Soluble ST2 Receptor: Biomarker of Left Ventricular Impairment and Functional Status in Patients with Inflammatory Cardiomyopathy
Abstract
:1. Introduction
2. Methods
2.1. Study Design
2.2. Endomyocardial Biopsy and Immunohistochemical Analysis
2.3. CMR Imaging
2.4. sST2 Assay
2.5. NT-proBNP, CK-MB, and Troponin T
2.6. Statistical Analysis
3. Results
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Cooper, L.T., Jr.; Keren, A.; Sliwa, K.; Matsumori, A.; Mensah, G.A. The global burden of myocarditis: Part 1: A systematic literature review for the Global Burden of Diseases, Injuries, and Risk Factors 2010 study. Glob. Heart 2014, 9, 121–129. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, P.P.; Mason, J.W. Advances in the understanding of myocarditis. Circulation 2001, 104, 1076–1082. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gupta, S.; Markham, D.W.; Drazner, M.H.; Mammen, P.P. Fulminant myocarditis. Nat. Clin. Pr. Cardiovasc. Med. 2008, 5, 693–706. [Google Scholar] [CrossRef]
- Mason, J.W. Myocarditis and dilated cardiomyopathy: An inflammatory link. Cardiovasc. Res. 2003, 60, 5–10. [Google Scholar] [CrossRef]
- Friedrich, M.G.; Sechtem, U.; Schulz-Menger, J.; Holmvang, G.; Alakija, P.; Cooper, L.T.; White, J.A.; Abdel-Aty, H.; Gutberlet, M.; Prasad, S.; et al. Cardiovascular Magnetic Resonance in Myocarditis: A JACC White Paper. J. Am. Coll. Cardiol. 2009, 53, 1475–1487. [Google Scholar] [CrossRef] [Green Version]
- Francone, M.; Chimenti, C.; Galea, N.; Scopelliti, F.; Verardo, R.; Galea, R.; Carbone, I.; Catalano, C.; Fedele, F.; Frustaci, A. CMR sensitivity varies with clinical presentation and extent of cell necrosis in biopsy-proven acute myocarditis. JACC Cardiovasc. Imaging 2014, 7, 254–263. [Google Scholar] [CrossRef] [PubMed]
- Caforio, A.L.; Pankuweit, S.; Arbustini, E.; Basso, C.; Gimeno-Blanes, J.; Felix, S.B.; Heliö, T.; Heymans, S.; Jahns, R.; Klingel, K.; et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur. Heart J. 2013, 34, 2636–2648. [Google Scholar] [CrossRef]
- Ammirati, E.; Cipriani, M.; Lilliu, M.; Sormani, P.; Varrenti, M.; Raineri, C.; Petrella, D.; Garascia, A.; Pedrotti, P.; Roghi, A.; et al. Survival and Left Ventricular Function Changes in Fulminant Versus Nonfulminant Acute Myocarditis. Circulation 2017, 136, 529–545. [Google Scholar] [CrossRef]
- Iwahana, H.; Yanagisawa, K.; Ito-Kosaka, A.; Kuroiwa, K.; Tago, K.; Komatsu, N.; Katashima, R.; Itakura, M.; Tominaga, S. Different promoter usage and multiple transcription initiation sites of the interleukin-1 receptor-related human ST2 gene in UT-7 and TM12 cells. Eur. J. Biochem. 1999, 264, 397–406. [Google Scholar] [CrossRef]
- Sanada, S.; Hakuno, D.; Higgins, L.J.; Schreiter, E.R.; McKenzie, A.N.J.; Lee, R.T. IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J. Clin. Investig. 2007, 117, 1538–1549. [Google Scholar] [CrossRef] [Green Version]
