Residual Pulmonary Hypertension more than 20 Years after Repair of Shunt Lesions.

Background and Objectives: After successful surgical repair of a congenital shunt lesion, pulmonary hypertension (PH) often disappears. However, PH can persist long-term after the closure. This study aimed to assess the prevalence of PH long-term after surgical repair of congenital heart disease (CHD), and to evaluate the outcomes and preoperative factors related to residual PH. Materials and Methods: In this retrospective cohort study, we reviewed patients who underwent right heart catheterisation in Vilnius University Hospital Santaros Klinikos during the period of 1985-2007. Among 4118 right heart catheterisations performed, 160 patients underwent congenital systemic-to-pulmonary shunt repair at a young age (<18 years) and had pre-operative PH. Half of the patients were foreigners whose follow-up data were unavailable. Eventually, 88 patients with available follow-up data were included in this study. Results: The median age at diagnosis of CHD with PH was 0.8 (0.6-3.0) and 1.1 (0.6-3.9) years at surgery (50% females). Residual PH was assessed 9.5 years after surgery and observed in 30.7% (n = 27) of the patients. It was associated with having more than one shunt (44.4% (n = 12), p = 0.016) and higher median pulmonary vascular resistance (3.4 (2.5-6.5) vs. 2.2 (1.0-3.7), p = 0.035) at baseline. After a median follow-up of 21 (15-24) years, 9.1% of the patients were deceased. Kaplan-Meier survival analysis revealed significantly higher mortality in the residual PH group (p = 0.035). Conclusions: Residual PH affects a significant proportion of patients after surgical repair of a shunt lesion and is associated with worse long-term outcome.

The prognostic value of various biomarkers in adults with pulmonary hypertension; a multi-biomarker approach.

BACKGROUND: This study aimed to investigate the prognostic value of six different biomarkers in patients with pulmonary hypertension (PH) and to explore whether a multi-biomarker approach can contribute to a better risk stratification. METHODS: In this prospective study, patients with PH were included at the day of the diagnostic right heart catheterization between May 2012 and October 2016. Venous blood sampling included; NT-proBNP, high sensitive troponin-T, high sensitive CRP, galectin-3, red blood cell distribution width and eGFR. Associations between biomarker levels and the primary endpoint (death or lung transplantation) and secondary endpoint (death, lung transplantation or heart failure) were assessed with Cox regression, adjusted for age and sex. Additionally, adjustment for the REVEAL risk score was performed. RESULTS: In total, 106 patients were included (median age 58.7 [IQR 47.0-69.2] years, 64% women, 51% pulmonary arterial hypertension). After a median follow-up duration of 23.9 [IQR 15.1-40.0] months, respectively 29 and 37 patients reached the primary and secondary endpoint. All six biomarkers, except eGFR, were significantly associated with the endpoints. A multi-biomarker approach including the number of elevated biomarkers per patient, demonstrated that patients were at higher risk of adverse events as more biomarker levels were elevated (HR for each extra elevated biomarker; 1.33, 95% CI 1.07-1.64, P = .01). However, a single as well as a combination of multiple biomarkers, did not yield prognostic value independent of the REVEAL risk score. CONCLUSIONS: Various biomarkers are associated with the event-free survival in adults with PH. However, risk stratification exclusively based on single or a combination of biomarkers seems not superior to existing risk scores.

The prevalence of pulmonary arterial hypertension before and after atrial septal defect closure at adult age: A systematic review.

BACKGROUND: The development or persistence of pulmonary arterial hypertension (PAH) after atrial septal defect (ASD) closure at adult age is associated with a poor prognosis. The objective of this review was to investigate the prevalence of PAH before and after ASD closure and to identify factors that are associated with PAH. METHODS: EMBASE and MEDLINE databases were searched for publications until March 2017. All studies reporting the prevalence of PAH or data on pulmonary artery pressures both before and after surgical or percutaneous ASD closure in an adult population (≥16 years of age) were included. Papers were methodologically checked and data was visualized in tables, bar charts and plots. RESULTS: A total of 30 papers were included. The prevalence of PAH ranged from 29% to 73% before ASD closure and from 5% to 50% after closure; being highest in older studies, small study cohorts, and studies with high rates of loss to follow-up. The pooled systolic pulmonary artery pressure (PAP) was 43±13 before ASD closure and 32±10 after closure. The overall mean PAP was 34±10 before closure and 28±8 after closure. Studies with a higher mean PAP before closure and a higher mean age of the study cohort reported greater PAP reductions. CONCLUSIONS: The prevalence of PAH and mean pulmonary pressures decreased in all studies, regardless of the mean age or pulmonary pressures of the cohort. The reported prevalence of PAH after ASD closure is substantial, although widely varying (5%-50%), which is likely affected by selection of the study cohort.

