http://orcid.org/0000-0002-8893-171X
Figures
Abstract
Background
Soluble suppression of tumorogenicity 2 (sST2) has been shown to be of prognostic value in patients with chronic and acute left heart failure. The present study aims to assess the predictive value of sST2 levels in adult patients with complex congenital heart disease (CHD).
Methods
In 169 consecutive patients with complex CHD and a mean age of 28.2 ± 12.0 years, sST2 levels were compared to 32 healthy controls and associated with clinical status as well as the occurrence of major adverse cardiac events (MACE). Mean follow-up time was 35.6 ± 24.9 months.
Results
In CHD patients, median sST2 levels were 29.7 ng/ml compared to 26.4 ng/ml in healthy controls (p = 0.007) and increased with different types of CHD and the severity of MACE. According to ROC analysis, the most important predictors of acute heart/Fontan failure were NYHA class III/IV (AUC 0.804, p<0.001, CI 0.668–0.941), NT-proBNP levels (AUC 0.794, p<0.001, CI 0.640–0.948), γGT levels (AUC 0.793, p<0.001, CI 0.678–0.909) and sST2 levels (AUC 0.742, p = 0.004, CI 0.626–0.858), with NYHA class III/IV as the strongest independent predictor (p<0.001). All-cause mortality was best predicted by sST2 levels (AUC 0.890, p<0.001, CI 0.741–1.000), NT-proBNP levels (AUC 0.875, p = 0.001, CI 0.766–0.984) and NYHA class III/IV (AUC 0.837, p = 0.003, CI 0.655–1.000) with sST2 as the strongest independent predictor (p<0.001). Moreover, AUC increased to 0.918 combining both biomarkers and net reclassification improved with the addition of sST2.
Citation: Laqqan M, Schwaighofer C, Graeber S, Raedle-Hurst T (2018) Predictive value of soluble ST2 in adolescent and adult patients with complex congenital heart disease. PLoS ONE 13(8): e0202406. https://doi.org/10.1371/journal.pone.0202406
Editor: Claudio Passino, Ospedale del Cuore G Pasquinucci Fondazione Toscana Gabriele Monasterio di Massa, ITALY
Received: May 12, 2018; Accepted: July 8, 2018; Published: August 17, 2018
Copyright: © 2018 Laqqan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information file.
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
The protein suppression of tumorogenicity 2 (ST2) is known to be involved in a wide range of pathophysiological processes. Before it was recognized to be involved in cardiovascular disease, it was mainly related to inflammatory and autoimmune disease [1]. It is expressed both in a transmembrane (ST2 ligand) and soluble form (sST2) with the latter blocking the cardioprotective effects of interleukin-33/ST2 ligand interaction and promoting myocardial apoptosis, fibrosis and hypertrophy [2,3]. Interleukin-33 and sST2 are expressed both in cardiac fibroblasts and cardiomyocytes and are induced either by biomechanical strain injury or angiotensin II [2]. Thus, expression levels are increased as a response to myocardial stress such a myocardial ischemia, mechanical overload or neurohormonal activation [4]. In cardiovascular disease, elevated sST2 levels maintained over time may indicate the presence of adverse myocardial remodeling and disease progression [5,6]. In the clinical setting, circulating sST2 levels have been shown to provide prognostic information in patients with acute and chronic left heart failure [7–13]. Moreover, serial measurement of sST2 concentrations may be useful for risk stratification and also predicting outcome in those patients [14–18]. In contrast to natriuretic peptides, sST2 levels seem not to be influenced by confounders such as age or renal function [17]. Additionally, the biologic and analytic variability of sST2 is much lower than that of natriuretic peptides suggesting that sST2 levels may be better in risk stratification and prognostication [19,20]. Thus, sST2 has been included in the ACC/AHA guidelines for additive risk stratification in patients with acute and chronic left heart failure [21].