- Kakkar, R.; Lee, R.T. The IL-33/ST2 pathway: Therapeutic target and novel biomarker. Nat. Rev. Drug. Discov. 2008, 7, 827–840. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mahrholdt, H.; Wagner, A.; Deluigi, C.C.; Kispert, E.; Hager, S.; Meinhardt, G.; Vogelsberg, H.; Fritz, P.; Dippon, J.; Bock, C.T.; et al. Presentation, patterns of myocardial damage, and clinical course of viral myocarditis. Circulation 2006, 114, 1581–1590. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Baccouche, H.; Mahrholdt, H.; Meinhardt, G.; Merher, R.; Voehringer, M.; Hill, S.; Klingel, K.; Kandolf, R.; Sechtem, U.; Yilmaz, A. Diagnostic synergy of non-invasive cardiovascular magnetic resonance and invasive endomyocardial biopsy in troponin-positive patients without coronary artery disease. Eur. Heart J. 2009, 30, 2869–2879. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lurz, P.; Eitel, I.; Adam, J.; Steiner, J.; Grothoff, M.; Desch, S.; Fuernau, G.; de Waha, S.; Sareban, M.; Luecke, C.; et al. Diagnostic performance of CMR imaging compared with EMB in patients with suspected myocarditis. JACC Cardiovasc. Imaging 2012, 5, 513–524. [Google Scholar] [CrossRef]
- Mahrholdt, H.; Goedecke, C.; Wagner, A.; Meinhardt, G.; Athanasiadis, A.; Vogelsberg, H.; Fritz, P.; Klingel, K.; Kandolf, R.; Sechtem, U. Cardiovascular magnetic resonance assessment of human myocarditis: A comparison to histology and molecular pathology. Circulation 2004, 109, 1250–1258. [Google Scholar] [CrossRef] [Green Version]
- Calabrese, F.; Angelini, A.; Carturan, E.; Thiene, G. Myocarditis and inflammatory cardiomyopathy: Histomorphological diagnosis. Ernst Scher. Res. Found Workshop 2006, 55, 305–321. [Google Scholar]
- Yilmaz, A.; Kindermann, I.; Kindermann, M.; Mahfoud, F.; Ukena, C.; Athanasiadis, A.; Hill, S.; Mahrholdt, H.; Voehringer, M.; Schieber, M.; et al. Comparative evaluation of left and right ventricular endomyocardial biopsy: Differences in complication rate and diagnostic performance. Circulation 2010, 122, 900–909. [Google Scholar] [CrossRef] [Green Version]
- Leone, O.; Veinot, J.P.; Angelini, A.; Baandrup, U.T.; Basso, C.; Berry, G.; Bruneval, P.; Burke, M.; Butany, J.; Calabrese, F.; et al. 2011 consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology. Cardiovasc. Pathol. 2012, 21, 245–274. [Google Scholar] [CrossRef]
- Müller-Bardorff, M.; Hallermayer, K.; Schröder, A.; Ebert, C.; Borgya, A.; Gerhardt, W.; Remppis, A.; Zehelein, J.; Katus, H.A. Improved troponin T ELISA specific for cardiac troponin T isoform: Assay development and analytical and clinical validation. Clin. Chem. 1997, 43, 458–466. [Google Scholar] [CrossRef]
- Abdel-Aty, H.; Boyé, P.; Zagrosek, A.; Wassmuth, R.; Kumar, A.; Messroghli, D.; Bock, P.; Dietz, R.; Friedrich, M.G.; Schulz-Menger, J. Diagnostic performance of cardiovascular magnetic resonance in patients with suspected acute myocarditis: Comparison of different approaches. J. Am. Coll. Cardiol. 2005, 45, 1815–1822. [Google Scholar] [CrossRef] [Green Version]
- Lurz, P.; Luecke, C.; Eitel, I.; Föhrenbach, F.; Frank, C.; Grothoff, M.; de Waha, S.; Rommel, K.P.; Lurz, J.A.; Klingel, K.; et al. Comprehensive Cardiac Magnetic Resonance Imaging in Patients with Suspected Myocarditis: The MyoRacer-Trial. J. Am. Coll. Cardiol. 2016, 67, 1800–1811. [Google Scholar] [CrossRef] [PubMed]
