. Sastry B.K.S. Sitbon O. Souza R. Torbicki A. Zeng X. Rubin L.J. Simonneau G. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N. Engl. J. Med. 2013; 369: 809-818 Crossref PubMed Scopus (959) Google Scholar ], including repaired CHD shunts. Desirable features of macitentan include the once-a-day profile (vs. b.i.d. for bosentan) and freedom from monthly liver function tests [ [6] Enderby C.Y. Burger C. Medical treatment update on pulmonary arterial hypertension. Ther. Adv. Chronic Dis. 2015; 6: 264-272 Crossref PubMed Scopus (18) Google Scholar ]. Furthermore, macitentan has enhanced tissue penetration [ [6] Enderby C.Y. Burger C. Medical treatment update on pulmonary arterial hypertension. Ther. Adv. Chronic Dis. 2015; 6: 264-272 Crossref PubMed Scopus (18) Google Scholar ] and achieves greater reduction in mean pulmonary artery pressures compared to bosentan in pre-clinical studies [ [7] Iglarz M. Binkert C. Morrison K. Fischli W. Gatfield J. Treiber A. Weller T. Bolli M.H. Boss C. Buchmann S. Capeleto B. Hess P. Qiu C. Clozel M. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J. Pharmacol. Exp. Ther. 2008; 327: 736-745 Crossref PubMed Scopus (266) Google Scholar ]. Therefore, macitentan might be an alternative to bosentan, or even superior. However, a direct clinical comparison with bosentan has not been investigated, and it is unclear whether PAH-CHD patients currently on bosentan will benefit from a therapy switch. The aim of the present study was to evaluate the effect of a switch from bosentan to macitentan on clinical status in patients with PAH-CHD.

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.

Background: Eisenmenger syndrome is associated with substantial morbidity and mortality. There is no consensus, however, on mortality risk stratification. We aimed to investigate survival and predictors of death in a large, contemporary cohort of Eisenmenger syndrome patients. Methods: In a multicenter approach, we identified adults with Eisenmenger syndrome under follow-up between 2000 and 2015. We examined survival and its association with clinical, electrocardiographic, echocardiographic, and laboratory parameters. Results: We studied 1098 patients (median age, 34.4 years; range, 16.1–84.4 years; 65.1% female; 31.9% with Down syndrome). The majority had a posttricuspid defect (n=643, 58.6%), followed by patients with a complex (n=315, 28.7%) and pretricuspid lesion (n=140, 12.7%). Over a median follow-up of 3.1 years (interquartile range, 1.4–5.9), allowing for 4361.6 patient-years observation, 278 patients died and 6 underwent transplantation. Twelve parameters emerged as significant predictors of death on univariable analysis. On multivariable Cox regression analysis, only age (hazard ratio [HR], 1.41/10 years; 95% confidence interval [CI], 1.24–1.59; P <0.001), pretricuspid shunt (HR, 1.56; 95% CI, 1.02–2.39; P =0.041), oxygen saturation at rest (HR, 0.53/10%; 95% CI, 0.43–0.65; P <0.001), presence of sinus rhythm (HR, 0.53; 95% CI, 0.32–0.88; P =0.013), and presence of pericardial effusion (HR, 2.41; 95% CI, 1.59–3.66; P <0.001) remained significant predictors of death. Conclusions: There is significant premature mortality among contemporary adults with Eisenmenger syndrome. We report, herewith, a multivariable mortality risk stratification model based on 5 simple, noninvasive predictors of death in this population.

Pulmonary arterial hypertension is a serious complication of adult congenital heart disease associated with systemic-to-pulmonary shunts. Although early shunt closure restricts development of pulmonary arterial hypertension, patients remain at risk even after repair. The development of pulmonary arterial hypertension is associated with a markedly increased morbidity and mortality. It is important to identify patients with a poor prognosis using disease specific markers. Echocardiography and biomarkers arise as practical tools to determine the risk of mortality. Although pulmonary arterial hypertension cannot be cured, four classes of disease-targeting therapies are currently available and several promising therapies are being studied. There is a shift in drug studies towards more clinically relevant endpoints such as time to clinical worsening and morbidity and mortality events.

Decrease in quality of life (QoL) in left-sided heart failure precedes poor survival, which can be reversed with exercise training. We investigated whether QoL is associated with mortality in pulmonary arterial hypertension due to congenital heart disease (PAH-CHD) patients.

Endothelin receptor antagonists are regarded a cornerstone in treatment of pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). Currently macitentan, a potential successor of the widely applied bosentan, is being introduced. A recent trial has proven its outstanding

Successful repair of shunts in patients with congenital heart disease (CHD) is often erroneously considered a cure, leading to a large number of patients lost to follow-up after discharge [(1)][1]. The prevalence of pulmonary hypertension (PH) appears to be high after shunt closure [(2)][2] and is