A Rising Star of the Multimarker Panel: Growth Differentiation Factor-15 Levels Are an Independent Predictor of Mortality in Acute Heart Failure Patients Admitted to an Emergency Clinical Hospital from Eastern Europe
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design, Patients, and Investigations
2.2. Statistical Analysis
2.3. Ethics
3. Results
3.1. Baseline Characteristics
3.2. Multimarker Panel
3.3. Diagnostic Performance of GDF-15
3.4. Multimarker Approach
4. Discussion
Limitations of the Study
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Groenewegen, A.; Rutten, F.H.; Mosterd, A.; Hoes, A.W. Epidemiology of heart failure. Eur. J. Heart Fail. 2020, 22, 1342–1356. [Google Scholar] [CrossRef]
- McDonagh, T.A.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Böhm, M.; Burri, H.; Butler, J.; Celutkiene, J.; Chioncel, O.; et al. 2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure. Eur. Heart J. 2021, 42, 3599–3726. [Google Scholar] [CrossRef]
- van Riet, E.E.; Hoes, A.W.; Wagenaar, K.P.; Limburg, A.; Landman, M.A.; Rutten, F.H. Epidemiology of heart failure: The prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur. J. Heart Fail. 2016, 18, 242–252. [Google Scholar] [CrossRef]
- Christiansen, M.N.; Køber, L.; Torp-Pedersen, C.; Gislason, G.H.; Schou, M.; Smith, J.G.; Vasan, R.S.; Andersson, C. Preheart failure comorbidities and impact on prognosis in heart failure patients: A nationwide study. J. Intern. Med. 2020, 287, 698–710. [Google Scholar] [CrossRef]
- Urban, S.; Błaziak, M.; Jura, M.; Iwanek, G.; Zdanowicz, A.; Guzik, M.; Borkowski, A.; Gajewski, P.; Biegus, J.; Siennicka, A.; et al. Novel Phenotyping for Acute Heart Failure-Unsupervised Machine Learning-Based Approach. Biomedicines 2022, 10, 1514. [Google Scholar] [CrossRef]
- Lippi, G.; Sanchis-Gomar, F. Global epidemiology and future trends of heart failure. AME Med. J. 2020, 5, 15. [Google Scholar] [CrossRef]
- Miftode, R.-S.; Costache, I.-I.; Cianga, P.; Petris, A.O.; Cianga, C.-M.; Maranduca, M.-A.; Miftode, I.-L.; Constantinescu, D.; Timpau, A.-S.; Crisan, A.; et al. The Influence of Socioeconomic Status on the Prognosis and Profile of Patients Admitted for Acute Heart Failure during COVID-19 Pandemic: Overestimated Aspects or a Multifaceted Hydra of Cardiovascular Risk Factors? Healthcare 2021, 9, 1700. [Google Scholar] [CrossRef]
- Badianyama, M.; Mpanya, D.; Adamu, U.; Sigauke, F.; Nel, S.; Tsabedze, N. New Biomarkers and Their Potential Role in Heart Failure Treatment Optimisation—An African Perspective. J. Cardiovasc. Dev. Dis. 2022, 9, 335. [Google Scholar] [CrossRef]
- Chan, M.M.; Santhanakrishnan, R.; Chong, J.P.; Chen, Z.; Tai, B.C.; Liew, O.W.; Ng, T.P.; Ling, L.H.; Sim, D.; Leong, K.T.; et al. Growth differentiation factor 15 in heart failure with preserved vs. reduced ejection fraction. Eur. J. Heart Fail. 2016, 18, 81–88. [Google Scholar] [CrossRef] [Green Version]
- George, M.; Jena, A.; Srivatsan, V.; Muthukumar, R.; Dhandapani, V.E. GDF 15-A Novel Biomarker in the Offing for Heart Failure. Curr. Cardiol. Rev. 2016, 12, 37–46. [Google Scholar] [CrossRef]
- Lok, D.J.; Klip, I.T.; Lok, S.I.; de la Porte, P.W.B.-A.; Badings, E.; van Wijngaarden, J.; Voors, A.A.; de Boer, R.A.; van Veldhuisen, D.J.; van der Meer, P. Incremental prognostic power of novel biomarkers (growth-differentiation factor-15, high-sensitivity C-reactive protein, galectin-3, and high-sensitivity troponin-T) in patients with advanced chronic heart failure. Am. J. Cardiol. 2013, 112, 831–837. [Google Scholar] [CrossRef]