Patients with complex CHD, namely those with a systemic morphological right ventricle or single ventricle physiology, are prone to develop acute heart/Fontan failure during long term follow-up [22,23]. However, risk stratification using natriuretic peptide levels is challenging in these patients due to the heterogeneity of the underlying lesions, different hemodynamics with univentricular or biventricular physiology and the presence of chronic hypoxia [24]. Nevertheless, natriuretic peptides have been proven to be of prognostic value in adult CHD patients [25].
To date, studies investigating sST2 levels in adult patients with complex CHD are lacking. According to the literature, there’s only one study available investigating sST2 levels in children and adolescents with CHD and dilated cardiomyopathy demonstrating a poor performance of sST2 in diagnosing pediatric heart failure [26]. However, the prognostic value of sST2 hasn’t been addressed in that study. Since sST2 has been proven to provide independent and incremental prognostic information in heart failure patients [9–11,14,27], the aim of our study was to measure sST2 concentrations and assess the predictive value of sST2 in adult patients with complex CHD.
Materials and methods
Patients
A total of 192 consecutive patients with complex CHD seen in our outpatient clinic between 22/12/2008 and 23/11/2016 were screened to be enrolled in the present study. Classification of CHD was performed according to current ACC/AHA guidelines [28] with complex CHD referring to as CHD of mostly great complexity such as all forms of pulmonary atresia, all forms of cyanotic CHD, Eisenmenger syndrome, transposition of the great arteries and all kinds of Fontan procedure as well as CHD at increased risk for heart failure such as tetralogy of Fallot, single ventricle physiology and transposition of the great arteries after atrial diversion procedure [23]. Exclusion criteria were other kinds of mild or moderate CHD, pregnancy, severe renal dysfunction or dialysis and incapability to understand or sign informed consent. Finally, 169 patients were included in this study of whom 61/169 (36.1%) patients had corrective surgery of congenital right heart disease (CRHD) such as pulmonary atresia or tetralogy of Fallot, 37/169 (21.9%) patients a systemic morphological right ventricle (SRV) of whom 10/37 patients presented with congenitally corrected transposition of the great arteries and 27/37 patients with d-transposition of the great arteries after atrial switch operation, 50/169 (29.6%) patients a single ventricle physiology after Fontan palliation (FONT) and 21/169 (12.4%) patients a non-corrected cyanotic heart defect or Eisenmenger physiology (EIS). Mean age was 28.2 ± 12.0 years (range 11–73 years). 84 patients were female and 85 patients male. Mean follow-up time was 35.6 ± 24.9 months with a median of 31 months. At each follow-up visit, a structured history and physical exam, a 12-lead surface electrocardiogram, measurement of blood pressure and transcutaneous oxygen saturation at rest and conventional two-dimensional echocardiography were performed in all patients. Follow-up investigations were made with special emphasis on clinical signs of pulmonary or systemic venous congestion including pleural effusions, ascites, peripheral edema with significant weight gain or protein losing enteropathy indicating acute heart/Fontan failure as well as the occurrence of supraventricular arrhythmias or atrial fibrillation. After echocardiography, venous blood was drawn for routine laboratory tests and blood sampling in all patients. Blood samples of patients were compared to those of 32 healthy subjects with a mean age of 29.6 ± 15.2 years (range 11–61 years) (S1 Dataset). The study complies with the Declaration of Helsinki, was approved by the Saarland medical association ethical board and all subjects or their guardians gave written and informed consent before enrollment.
Conventional two-dimensional echocardiography
Two-dimensional echocardiography was performed using a Vivid 9 ultrasound system (GE Healthcare, Horten, Norway) with a transducer operating at 3.5 MHz. Apical 4-chamber views were acquired as loops for the planimetric calculation of the ejection fraction as well as endsystolic and enddiastolic volumes of the systemic ventricle according to the modified Simpson’s method [29]. Pulsed-wave Doppler echocardiography was performed to obtain the outflow pattern above the aortic valve to measure velocity time integral (VTI). Continuous-wave Doppler was used to estimate pressure gradients across the aortic or pulmonary valve. Colored Doppler flow was used to assess the severity of regurgitation across the systemic atrioventricular and aortic or pulmonary valve.