- Seki, K.; Sanada, S.; Kudinova, A.Y.; Steinhauser, M.L.; Handa, V.; Gannon, J.; Lee, R.T. Interleukin-33 prevents apoptosis and improves survival after experimental myocardial infarction through ST2 signaling. Circ. Heart Fail. 2009, 2, 684–691. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Weinberg, E.O.; Shimpo, M.; de Keulenaer, G.W.; MacGillivray, C.; Tominaga, S.; Solomon, S.D.; Rouleau, J.-L.; Lee, R.T. Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation 2002, 106, 2961–2966. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Aimo, A.; Vergaro, G.; Passino, C.; Ripoli, A.; Ky, B.; Miller, W.L.; Bayes-Genis, A.; Anand, I.; Januzzi, J.L.; Emdin, M. Prognostic Value of Soluble Suppression of Tumorigenicity-2 in Chronic Heart Failure: A Meta-Analysis. JACC Heart Fail. 2017, 5, 280–286. [Google Scholar] [CrossRef] [PubMed]
- Shimpo, M.; Morrow, D.A.; Weinberg, E.O.; Sabatine, M.S.; Murphy, S.A.; Antman, E.M.; Lee, R.T. Serum levels of the interleukin-1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarction. Circulation 2004, 109, 2186–2190. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Januzzi, J.L., Jr.; Peacock, W.F.; Maisel, A.S.; Chae, C.U.; Jesse, R.L.; Baggish, A.L.; O’Donoghue, M.; Sakhuja, R.; Chen, A.A.; van Kimmenade, R.R.; et al. 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. 2007, 50, 607–613. [Google Scholar] [CrossRef] [Green Version]
- Tschöpe, C.; Ammirati, E.; Bozkurt, B.; Caforio, A.L.P.; Cooper, L.T.; Felix, S.B.; Hare, J.M.; Heidecker, B.; Heymans, S.; Hübner, N.; et al. Myocarditis and inflammatory cardiomyopathy: Current evidence and future directions. Nat. Rev. Cardiol. 2021, 18, 169–193. [Google Scholar] [CrossRef]
- Pollack, A.; Kontorovich, A.R.; Fuster, V.; Dec, G.W. Viral myocarditis-diagnosis, treatment options, and current controversies. Nat. Rev. Cardiol. 2015, 12, 670–680. [Google Scholar] [CrossRef]
- Caforio, A.L.P.; Malipiero, G.; Marcolongo, R.; Iliceto, S. Myocarditis: A Clinical Overview. Curr. Cardiol. Rep. 2017, 19, 63. [Google Scholar] [CrossRef]
- Oshikawa, K.; Kuroiwa, K.; Tago, K.; Iwahana, H.; Yanagisawa, K.; Ohno, S.; Tominaga, S.I.; Sugiyama, Y. Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. Am. J. Respir. Crit. Care Med. 2001, 164, 277–281. [Google Scholar] [CrossRef]
- Kuroiwa, K.; Arai, T.; Okazaki, H.; Minota, S.; Tominaga, S. Identification of human ST2 protein in the sera of patients with autoimmune diseases. Biochem. Biophys Res. Commun. 2001, 284, 1104–1108. [Google Scholar] [CrossRef] [PubMed]
Clinical Variable | All Patients | Inflammatory Cardiomyopathy (n = 60) | Dilated Cardiomyopathy (n = 29) | p Value |
---|---|---|---|---|
Age (years, mean ± SD) | 46 ± 15 | 47 ± 15 | 43 ± 14 | 0.77 |
Female (%) | 26 | 28 | 24 | 0.68 |
BMI (kg/m2) | 31 | 32 | 31 | 0.71 |
NYHA class at presentation (% of patients) | 0.85 | |||
NYHA class I/II | 66 | 63 | 71 | |
NYHA class III/IV | 34 | 37 | 29 | |
CMR findings | ||||
T2-weghted edema of LV (% of patients) | 11 | 11 | 11 | 0.43 |
EGE of LV (% of patients) | 63 | 69 | 44 | 0.01 |
LGE of LV (% of LV) | 13 ± 8 | 13 ± 7 | 12 ± 7 | 0.88 |
Echocardiography findings | ||||
LV-EF (%, mean ± SD) | 37 ± 16 | 36 ± 14 | 35 ± 20 | 0.69 |
LVEDD (mm, mean ± SD) | 162 ± 70 | 154 ± 58 | 180 ± 91 | 0.76 |
LVESD (mm, mean ± SD) | 106 ± 64 | 102 ± 54 | 116 ± 85 | 0.22 |