- Biasucci, L.M.; Maino, A.; Grimaldi, M.C.; Cappannoli, L.; Aspromonte, N. Novel Biomarkers in Heart Failure: New Insight in Pathophysiology and Clinical Perspective. J. Clin. Med. 2021, 10, 2771. [Google Scholar] [CrossRef]
- Ho, J.E.; Lyass, A.; Courchesne, P.; Chen, G.; Liu, C.; Yin, X.; Hwang, S.J.; Massaro, J.M.; Larson, M.G.; Levy, D. Protein biomarkers of cardiovascular disease and mortality in the community. J. Am. Heart Assoc. 2018, 7, e008108. [Google Scholar] [CrossRef] [Green Version]
- May, B.M.; Pimentel, M.; Zimerman, L.I.; Rohde, L.E. GDF-15 as a Biomarker in Cardiovascular Disease. Arq. Bras. Cardiol. 2021, 116, 494–500. [Google Scholar]
- Min, K.W.; Liggett, J.L.; Silva, G.; Wu, W.W.; Wang, R.; Shen, R.F.; Eling, T.E.; Baek, S.J. NAG-1/GDF15 accumulates in the nucleus and modulates transcriptional regulation of the Smad pathway. Oncogene 2016, 35, 377–388. [Google Scholar] [CrossRef] [Green Version]
- Baek, S.J.; Eling, T. Growth differentiation factor 15 (GDF15): A survival protein with therapeutic potential in metabolic diseases. Pharmacol. Ther. 2019, 198, 46–58. [Google Scholar] [CrossRef]
- Xu, X.; Li, Z.; Gao, W. Growth differentiation factor 15 in cardiovascular diseases: From bench to bedside. Biomarkers 2011, 16, 466–475. [Google Scholar] [CrossRef]
- Breit, S.N.; Johnen, H.; Cook, A.D.; Tsai, V.W.; Mohammad, M.G.; Kuffner, T.; Zhang, H.P.; Marquis, C.P.; Jiang, L.; Lockwood, G.; et al. The TGF-β superfamily cytokine, MIC-1/GDF15: A pleotrophic cytokine with roles in inflammation, cancer and metabolism. Growth Factors 2011, 29, 187–195. [Google Scholar] [CrossRef]
- Williams, B.; Mancia, G.; Spiering, W.; Agabiti Rosei, E.; Azizi, M.; Burnier, M.; Clement, D.L.; Coca, A.; de Simone, G.; Dominiczak, A.; et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur. Heart J. 2018, 39, 3021–3104. [Google Scholar] [CrossRef] [Green Version]
- WHO. Diagnosis of Anaemia and Assessment of Severity. Vitamin and Mineral Nutrition Information System. WHO/NMH/NHD/MNM/11.1. World Health Organization: Geneva, Switzerland. 2011. Available online: http://www.who.int/vmnis/indicators/haemoglobin.pdf (accessed on 14 November 2022).
- American Diabetes Association. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2021. Diabetes Care 2021, 44 (Suppl. 1), S15–S33. [Google Scholar] [CrossRef]
- Camps-Vilaró, A.; Delgado-Jiménez, J.F.; Farré, N.; Tizón-Marcos, H.; Álvarez-García, J.; Cinca, J.; Dégano, I.R.; Marrugat, J. Estimated Population Prevalence of Heart Failure with Reduced Ejection Fraction in Spain, According to DAPA-HF Study Criteria. J. Clin. Med. 2020, 9, 2089. [Google Scholar] [CrossRef]
- Chioncel, O.; Lainscak, M.; Seferovic, P.M.; Anker, S.; Crespo-Leiro, M.G.; Harjola, V.P.; Parissis, J.; Laroche, C.; Piepoli, M.; Fonseca, C.; et al. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: An analysis of the ESC Heart Failure Long-Term Registry. Eur. J. Heart Fail. 2017, 19, 1574–1585. [Google Scholar] [CrossRef] [Green Version]
- Jirak, P.; Pistulli, R.; Lichtenauer, M.; Wernly, B.; Paar, V.; Motloch, L.J.; Rezar, R.; Jung, C.; Hoppe, U.C.; Schulze, P.C.; et al. Expression of the Novel Cardiac Biomarkers sST2, GDF-15, suPAR, and H-FABP in HFpEF Patients Compared with ICM, DCM, and Controls. J. Clin. Med. 2020, 9, 1130. [Google Scholar] [CrossRef] [Green Version]