Biochemical analyses
In all participants, venous blood samples were drawn into standard sampling tubes after echocardiography. Each sample was centrifuged and serum removed, allocated and frozen at -80°C before analysis of sST2 levels. In the patient group, routine laboratory tests such as liver function tests and creatinine measurements were performed using standard laboratory techniques. NT-proBNP levels were measured using an electrochemiluminescence sandwich immunoassay (Cobas® proBNP II, Roche Diagnostics, Basel, Switzerland) on the Elecsys® 2010 analyzer. Levels of sST2 were measured using a commercially available enzyme-linked immunosorbent assay (Presage®ST2, Critical Diagnostics, San Diego, California, USA) on the Sunrise™ Absorbance Microplate Reader (Tecan Trading AG, Mannedorf, Switzerland). All biochemical analyses were performed by investigators blinded to the clinical data of the patients. Glomerular filtration rate (GFR) was estimated using the chronic kidney disease epidemiology collaboration (CKD-EPI) creatinine equation [30].
Data analysis
Clinical data of the patients were collected from medical records. The echocardiographic loops and Doppler images were stored digitally and analysed on an Echopac server (Echopac Version 6, GE Healthcare). Echocardiographic data sets were assessed by investigators blinded to the laboratory results. The presence of supraventricular arrhythmias or atrial fibrillation was confirmed either on the 12-lead surface or Holter electrocardiogram. Major adverse cardiac events (MACE) were defined as the occurrence of acute heart/Fontan failure or death from any cause. Patients were followed for fatal and non-fatal events until 31/12/2017.
Statistical analysis
Data were analysed using standard statistical software (SPSS version 19; SPSS Inc., Chicago, Illinois). Continuous variables are expressed as mean ± standard deviation or median (interquartile interval) as appropriate. Differences between unpaired groups were analysed using a Mann-Whitney-U test for continuous variables and a chi-square test (or Fisher exact test, if numbers were small) for nominal variables. Correlations were evaluated using Spearman’s regression coefficient. For further analysis, log10 transformed biomarker values were used due to their skewed distribution. Receiver-operating characteristic (ROC) curve analysis was used for the prediction of acute heart/Fontan failure and all-cause mortality. Comparison of areas under the curve (AUCs) was performed using the DeLong method [31] and logistic regression analyses were used to assess combined biomarker models. Multivariate analysis was performed using Cox regression analysis to identify variables that independently predict MACE. Variables entered into the multivariate model were those that gave statistically significant results in the univariate analysis and didn’t show any multicollinearity. Furthermore, reclassification analysis was performed using net reclassification improvement (NRI) analysis [32]. A two-tailed p-value <0.05 was considered statistically significant.
Results and discussion
Results
Clinical data.
During follow-up, a total of 28 adverse cardiac events occurred in 25/169 (13.0%) patients: 7/169 (4.1%) patients died (3 patients due to sudden cardiac death, 3 patients due to progressive heart/Fontan failure, 1 patient due to septicemia), 13 patients presented with acute heart/Fontan failure, and 8 patients had recurrent supraventricular arrhythmias or permanent atrial fibrillation indicating high atrial arrhythmic burden. Finally, 17/169 (10.0%) patients experienced MACE whereas 152/169 (90.0%) patients were in a clinically stable condition (S1 Dataset). Characteristics of patients with and without MACE are shown in Table 1.
Measurement of sST2 levels.
sST2 levels ranged from 14.7 to 73.2 ng/ml with a median of 29.9 ng/ml (24.5–37.6 ng/ml) in the patient group and were significantly elevated as compared to healthy controls showing a median sST2 level of 26.4 ng/ml (23.0–30.5 ng/ml; p = 0.007). Significantly elevated sST2 levels were found in SRV patients with a median of 30.5 ng/ml (24.6–38.2 ng/ml; p = 0.016), in FONT patients with a median of 32.5 ng/ml (26.1–39.7 ng/ml; p = 0.001) and in EIS patients with a median of 37.2 ng/ml (26.7–49.1 ng/ml; p<0.001) (Fig 1) (S1 Dataset).