Heart rate: an accessible risk indicator in adult congenital heart disease.

BACKGROUND: Higher resting heart rate has been described as a risk factor for adverse outcome in healthy individuals and cardiovascular patients. The aim of this study was to evaluate resting heart rate as risk factor in adult congenital heart disease (ACHD). METHODS: In this prospective observational cohort study, patients with moderate or complex ACHD were included at routine outpatient visit. Standard 12-lead ECGs were obtained in rest. Heart rate was obtained from the ECG automatically by the Modular ECG Analysis System (MEANS). The primary endpoint was all-cause mortality and the secondary endpoint was a composite of all-cause mortality and heart failure. Survival was derived using the Kaplan-Meier estimator. Subgroups based on heart rate tertiles were compared by the log-rank test. Cox proportional hazards models were adjusted for clinical factors including age, sex and diagnosis (moderate vs complex ACHD). RESULTS: A total of 556 patients were included (median age 32 years (IQR 24-41), 57.6% male). Mean heart rate was 69±13 bpm. Negative chronotropic medication was used by 74 (13.3%) patients. During a median follow-up of 10.1 (IQR 9.6-10.5) years, 36 patients (6.5%) died and 83 (14.9%) reached the secondary endpoint. Patients with higher heart rates had significantly lower survival and heart failure-free survival. After adjusting for clinical factors, heart rate remained associated with mortality (HR 1.57 per 10 bpm, 95% CI 1.26 to 1.96) and mortality or heart failure (HR 1.33 per 10 bpm, 95% CI 1.13 to 1.57). CONCLUSION: Higher heart rate is associated with lower survival and heart failure-free survival in ACHD.

Blood and Imaging Biomarkers in the Long-term Follow-up of Bicuspid Aortic Valve Patients.

Background: Bicuspid aortic valve (BAV) is a common congenital heart defect. Patients with BAV are at risk for long-term complications such as valve stenosis and regurgitation. This study aimed to investigate sex differences in blood and imaging biomarkers and to describe the long-term prognostic value of blood and echocardiographic biomarkers. Methods: Patients were included from 2 prospective observational cohort studies; they underwent venous blood sampling and transthoracic echocardiography including speckle tracking. Analyzed blood biomarkers were red-cell distribution width (RDW), creatinine, C-reactive protein (CRP), troponin T, N-terminal pro B-type natriuretic peptide (NT-proBNP), and transforming growth factor-beta (TGF-ß). Sex differences were analyzed at baseline. Associations between biomarkers and arrhythmia-free and intervention-free survival were determined by Cox regression, adjusted for age and sex. Results: A total of 182 patients with BAV were included: median age 34; interquartile range [IQR]: 23-46 years; 55.5% male. CRP, NT-proBNP, and RDW were higher in women, whereas creatinine, troponin T and TGF-ß were higher among men. After a median follow-up time of 6.9 (IQR: 6.5-9.9) years, arrhythmia-free and intervention-free survival was, 81.0% and 73.1%, respectively. NT-proBNP was associated with both arrhythmia-free and intervention-free survival (hazard ratio [HR], 1.94, P = 0.005 and HR, 2.06, P = 0.002, respectively). On echocardiography higher left atrial (LA) size, left ventricular end-diastolic diameter (LVEDD), left ventricular (LV) mass index and E/e' ratio were associated with lower arrhythmia-free survival, whereas higher LA size, LV mass index, aortic valve peak velocity, and aortic regurgitation were associated with lower intervention-free survival. Conclusions: Differences were observed in blood biomarkers between men and women with BAV. Besides LV systolic parameters, diastolic LV function and NT-proBNP should have a more prominent role as prognostic markers in clinical care.