- Villacorta, H.; Maisel, A.S. Soluble st2 testing: A promising biomarker in the management of heart failure. Arq. Bras. Cardiol. 2016, 106, 145–152. [Google Scholar] [CrossRef]
- Miftode, R.-S.; Constantinescu, D.; Cianga, C.M.; Petris, A.O.; Timpau, A.-S.; Crisan, A.; Costache, I.-I.; Mitu, O.; Anton-Paduraru, D.-T.; Miftode, I.-L.; et al. A Novel Paradigm Based on ST2 and Its Contribution towards a Multimarker Approach in the Diagnosis and Prognosis of Heart Failure: A Prospective Study during the Pandemic Storm. Life 2021, 11, 1080. [Google Scholar] [CrossRef]
- Kempf, T.; von Haehling, S.; Peter, T.; Allhoff, T.; Cicoira, M.; Doehner, W.; Ponikowski, P.; Filippatos, G.S.; Rozentryt, P.; Drexler, H.; et al. Prognostic utility of growth differentiation factor-15 in patients with chronic heart failure. J. Am. Coll. Cardiol. 2007, 50, 1054–1060. [Google Scholar] [CrossRef] [Green Version]
- Santhanakrishnan, R.; Chong, J.P.; Ng, T.P.; Ling, L.H.; Sim, D.; Leong, K.T.; Yeo, P.S.; Ong, H.Y.; Jaufeerally, F.; Wong, R.; et al. Growth differentiation factor 15, ST2, high-sensitivity troponin T, and N-terminal pro brain natriuretic peptide in heart failure with preserved vs. reduced ejection fraction. Eur. J. Heart Fail. 2012, 14, 1338–1347. [Google Scholar] [CrossRef]
- Luo, J.W.; Duan, W.H.; Song, L.; Yu, Y.Q.; Shi, D.Z. A Meta-Analysis of Growth Differentiation Factor-15 and Prognosis in Chronic Heart Failure. Front. Cardiovasc. Med. 2021, 8, 630818. [Google Scholar] [CrossRef]
- Wesseling, M.; de Poel, J.H.C.; de Jager, S.C.A. Growth differentiation factor 15 in adverse cardiac remodelling: From biomarker to causal player. ESC Heart Fail. 2020, 7, 1488–1501. [Google Scholar] [CrossRef]
- Méloux, A.; Rochette, L.; Maza, M.; Bichat, J.C.; Beer, F.; Chagué, F.; Cottin, Y.; Zeller, M.; Vergely-Vandriesse, C. Growth differentiation factor 15 as an integrative biomarker of heart failure in patients with acute myocardial infarction. Arch Cardiovasc. Dis. 2019, 11, 239–240. [Google Scholar]
- Lok, S.I.; Winkens, B.; Goldschmeding, R.; van Geffen, A.J.; Nous, F.M.; van Kuik, J.; van der Weide, P.; Klopping, C.; Kirkels, J.H.; Lahpor, J.R.; et al. Circulating growth differentiation factor-15 correlates with myocardial fibrosis in patients with non-ischaemic dilated cardiomyopathy and decreases rapidly after left ventricular assist device support. Eur. J. Heart Fail. 2012, 14, 1249–1256. [Google Scholar] [CrossRef]
- Nair, N.; Gongora, E. Correlations of GDF-15 with sST2, MMPs, and worsening functional capacity in idiopathic dilated cardiomyopathy: Can we gain new insights into the pathophysiology? J. Circ. Biomark. 2018, 7, 1849454417751735. [Google Scholar] [CrossRef]
- Rochette, L.; Dogon, G.; Zeller, M.; Cottin, Y.; Vergely, C. GDF15 and Cardiac Cells: Current Concepts and New Insights. Int. J. Mol. Sci. 2021, 22, 8889. [Google Scholar] [CrossRef] [PubMed]
- Mornos, C.; Petrescu, L.; Cozma, D.; Ionac, A. A new tissue Doppler index to predict cardiac death in patients with heart failure. Arq. Bras. Cardiol. 2014, 102, 19–29. [Google Scholar] [CrossRef]
- Vairappan, B. Endothelial dysfunction in cirrhosis: Role of inflammation and oxidative stress. World J. Hepatol. 2015, 7, 443–459. [Google Scholar] [CrossRef]
- Wang, S.; Li, M.; Zhang, W.; Hua, H.; Wang, N.; Zhao, J.; Ge, J.; Jiang, X.; Zhang, Z.; Ye, D.; et al. Growth differentiation factor 15 promotes blood vessel growth by stimulating cell cycle progression in repair of critical-sized calvarial defect. Sci. Rep. 2017, 7, 9027. [Google Scholar] [CrossRef] [Green Version]