Biomarkers (plasma concentration) | ||||
sST2 (ng/mL; mean ± SD) | 45 ± 26 | 46 ± 29 | 44 ± 19 | 0.48 |
NT-proBNP (pg/mL; mean ± SD) | 2866 ± 5010 | 3208 ± 5726 | 1994 ± 2255 | 0.09 |
CK-MB (U/L; mean ± SD) | 64 ± 324 | 30 ± 35 | 135 ± 564 | 0.01 |
hsCRP (mg/L; mean ± SD) | 26 ± 40 | 29 ± 43 | 19 ± 32 | 0.08 |
Myoglobin (µg/L; mean ± SD) | 217 ± 260 | 198 ± 271 | 269 ± 228 | 0.61 |
Troponin T (ng/L; mean ± SD) | 202 ± 539 | 269 ± 643 | 64 ± 111 | 0.009 |
Immunohistochemistry (left ventricle) | ||||
CD3+ T cells (cells/cm2 ± SD) | 11 ± 13 | 14 ± 14 | 3 ± 2 | 0.001 |
CD68+ macrophages (cells/cm2 ± SD) | 25 ± 19 | 31 ± 20 | 11 ± 5 | 0.009 |
Enhanced MHC class II expression (n, %) | - | 60 (100) | 5 (18) | 0.001 |
Viral genome in EMB | ||||
EBV (%) | 12 | 14 | - | 0.001 |
HSV6/HSV7 (%) | 20 | 21 | - | 0.001 |
Parvovirus B19 (%) | 5 | 4 | - | 0.001 |
Enhanced MHC class II expression (%) | 64 | 100 | 19 | 0.001 |
Cardiovascular risk factors | ||||
History of Hypertension (%) | 59 | 56 | 64 | 0.48 |
History of Diabetes (%) | 11 | 11 | 10 | 0.97 |
Tobacco use (%) | 42 | 40 | 46 | 0.57 |
Functional Class NYHA III/IV at 12 Months | ||||||
Inflammatory Cardiomyopathy | Dilated Cardiomyopathy | |||||
Variables | Odds-Ratio | CI 95% | p | Odds-Ratio | CI 95% | p |
sST2 (ng/mL) | 1.21 | 1.01–1.30 | 0.02 | 0.92 | 0.80–1.06 | 0.28 |
LLC (≥2) | 0.92 | 0.27–3.15 | 0.90 | 1.10 | 0.30–8.79 | 0.95 |
NT-pro-BNP (pg/mL) | 1.01 | 1.0–1.11 | 0.57 | 1.00 | 0.99–1.01 | 0.27 |
Troponin-T (ng/L) | 0.99 | 0.98–1.01 | 0.44 | 0.94 | 0.93–1.02 | 0.30 |
CardiovascularOutcome at 12 Months (Cardiovascular Mortality, Malignant Arrhythmias/ICD Implantation, Hospitalization Due to Heart Failure) | ||||||
Inflammatory Cardiomyopathy | Dilated Cardiomyopathy | |||||
Variables | Odds-Ratio | CI 95% | p | Odds-Ratio | CI 95% | p |
sST2 (ng/mL) | 1.02 | 0.99–1.10 | 0.15 | 1.01 | 0.92–1.11 | 0.81 |
LLC (≥2) | 0.81 | 0.21–3.18 | 0.76 | 2.01 | 0.28–5.54 | 0.31 |
NT-pro-BNP (pg/mL) | 0.99 | 0.98–1.01 | 0.83 | 1.00 | 0.99–1.03 | 0.75 |
Troponin-T (ng/L) | 0.99 | 0.98–1.01 | 0.56 | 0.99 | 0.95–1.01 | 0.61 |
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Obradovic, D.M.; Büttner, P.; Rommel, K.-P.; Blazek, S.; Loncar, G.; von Haehling, S.; von Roeder, M.; Lücke, C.; Gutberlet, M.; Thiele, H.; et al. Soluble ST2 Receptor: Biomarker of Left Ventricular Impairment and Functional Status in Patients with Inflammatory Cardiomyopathy. Cells 2022, 11, 414. https://doi.org/10.3390/cells11030414
Obradovic DM, Büttner P, Rommel K-P, Blazek S, Loncar G, von Haehling S, von Roeder M, Lücke C, Gutberlet M, Thiele H, et al. Soluble ST2 Receptor: Biomarker of Left Ventricular Impairment and Functional Status in Patients with Inflammatory Cardiomyopathy. Cells. 2022; 11(3):414. https://doi.org/10.3390/cells11030414
Chicago/Turabian StyleObradovic, Danilo Momira, Petra Büttner, Karl-Philipp Rommel, Stephan Blazek, Goran Loncar, Stephan von Haehling, Maximilian von Roeder, Christian Lücke, Matthias Gutberlet, Holger Thiele, and et al. 2022. "Soluble ST2 Receptor: Biomarker of Left Ventricular Impairment and Functional Status in Patients with Inflammatory Cardiomyopathy" Cells 11, no. 3: 414. https://doi.org/10.3390/cells11030414