Contexte: La bicuspide valvulaire aortique (BVA) est une anomalie cardiaque congénitale fréquente. Les patients atteints d'une BVA présentent des risques de complications à long terme, comme la sténose valvulaire ou la régurgitation valvulaire. Cette étude visait 1) à évaluer les différences entre les sexes en ce qui concerne les biomarqueurs sanguins et les biomarqueurs à l'imagerie; et 2) à décrire la valeur pronostique à long terme des biomarqueurs sanguins et échocardiographiques. Méthodologie: Des patients de 2 études de cohortes observationnelles prospectives ont été inclus dans l'analyse. Des échantillons de sang veineux ont été prélevés, et des échocardiographies transthoraciques, y compris le suivi des marqueurs acoustiques, ont été effectuées. Les biomarqueurs sanguins analysés étaient les suivants : indice de distribution des globules rouges (IDR), créatinine, protéine C-réactive (CRP), troponine T, propeptide natriurétique de type B N-terminal (NT-proBNP) et facteur de croissance transformant ß (TGF-ß). Les différences entre les sexes ont été analysées au départ. Les liens entre les biomarqueurs et la survie sans arythmie et sans intervention ont été déterminés par la régression de Cox, avec correction en fonction de l'âge et du sexe. Résultats: Cent quatre-vingt-deux patients présentant une BVA étaient inclus (âge médian de 34 [écart interquartile : 23-46] ans, 55,5 % hommes). La CRP, la NT-proBNP et l'IDR étaient plus élevées chez les femmes, alors que la créatinine, la troponine T et le TGF-ß étaient plus élevés chez les hommes. Après une période de suivi médiane de 6,9 (écart interquartile : 6,5-9,9) ans, les taux de survie sans arythmie et sans intervention étaient respectivement de 81,0 % et de 73,1 %. La NT-proBNP a été associée à la survie sans arythmie (rapport des risques instantanés [RRI] : 1,94, p = 0,005) et à la survie sans intervention (RRI : 2,06, p = 0,002). À l'échocardiographie, des valeurs élevées pour la taille de l'oreillette gauche, le diamètre télédiastolique du ventricule gauche (VG), l'indice de masse du VG et le rapport E/e' étaient associées à un faible taux de survie sans arythmie, alors que des valeurs élevées pour la taille de l'oreillette gauche, l'indice de masse du VG, la vitesse maximale aortique et la régurgitation aortique étaient associées à un faible taux de survie sans intervention. Conclusions: Les biomarqueurs sanguins variaient en fonction du sexe des personnes présentant une BVA. Outre les paramètres systoliques du VG, la fonction VG diastolique et la NT-proBNP devraient être davantage utilisées comme marqueurs pronostiques en soins cliniques.

Role of the electrocardiogram in the risk stratification of pulmonary hypertension.

INTRODUCTION: The prognosis of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) remains dismal. Better risk prediction is needed. This study investigated the prognostic value of ECG characteristics. METHODS: In this single-centre prospective study, consecutive treatment-naïve patients with PAH or CTEPH were included at time of diagnosis. From the 12-lead ECG, obtained at baseline, the following parameters were collected: heart rate (HR), rhythm, QRS axis, conduction times, P-top amplitudes in II, R-top and S-wave amplitudes in V1 and V5 and repolarisation disorders. Associations between the ECG and transplant-free survival was assessed by Kaplan-Meier curves and Cox-proportional hazard regressions. RESULTS: In total, 140 patients were included (median age: 60.7 years, 63.6% female). The ECG was abnormal in 86.2%: sinus rhythm was not present in 9.3%, right QRS axis was observed in 47.8%, mean QRS duration was 101±17 ms. Only 42.5% of the patients had normal repolarisation, 34.5% had right ventricular strain and 14.4% non-specific repolarisation disorders. Over a median follow-up time of 3.49 (IQR: 1.37-6.42) years, 45 patients (32.5%) died or underwent lung transplantation. Transplant-free survival was worse in patients presenting with an abnormal ECG (64.0% vs 86.0%; p=0.037). The following ECG characteristics were associated with all-cause mortality or lung transplantation: heart rate (HR 1.02, 95% CI: 1.00 to 1.05), QRS duration >120 ms (HR 2.61, 95% CI: 1.01 to 6.71) and S-wave amplitude in V5 (HR 1.10, 95% CI: 1.04 to 1.17). CONCLUSION: Only 13.8% of patients with PAH and CTEPH presented with a normal ECG, which is associated with favourable outcome. The ECG provides additional prognostic value to current clinical parameters and should be considered in risk prediction.

Novel biomarkers associated with thoracic aortic disease.