CRHD, corrected congenital right heart disease; SRV, systemic right ventricle; FONT, Fontan palliation; EIS, Eisenmenger physiology or unrepaired cyanotic heart defect.
Median sST2 levels also increased according to MACE with highest levels found in deceased patients (Fig 2).
SVT, supraventricular tachycardia; AF, atrial fibrillation.
Levels of sST2 were only weakly related to NT-proBNP levels (r = 0.286; p<0.001). Relations of both biomarkers to clinical, echocardiographic and laboratory parameters are given in Table 2.
Prediction of acute heart/Fontan failure.
ROC curve analysis was used to identify predictors of acute heart/Fontan failure in all patients. The most significant predictors were a higher NYHA class III/IV, NT-proBNP levels, γGT levels and sST2 levels, respectively. Multivariate analysis identified a higher NYHA class III/IV as independent predictor of acute heart/Fontan failure (p<0.001) (Table 3).
ROC curves of NT-proBNP and sST2 levels demonstrated no significant difference of AUCs of both biomarkers (p = 0.585), however, AUC increased slightly with the use of the combined biomarker model (Fig 3).
AUC, area under the curve.
The optimal cut-off of sST2 levels for the prediction of acute heart/Fontan failure was calculated to be 31.1 ng/ml with a sensitivity of 84.6%, specificity of 58.3%, positive predictive value of 14.5% and negative predictive value of 97.8%. The optimal cut-off of NT-proBNP levels was calculated to be 349.5 ng/l with a sensitivity of 84.6%, specificity of 75.6%, positive predictive value of 22.4% and negative predictive value of 98.3%. NRI analysis was performed and components were calculated revealing an event NRI of 0% and a non-event NRI of -23.3% indicating no improvement of classification or risk prediction with the additional use of sST2.
Prediction of all-cause mortality.
According to ROC curve analysis, the most significant predictors of all-cause mortality were sST2 levels, NT-proBNP levels, NYHA class III/IV, glomerular filtration rate and ejection fraction of the systemic ventricle, respectively. In the multivariate analysis, sST2 levels (p<0.001) turned out to be the most significant independent predictor of all-cause mortality (Table 3). Direct comparison of AUCs of NT-proBNP and sST2 levels revealed no significant difference (p = 0.788). However, AUC increased slightly using the combined biomarker model indicating an additive value of sST2 (Fig 4).
AUC, area under the curve.
The optimal cut-off of sST2 levels for the prediction of all-cause mortality was calculated to be 42.8 ng/ml with a sensitivity of 85.7%, specificity of 88.3%, positive predictive value of 24.0% and negative predictive value of 99.3%. The optimal cut-off of NT-proBNP levels was calculated to be 774.6 ng/l with a sensitivity of 71.4%, specificity of 88.9%, positive predictive value of 21.7% and negative predictive value of 98.6%. Reclassification analysis using NRI showed an event NRI of 4.3% and a non-event NRI of -0.7% indicating that addition of sST2 improved classification and risk prediction of individuals with events, with almost no loss for non-events.
Discussion
sST2 has emerged as a promising marker in patients with acute and chronic left heart failure providing incremental prognostic information and additional risk stratification to natriuretic peptides [10–14,18,27]. Thus, the aim of our study was to measure sST2 levels in patients with complex CHD and assess the predictive value of sST2 in this cohort of patients.
sST2 and its association with clinical status and adverse cardiac events.
Our study demonstrates that sST2 levels are significantly elevated in the patient group as compared to healthy controls and increase with different types of CHD and the severity of MACE (Figs 1 and 2). Thus, highest sST2 levels were found in patients with Eisenmenger physiology and deceased patients being in agreement with previous studies that elevated sST2 levels are strongly associated with increased risk of death [8,9].
In our study, NT-proBNP but not sST2 was significantly related to measures of systolic ventricular function such as ejection fraction of the systemic ventricle and VTI above the aortic valve. Moreover, sST2 levels were not associated with high atrial arrhythmic burden reflecting altered loading conditions due to reduced systemic ventricular function or disease progression. Furthermore, sST2 and NT-proBNP levels were only slightly related to each other. Taken together, all these findings indicate a different pathophysiological mechanism of sST2 and NT-proBNP concentrations and thus a complementary or independent role of sST2.
Prediction of acute heart/Fontan failure.
According to ROC curve analysis, the most significant predictors of acute heart/Fontan failure were a higher NYHA class III/IV, NT-proBNP, γGT and sST2 levels with an AUC of 0.804, 0.794, 0.792 and 0.742, respectively (Table 3). These findings are not surprising because NYHA class is known to be a strong and reliable predictor of acute heart failure and mortality in patients with chronic left heart failure and either reduced or preserved systolic ventricular function [33,34]. Natriuretic peptides are also well known for their prognostic capabilities in left heart failure but also CHD patients [21,25]. The predictive value of γGT levels in our study can be explained by the systemic venous congestion of the liver that is frequently present in patients with Fontan palliation or uncorrected complex heart defects without any palliation. sST2 was also found to be a significant predictor, however, didn’t show any improvement for the prediction of acute heart/Fontan failure using NRI analysis. Despite its subjective aspect of classification, a higher NYHA class III/IV turned out to be the strongest independent predictor in the multivariate analysis (p<0.001).
Prediction of all-cause mortality.
The most important predictors of all-cause mortality in our cohort of patients were sST2, NT-proBNP, a higher NYHA class III/IV, glomerular filtration rate and ejection fraction of the systemic ventricle with an AUC of 0.890, 0.875, 0.837, 0.810 and 0.801, respectively. On multivariate analysis, sST2 turned out to be the strongest independent predictor of all-cause mortality (p<0.001). Moreover, ROC curve analysis showed an increase of AUC for the combined biomarker model. In addition, an improved classification of individuals with events was seen using NRI analysis thus underlining the potential additive value of sST2 for the prediction of death in CHD patients. Due to the small number of deceased patients in our study, however, these results should be validated in a larger cohort of CHD patients.
Nevertheless, our findings are in line with previous studies identifying sST2 as a robust prognostic marker in patients with left heart failure that may be due to the fact that sST2 is known to be a marker of myocardial fibrosis and inversed cardiac remodeling thus representing long-term cardiac alterations [2,4]. In contrast, natriuretic peptides respond to myocardial wall stretch and different loading conditions reflecting a completely different pathophysiological mechanism. The fact that sST2 has a lower biological and analytical variability [19,20] and is less influenced by confounders than natriuretic peptides [17] may also contribute to a better long-term prognostication.
Study limitations.
This is a study that aims to assess the predictive value of sST2 in a high-risk subset of patients with complex CHD. Therefore, the period for patient recruitment is rather long and there is a wide range of ages in this cohort of patients in order not to miss patients with a failing Fontan circuit because Fontan failure can also occur at younger ages whereas acute heart failure in CRHD or SRV patients is more likely to occur in later adulthood. Nevertheless, it is surprising that the rate of MACE is rather low in this selected high-risk population thus indicating the need for a larger cohort of high-risk CHD patients and also a larger control group to be evaluated. Moreover, it would be interesting to know if serial sST2 measurements in CHD patients might be superior for prognostication than single measurements as has been shown in patients with left heart failure [16,18].