BACKGROUND: Biomarkers might help to improve diagnosis, surveillance and risk stratification of thoracic aortic disease (TAD). We explored the association between a broad spectrum of cardiovascular biomarkers with clinical characteristics and thoracic aortic diameter in TAD patients. METHODS: Venous blood-samples were obtained in 158 clinically stable TAD patients visiting our outpatient clinic (2017-2020). TAD was defined as a thoracic aortic diameter ≥ 40 mm, or genetic confirmation (hereditary TAD). The cardiovascular panel III of the Olink multiplex platform was used for batch analysis of 92 proteins. A comparison was made between biomarker levels in patients with and without previous aortic dissection and/or surgery, and with and without hereditary TAD. Linear regression analyses were applied to identify (relative, normalized) biomarker concentrations associated with the absolute thoracic aortic diameter (ADmax), and thoracic aortic diameter indexed for body surface area (IDmax). RESULTS: Median age of study patients was 61.0 (IQR 50.3-68.8) years, 37.3% females. Mean ADmax and IDmax were 43.3 ± 5.4 mm and 21.3 ± 3.3 mm/m2. After multivariable adjustment, Matrix Metalloproteinase-3 (MMP-3) and Insulin-like growth factor binding protein 2 (IGFBP-2) showed a significant positive association with ADmax and IDmax, respectively. Patients with previous aortic surgery/dissection had higher N-terminal-pro hormone BNP (NTproBNP) (median 3.67 [IQR 3.01-3.99] vs 2.84 [2.32-3.26], p ≤0.001). Patients with hereditary TAD had higher Trem-like transcript protein 2 (TLT-2) (median 4.64 [IQR 4.45-4.84]) than those with non-heriditary TAD (4.40 [4.17-4.64]; p = 0.00042). CONCLUSIONS: Among a broad range of biomarkers, MMP-3 and IGFBP-2 were associated with disease severity in TAD patients. The pathophysiological pathways uncovered by these biomarkers, and their potential clinical use warrants further research.

Tuning and external validation of an adult congenital heart disease risk prediction model.

AIMS: Adequate risk prediction can optimize the clinical management in adult congenital heart disease (ACHD). We aimed to update and subsequently validate a previously developed ACHD risk prediction model. METHODS AND RESULTS: A prediction model was developed in a prospective cohort study including 602 moderately or severely complex ACHD patients, enrolled as outpatients at a tertiary centre in the Netherlands (2011-2013). Multivariable Cox regression was used to develop a model for predicting the 1-year risks of death, heart failure (HF), or arrhythmia (primary endpoint). The Boston ACHD Biobank study, a prospectively enrolled cohort (n = 749) of outpatients who visited a referral centre in Boston (2012-2017), was used for external validation. The primary endpoint occurred in 153 (26%) and 191 (28%) patients in the derivation and validation cohorts over median follow-up of 5.6 and 2.3 years, respectively. The final model included 5 out of 14 pre-specified predictors with the following hazard ratios; New York Heart Association class ≥II: 1.92 [95% confidence interval (CI) 1.28-2.90], cardiac medication 2.52 (95% CI 1.72-3.69), ≥1 reintervention after initial repair: 1.56 (95% CI 1.09-2.22), body mass index: 1.04 (95% CI 1.01-1.07), log2 N-terminal pro B-type natriuretic peptide (pmol/L): 1.48 (95% CI 1.32-1.65). At external validation, the model showed good discrimination (C-statistic 0.79, 95% CI 0.74-0.83) and excellent calibration (calibration-in-the-large = -0.002; calibration slope = 0.99). CONCLUSION: These data support the validity and applicability of a parsimonious ACHD risk model based on five readily available clinical variables to accurately predict the 1-year risk of death, HF, or arrhythmia. This risk tool may help guide appropriate care for moderately or severely complex ACHD.

Kynurenine metabolites predict survival in pulmonary arterial hypertension: A role for IL-6/IL-6Rα.

Activation of the kynurenine pathway (KP) has been reported in patients with pulmonary arterial hypertension (PAH) undergoing PAH therapy. We aimed to determine KP-metabolism in treatment-naïve PAH patients, investigate its prognostic values, evaluate the effect of PAH therapy on KP-metabolites and identify cytokines responsible for altered KP-metabolism. KP-metabolite levels were determined in plasma from PAH patients (median follow-up 42 months) and in rats with monocrotaline- and Sugen/hypoxia-induced PH. Blood sampling of PAH patients was performed at the time of diagnosis, six months and one year after PAH therapy. KP activation with lower tryptophan, higher kynurenine (Kyn), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA), and anthranilic acid was observed in treatment-naïve PAH patients compared with controls. A similar KP-metabolite profile was observed in monocrotaline, but not Sugen/hypoxia-induced PAH. Human lung primary cells (microvascular endothelial cells, pulmonary artery smooth muscle cells, and fibroblasts) were exposed to different cytokines in vitro. Following exposure to interleukin-6 (IL-6)/IL-6 receptor α (IL-6Rα) complex, all cell types exhibit a similar KP-metabolite profile as observed in PAH patients. PAH therapy partially normalized this profile in survivors after one year. Increased KP-metabolites correlated with higher pulmonary vascular resistance, shorter six-minute walking distance, and worse functional class. High levels of Kyn, 3-HK, QA, and KA measured at the latest time-point were associated with worse long-term survival. KP-metabolism was activated in treatment-naïve PAH patients, likely mediated through IL-6/IL-6Rα signaling. KP-metabolites predict response to PAH therapy and survival of PAH patients.

Heart failure in congenital heart disease: management options and clinical challenges.

INTRODUCTION: The population of adults with congenital heart disease (ACHD) is rapidly expanding and one of the major complications is heart failure. Timely diagnosis and treatment are crucial, but strong evidence for effectiveness of heart failure treatment in ACHD is currently lacking. Components of the medical history, physical examination, and further diagnostic tests including ECG, echocardiography, cardiac magnetic resonance imaging, exercise testing, and biomarkers can identify patients at risk for early mortality or heart failure. AREAS COVERED: Although the number of studies guiding evidence-based treatment are expanding, many clinical questions have not been completely answered yet. Therefore, in this review we provide an overview of current available insights in epidemiology, diagnosis, risk stratification, and treatment options in ACHD patients, including non-medical therapies and advanced care planning. EXPERT OPINION: We strongly advocate expanding current use of biomarkers in the diagnostic process and timely initiation of discussing advanced treatment options and advanced care planning with patients and their loved ones. More research in multi-center collaborations is needed to study all aspects of care of adult congenital heart disease patients.

Evolution of blood biomarker levels following percutaneous atrial septal defect closure in adults.

BACKGROUND: We sought to assess the effects of percutaneous atrial septal defect (ASD) closure on blood biomarker levels that possibly reflect reverse cardiac remodeling. Therefore, this study investigated temporal changes in six blood biomarkers following percutaneous ASD closure in adults. METHODS: In this prospective observational cohort study, adults with ASD type II scheduled for percutaneous closure were included (2012-2016). NT-proBNP, high-sensitive troponin-T (hs-TnT), high-sensitive C-reactive protein (hs-CRP), red blood cell distribution width (RDW), growth differentiation factor-15 (GDF-15) and galectin-3 were measured one day prior to ASD closure and one day, three months and one year post ASD closure, and changes were evaluated using paired T-tests. Echocardiographic measurements were obtained. RESULTS: Fifty patients were included (median age 50 years, 62% women, 32% NYHA II). At baseline, biomarker levels were elevated in a substantial number of patients; NT-proBNP n = 22 (45%), hs-TnT n = 6 (13%) hs-CRP n = 19 (40%), galectin-3 n = 5 (11%) and GDF n = 10 (23%). One day after ASD closure, significant increases of hs-TnT (median change (Δ) = 12 ng/L), hs-CRP (Δ = 1.9 mg/L), GDF-15(Δ = 129 pg/mL) and RDW (Δ = 0.1%) were observed, and a decrease in galectin-3 (Δ = -1.0 ng/mL). Consequently, 92% had at least one abnormal biomarker directly after closure. At three months biomarker levels returned to baseline, and while echocardiographic measures 1 year post closure were indicative of reverse cardiac remodeling, biomarker levels did not further decrease. CONCLUSION: Percutaneous ASD closure in adults leads to a direct increase in most blood biomarkers, in particular hs-CRP and hs-TnT. After three months, biomarkers returned to baseline levels and remained stable up to one year.

Prognostic value of C-reactive protein in adults with congenital heart disease.

BACKGROUND: High-sensitivity C reactive protein (hs-CRP) has been associated with outcomes in adult congenital heart disease (ACHD). However, its prognostic value beyond N-terminal pro B type natriuretic peptide (NT-proBNP) or troponin T remains unknown. We studied the temporal evolution of hs-CRP, as well as the relation between hs-CRP and adverse clinical outcomes independent of NT-proBNP and troponin T in patients with ACHD. METHODS: In this prospective cohort study, we enrolled 602 patients with ACHD (2011-2013) who underwent baseline and thereafter annual blood sampling during 4 years. Hs-CRP, hs-troponin T and NT-proBNP were measured. The primary endpoint was composed of death or heart failure (HF). Cox regression and Joint Modelling was used to relate 2log hs-CRP levels with the endpoint, with adjustment for baseline characteristics and (repeated) hs-troponin T and NT-proBNP measurements. RESULTS: Hs-CRP was measured at baseline in 591 patients, median age 33 years, 58% men, 90% New York Heart Association I with an average of 4.3 measurements per patient. Median follow-up was 5.9 (IQR 5.3-6.3) years (99.2% complete) and 69 patients met the endpoint. Higher baseline hs-CRP was independently associated with higher risk of death or HF (HR 1.36, 95% CI 1.19 to 1.55). Hs-CRP increased over time prior to death or HF, and repeated hs-CRP measurements were associated with the endpoint, independent of repeated NT-proBNP and hs-troponin T (HR 1.54, 95% CI 1.24 to 1.98). CONCLUSIONS: Hs-CRP carries incremental prognostic value for the risk of death or HF, beyond NT-proBNP and hs-troponin T. Hs-CRP increased prior to the occurrence of HF or death, supporting the role of inflammation in the clinical deterioration of patients with ACHD.