Supporting information
S1 Dataset. Raw data of patients and controls.
https://doi.org/10.1371/journal.pone.0202406.s001
(XLSX)
References
- 1. Kakkar R, Lee RT (2008) The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov 7: 827–840. pmid:18827826
- 2. Sanada S, Hakuno D, Higgins LJ, Schreiter ER, McKenzie AN, et al. (2007) IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J Clin Invest 117: 1538–1549. pmid:17492053
- 3. Seki K, Sanada S, Kudinova AY, Steinhauser ML, Handa V, et al. (2009) Interleukin-33 prevents apoptosis and improves survival after experimental myocardial infarction through ST2 signaling. Circ Heart Fail 2: 684–691. pmid:19919994
- 4. Pascual-Figal DA, Januzzi JL (2015) The biology of ST2: the International ST2 Consensus Panel. Am J Cardiol 115: 3b–7b. pmid:25665766
- 5. Shah RV, Chen-Tournoux AA, Picard MH, van Kimmenade RR, Januzzi JL (2009) Serum levels of the interleukin-1 receptor family member ST2, cardiac structure and function, and long-term mortality in patients with acute dyspnea. Circ Heart Fail 2: 311–319. pmid:19808354
- 6. Daniels LB, Clopton P, Iqbal N, Tran K, Maisel AS (2010) Association of ST2 levels with cardiac structure and function and mortality in outpatients. Am Heart J 160: 721–728. pmid:20934567
- 7. Januzzi JL Jr., Peacock WF, Maisel AS, Chae CU, Jesse RL, et al. (2007) Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. J Am Coll Cardiol 50: 607–613. pmid:17692745
- 8. Rehman SU, Mueller T, Januzzi JL Jr. (2008) Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure. J Am Coll Cardiol 52: 1458–1465. pmid:19017513
- 9. Ky B, French B, McCloskey K, Rame JE, McIntosh E, et al. (2011) High-sensitivity ST2 for prediction of adverse outcomes in chronic heart failure. Circ Heart Fail 4: 180–187. pmid:21178018
- 10. Bayes-Genis A, de Antonio M, Galan A, Sanz H, Urrutia A, et al. (2012) Combined use of high-sensitivity ST2 and NTproBNP to improve the prediction of death in heart failure. Eur J Heart Fail 14: 32–38. pmid:22179033
- 11. Manzano-Fernandez S, Mueller T, Pascual-Figal D, Truong QA, Januzzi JL (2011) Usefulness of soluble concentrations of interleukin family member ST2 as predictor of mortality in patients with acutely decompensated heart failure relative to left ventricular ejection fraction. Am J Cardiol 107: 259–267. pmid:21211603
- 12. Aimo A, Vergaro G, Passino C, Ripoli A, Ky B, et al. (2017) Prognostic Value of Soluble Suppression of Tumorigenicity-2 in Chronic Heart Failure: A Meta-Analysis. JACC Heart Fail 5: 280–286. pmid:27816512
- 13. Aimo A, Vergaro G, Ripoli A, Bayes-Genis A, Pascual Figal DA, et al. (2017) Meta-Analysis of Soluble Suppression of Tumorigenicity-2 and Prognosis in Acute Heart Failure. JACC Heart Fail 5: 287–296. pmid:28189578
- 14. Anand IS, Rector TS, Kuskowski M, Snider J, Cohn JN (2014) Prognostic value of soluble ST2 in the Valsartan Heart Failure Trial. Circ Heart Fail 7: 418–426. pmid:24622243
- 15. Manzano-Fernandez S, Januzzi JL, Pastor-Perez FJ, Bonaque-Gonzalez JC, Boronat-Garcia M, et al. (2012) Serial monitoring of soluble interleukin family member ST2 in patients with acutely decompensated heart failure. Cardiology 122: 158–166. pmid:22832599
- 16. Gaggin HK, Szymonifka J, Bhardwaj A, Belcher A, De Berardinis B, et al. (2014) Head-to-head comparison of serial soluble ST2, growth differentiation factor-15, and highly-sensitive troponin T measurements in patients with chronic heart failure. JACC Heart Fail 2: 65–72. pmid:24622120
- 17. Dieplinger B, Mueller T (2015) Soluble ST2 in heart failure. Clin Chim Acta 443: 57–70. pmid:25269091