Prognostic Value of Serial High-Sensitivity Troponin T Measurements in Adults With Congenital Heart Disease.

BACKGROUND: Single high-sensitivity troponin T (hs-TnT) measurement is predictive of cardiac events in adults with congenital heart disease (ACHD). We aimed to study the prognostic value of serial hs-TnT measurements in stable patients with ACHD. METHODS: In total, 602 consecutive patients with ACHD were enrolled in this prospective study (2011-2013). Blood sampling was performed at enrollment and thereafter yearly during scheduled visits, up to 4 years. Hs-TnT, N-terminal pro B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR) were measured. The composite primary endpoint was defined as all-cause mortality, heart failure, arrhythmia, hospitalization, cardiac (re)interventions, or thromboembolic events. The relationship between changes in serial hs-TnT and the primary endpoint was studied by joint models with adjustment for repeated NT-proBNP and eGFR. RESULTS: In 601 patients (median age, 33 [interquartile range, 25-41] years, 42% women, 90% NYHA I), at least 1 hs-TnT measurement was performed; a mean of 4.3 hs-TnT measurements per patient were collected. After a median follow-up of 5.8 [interquartile range, 5.3-6.3] years, 229 (38.1%) patients reached the primary endpoint. On average, hs-TnT levels increased over time, and more in patients who reached the primary endpoint (P < 0.001). A 2-fold higher hs-TnT was associated with the primary endpoint (unadjusted hazard ratio, 1.62; 95% confidence interval, 1.44-1.82; P < 0.001). The association remained after adjustment for repeated eGFR but not when adjusted for repeated NT-proBNP; repeated NT-proBNP remained associated with the primary endpoint. CONCLUSION: In stable patients with ACHD, hs-TnT levels increased before the occurrence of an event and repeated hs-TnT was associated with the risk of adverse cardiac events. However, repeated hs-TnT was not superior to repeated NT-proBNP.

Growth differentiation factor-15 as candidate predictor for mortality in adults with pulmonary hypertension.

OBJECTIVE: Despite its predictive value for mortality in various diseases, the relevance of growth differentiation factor-15 (GDF-15) as prognostic biomarker in pulmonary hypertension (PH) remains unclear. This study investigated the association between GDF-15 and outcomes in adults with PH. METHODS: This is a single-centre prospective observational cohort study. All adults with PH were included at the day of their diagnostic right heart catheterisation between 2012 and 2016. PH due to left heart disease was excluded. Venous blood sampling was performed and included GDF-15 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements. Kaplan-Meier curves and Cox regression analysis were used to investigate the association between GDF-15 and a composite endpoint of death or lung transplantation. We adjusted for age and NT-proBNP in multivariable analysis. Reference values were established by GDF-15 measurements in healthy controls. RESULTS: GDF-15 was measured in 103 patients (median age 59.2 years, 65% women, 51% pulmonary arterial hypertension). GDF-15 was elevated in 76 patients (74%). After a median follow-up of 3.4 (IQR 2.3-4.6) years, 32 patients (31.1%) reached the primary endpoint. Event-free survival 2 years after diagnosis was 100% in patients with normal GDF-15 versus 72.4% in patients with elevated GDF-15 (p=0.007). A significant association was found between GDF-15 and the primary endpoint (HR per twofold higher value 1.77, 95% CI 1.39 to 2.27, p<0.001), also after adjustment for age and NT-proBNP (HR 1.41, 95% CI 1.02 to 1.94, p=0.038). CONCLUSIONS: High GDF-15 levels are associated with an increased risk of death or transplant in adults with PH, independent of age and NT-proBNP. As non-specific biomarker, GDF-15 could particularly be useful to detect low-risk patients.

Lower Plasma Melatonin Levels Predict Worse Long-Term Survival in Pulmonary Arterial Hypertension.

: Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms are involved, with melatonin exerting anti-oxidant and anti-inflammatory effects, as well as inducing vasodilation and cardio-protection. However, endogenous levels of melatonin in treatment-naïve patients with PH and their clinical significance are still unknown. Plasma levels of endogenous melatonin were measured by liquid chromatography-tandem mass spectrometry in PH patients (n = 64, 43 pulmonary arterial hypertension (PAH) and 21 chronic thromboembolic PH (CTEPH)) and healthy controls (n = 111). Melatonin levels were higher in PH, PAH, and CTEPH patients when compared with controls (Median 118.7 (IQR 108.2-139.9), 118.9 (109.3-147.7), 118.3 (106.8-130.1) versus 108.0 (102.3-115.2) pM, respectively, p all < 0.001). The mortality was 26% (11/43) in the PAH subgroup during a long-term follow-up of 42 (IQR: 32-58) months. Kaplan-Meier analysis showed that, in the PAH subgroup, patients with melatonin levels in the 1st quartile (<109.3 pM) had a worse survival than those in quartile 2-4 (Mean survival times were 46 (95% CI: 30-65) versus 68 (58-77) months, Log-rank, p = 0.026) with an increased hazard ratio of 3.5 (95% CI: 1.1-11.6, p = 0.038). Endogenous melatonin was increased in treatment-naïve patients with PH, and lower levels of melatonin were associated with worse long-term survival in patient with PAH.

Blood biomarkers in patients with bicuspid aortic valve disease.

BACKGROUND: Patients with a bicuspid aortic valve (BAV) are at risk of developing valve deterioration and aortic dilatation. We aimed to investigate whether blood biomarkers are associated with disease stage in patients with BAV. METHODS: Serum levels of high sensitivity C-reactive protein (hsCRP), high sensitivity troponin T (hsTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and total transforming growth factor-beta 1 (TGF-ß1) were measured in adult BAV patients with valve dysfunction or aortic pathology. Age-matched general population controls were included for TGFß-1 measurements. Correlation analyses and multivariable linear regression were used to determine the association between (2log-transformed) biomarker levels and aortic valve regurgitation, aortic valve stenosis, aortic dilatation, or left ventricular function. RESULTS: hsCRP and hsTnT were measured in the total group of 183 patients (median age 34 years, 25th-75th percentile 23-46), NT-proBNP in 162 patients, and TGF-ß1 beta in 108 patients. Elevated levels of NT-proBNP were found in 20% of the BAV patients, elevated hsTnT in 6%, and elevated hsCRP in 7%. Higher hsTnT levels were independently associated with aortic regurgitation [odds ratio per doubling (OR2log) 1.34, 95% CI 1.01;1.76] and higher NT-proBNP levels with aortic valve maximal velocity (ß2log 0.17, 95%CI 0.07;0.28) and aortic regurgitation (OR2log 1.41, 95%CI 1.11;1.79). Both BAV patients with (9.9 ± 2.7 ng/mL) and without aortic dilatation (10.4 ± 2.9 ng/mL) showed lower TGF-ß1 levels compared to general population controls (n = 85, 11.8 ± 3.2 ng/mL). CONCLUSIONS: Higher NT-proBNP and hsTNT levels were associated with aortic valve disease in BAV patients. TGF-ß1 levels were lower in BAV patients than in the general population, and not related to aortic dilatation. Longitudinal data are needed to further investigate the prognostic value of biomarkers in these patients.

The Prognostic Value of Soluble ST2 in Adults with Pulmonary Hypertension.

Soluble ST2 (sST2) is upregulated in response to myocardial stress and may serve as biomarker in adults with pulmonary hypertension (PH). This prospective cohort study investigated sST2 levels and its association with echocardiographic and hemodynamic measures, and adverse clinical outcomes in adults with PH of different etiologies. sST2 was measured during the diagnostic right heart catheterization for PH, in adult patients enrolled between May 2012 and October 2016. PH due to left heart failure was excluded. The association between sST2 and a primary endpoint composed of death or lung transplantation and a secondary composite endpoint including death, lung transplantation or heart failure, was investigated using Cox regression with adjustment for NT-proBNP. In total 104 patients were included (median age was 59 years, 66% woman, 51% pulmonary arterial hypertension). Median sST2 was 28 [IQR 20-46] ng/mL. Higher sST2 was associated with worse right ventricular dysfunction and higher mean pulmonary and right atrial pressures. Median follow-up was 3.3 [IQR 2.3-4.6] years. The primary and secondary endpoint occurred in 33 (31.7%) and 43 (41.3%) patients, respectively. sST2 was significantly associated with both endpoints (HR per 2-fold higher value 1.53, 95%CI 1.12-2.07, p = 0.007 and 1.45, 95%CI 1.10-1.90, p = 0.008, respectively). However, after adjustment for NT-proBNP, both associations did not reach statistical significance. In conclusions, higher sST2 levels are associated with more severe PH and right ventricular dysfunction and yields prognostic value in adults with PH, although not independently of NT-proBNP.