- 18. Boisot S, Beede J, Isakson S, Chiu A, Clopton P, et al. (2008) Serial sampling of ST2 predicts 90-day mortality following destabilized heart failure. J Card Fail 14: 732–738. pmid:18995177
- 19. Wu AH, Wians F, Jaffe A (2013) Biological variation of galectin-3 and soluble ST2 for chronic heart failure: implication on interpretation of test results. Am Heart J 165: 995–999. pmid:23708172
- 20. Piper S, deCourcey J, Sherwood R, Amin-Youssef G, McDonagh T (2016) Biologic Variability of Soluble ST2 in Patients With Stable Chronic Heart Failure and Implications for Monitoring. Am J Cardiol 118: 95–98. pmid:27189812
- 21. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr., et al. (2013) 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 62: e147–239. pmid:23747642
- 22. Piran S, Veldtman G, Siu S, Webb GD, Liu PP (2002) Heart failure and ventricular dysfunction in patients with single or systemic right ventricles. Circulation 105: 1189–1194. pmid:11889012
- 23. Shaddy RE, Webb G (2008) Applying heart failure guidelines to adult congenital heart disease patients. Expert Rev Cardiovasc Ther 6: 165–174. pmid:18248271
- 24. Hopkins WE, Chen Z, Fukagawa NK, Hall C, Knot HJ, et al. (2004) Increased atrial and brain natriuretic peptides in adults with cyanotic congenital heart disease: enhanced understanding of the relationship between hypoxia and natriuretic peptide secretion. Circulation 109: 2872–2877. pmid:15173030
- 25. Baggen VJ, van den Bosch AE, Eindhoven JA, Schut AW, Cuypers JA, et al. (2017) Prognostic Value of N-Terminal Pro-B-Type Natriuretic Peptide, Troponin-T, and Growth-Differentiation Factor 15 in Adult Congenital Heart Disease. Circulation 135: 264–279. pmid:27832613
- 26. Hauser JA, Demyanets S, Rusai K, Goritschan C, Weber M, et al. (2016) Diagnostic performance and reference values of novel biomarkers of paediatric heart failure. Heart 102: 1633–1639. pmid:27220692
- 27. Gruson D, Lepoutre T, Ahn SA, Rousseau MF (2014) Increased soluble ST2 is a stronger predictor of long-term cardiovascular death than natriuretic peptides in heart failure patients with reduced ejection fraction. Int J Cardiol 172: e250–252. pmid:24467978
- 28. Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, et al. (2008) ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines on the Management of Adults With Congenital Heart Disease). Developed in Collaboration With the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 52: e143–263. pmid:19038677
- 29. Wyatt HL, Meerbaum S, Heng MK, Gueret P, Corday E (1980) Cross-sectional echocardiography. III. Analysis of mathematic models for quantifying volume of symmetric and asymmetric left ventricles. Am Heart J 100: 821–828. pmid:7446384
- 30. Levey AS, Stevens LA (2010) Estimating GFR using the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, and better risk predictions. Am J Kidney Dis 55: 622–627. pmid:20338463
- 31. DeLong ER, DeLong DM, Clarke-Pearson DL (1988) Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44: 837–845. pmid:3203132
- 32. Pencina MJ, D’Agostino RB Sr. D’Agostino RB Jr., Vasan RS (2008) Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 27: 157–172; discussion 207–112. pmid:17569110
- 33. Ahmed A, Aronow WS, Fleg JL (2006) Higher New York Heart Association classes and increased mortality and hospitalization in patients with heart failure and preserved left ventricular function. Am Heart J 151: 444–450. pmid:16442912
- 34. Holland R, Rechel B, Stepien K, Harvey I, Brooksby I (2010) Patients’ self-assessed functional status in heart failure by New York Heart Association class: a prognostic predictor of hospitalizations, quality of life and death. J Card Fail 16: 150–156. pmid:20142027