Prognostic value of soluble ST2 in adults with congenital heart disease.

OBJECTIVE: Soluble suppression of tumourigenicity-2 (sST2) is upregulated as response to myocardial stress and may be a potential biomarker for risk stratification in patients with adult congenital heart disease (ACHD). This study aimed to investigate the release of sST2 and its association with cardiovascular events in ACHD. METHODS: In this prospective cohort study, 602 consecutive patients with ACHD visiting the outpatient clinic were included (2011-2013). The association between sST2 and a primary composite endpoint of all-cause mortality, heart failure, hospitalisation, arrhythmia, thromboembolic events or cardiac interventions was investigated using multivariable Cox regression. RESULTS: sST2 was measured in 590 (98%) patients (median age 33 [25-41] years, 42% women). After a median follow-up of 5.8 [IQR 5.1-6.2) years, 225 (38.5%) reached the primary endpoint. sST2 was significantly associated with the primary endpoint when adjusted for age, sex, creatinine and N terminal pro-B type brain natriuretic peptide (NT-proBNP) (HR per twofold higher sST2: 1.28, 95% CI 1.03 to 1.58, p=0.025). This association negated when adjusted for clinical variables and NT-proBNP (HR per twofold higher sST2: 1.19, 95% CI 0.96 to 1.48, p=0.106). Stratified analysis in complex ACHD did show a significant association between sST2 and the primary endpoint when adjusted for clinical variables and NT-proBNP (HR per twofold higher sST2: 1.31, 95% CI 1.01 to 1.69, p=0.043). Sex-specific analysis showed an association between sST2 and the primary endpoint in women (HR per twofold higher sST2 1.80, 95% CI 1.30 to 2.49, p<0.001) but not in men (HR per twofold higher sST2 1.19, 95% CI 0.90 to 1.56, p=0.223). CONCLUSIONS: sST2 is a promising novel biomarker in patients with ACHD, specifically in complex ACHD and women. Future research is warranted to elucidate sex-specific and diagnosis-specific differences.

Exploring the Prognostic Value of Novel Markers in Adults With a Systemic Right Ventricle.

Background Adults with a systemic right ventricle (sRV) have a high risk of cardiac complications. This study aimed to identify prognostic markers in adults with sRV based on clinical evaluation, echocardiography, and blood biomarkers. Methods and Results In this prospective cohort study, consecutive clinically stable adults with sRV caused by Mustard- or congenitally corrected transposition of the great arteries were included (2011-2013). Eighty-six patients were included (age 37±9 years, 65% male, 83% New York Heart Association functional class I, 76% Mustard transposition of the great arteries, 24% congenitally corrected transposition of the great arteries). Venous blood sampling was performed including N-terminal pro B-type natriuretic peptide, high-sensitive-troponin-T, high-sensitivity C-reactive protein, growth differentiation factor-15, galectin-3, red cell distribution width, estimated glomerular filtration rate, and hemoglobin. Besides conventional echocardiographic measurements, longitudinal, circumferential, and radial strain were assessed using strain analysis. During a median follow-up of 5.9 (interquartile range 5.3-6.3) years, 19 (22%) patients died or had heart failure (primary end point) and 29 (34%) patients died or had arrhythmia (secondary end point). Univariable Cox regression analysis was performed using dichotomous or standardized continuous variables. New York Heart Association functional class >I, systolic blood pressure, and most blood biomarkers were associated with the primary and secondary end point (galectin-3 not for primary, N-terminal pro B-type natriuretic peptide and high-sensitivity C-reactive protein not for secondary end point). Growth differentiation factor-15 showed the strongest association with both end points (hazard ratios; 2.44 [95% CI 1.67-3.57, P<0.001], 2.00 [95% CI 1.46-2.73, P<0.001], respectively). End-diastolic basal dimension of the subpulmonary ventricle was associated with both end points (hazard ratio: 1.95 [95% CI 1.34-2.85], P<0.001, 1.70 [95% CI 1.21-2.38, P=0.002], respectively). Concerning strain analysis, only sRV septal strain was associated with the secondary end point (hazard ratio 0.58 [95% CI 0.39-0.86], P=0.006). Conclusions Clinical, conventional echocardiographic, and blood measurements are important markers for risk stratification in adults with a sRV. The value of novel echocardiographic strain analysis seems limited.