- Lind, L.; Wallentin, L.; Kempf, T.; Tapken, H.; Quint, A.; Lindahl, B.; Olofsson, S.; Venge, P.; Larsson, A.; Hulthe, J.; et al. Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly: Results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study. Eur. Heart J. 2009, 30, 2346–2353. [Google Scholar] [CrossRef] [Green Version]
- Paulus, W.J.; Tschope, C. A novel paradigm for heart failure with preserved ejection fraction: Comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J. Am. Coll. Cardiol. 2013, 62, 263–271. [Google Scholar] [CrossRef] [Green Version]
- Park, H.; Kim, C.H.; Jeong, J.H.; Park, M.; Kim, K.S. GDF15 contributes to radiation-induced senescence through the ROS-mediated p16 pathway in human endothelial cells. Oncotarget 2016, 7, 9634–9644. [Google Scholar] [CrossRef] [Green Version]
- Huang, H.; Chen, Z.; Li, Y.; Gong, K.; Xiao, L.; Fu, H.; Yang, J.; Wang, X.; Meng, Q. GDF-15 Suppresses Atherosclerosis by Inhibiting oxLDL-Induced Lipid Accumulation and Inflammation in Macrophages. Evid. Based Complement. Alternat. Med. 2021, 2021, 6497568. [Google Scholar] [CrossRef]
- Ackermann, K.; Bonaterra, G.A.; Kinscherf, R.; Schwarz, A. Growth differentiation factor-15 regulates oxLDL-induced lipid homeostasis and autophagy in human macrophages. Atherosclerosis 2019, 281, 128–136. [Google Scholar] [CrossRef] [PubMed]
- Al Aseri, Z.A.; Habib, S.S.; Marzouk, A. Predictive value of high sensitivity C-reactive protein on progression to heart failure occurring after the first myocardial infarction. Vasc. Health Risk Manag. 2019, 15, 221–227. [Google Scholar] [CrossRef] [PubMed]
- Lakhani, I.; Wong, M.V.; Hung, J.; Gong, M.; Waleed, K.B.; Xia, Y.; Lee, S.; Roever, L.; Liu, T.; Tse, G.; et al. Diagnostic and prognostic value of serum C-reactive protein in heart failure with preserved ejection fraction: A systematic review and meta-analysis. Heart Fail. Rev. 2021, 26, 1141–1150. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Timpau, A.S.; Miftode, R.; Petris, A.O.; Costache, I.I.; Miftode, I.L.; Rosu, F.M.; Anton-Paduraru, D.T.; Leca, D.; Miftode, E.G. Mortality Predictors in Severe COVID-19 Patients from an East European Tertiary Center: A Never-Ending Challenge for a No Happy Ending Pandemic. J. Clin. Med. 2021, 11, 58. [Google Scholar] [CrossRef]
- Cao, Z.; Jia, Y.; Zhu, B. BNP and NT-proBNP as Diagnostic Biomarkers for Cardiac Dysfunction in Both Clinical and Forensic Medicine. Int. J. Mol. Sci. 2019, 20, 1820. [Google Scholar] [CrossRef] [Green Version]
- Huang, F.Y.; Wang, H.; Huang, B.T.; Liu, W.; Peng, Y.; Zhang, C.; Xia, T.-L.; Wang, P.-J.; Zuo, Z.-L.; Heng, Y.; et al. The influence of body composition on the N-terminal pro-B-type natriuretic peptide level and its prognostic performance in patients with acute coronary syndrome: A cohort study. Cardiovasc. Diabetol. 2016, 15, 58. [Google Scholar] [CrossRef] [Green Version]
- Timpau, A.-S.; Miftode, R.-S.; Leca, D.; Timpau, R.; Miftode, I.-L.; Petris, A.O.; Costache, I.I.; Mitu, O.; Nicolae, A.; Oancea, A.; et al. A Real Pandora’s Box in Pandemic Times: A Narrative Review on the Acute Cardiac Injury Due to COVID-19. Life 2022, 12, 1085. [Google Scholar] [CrossRef]
- Miftode, E.; Luca, C.; Manciuc, C.; Vâță, A.; Hunea, I.; Miftode, L.; Bădescu, A.; Dorneanu, O. COVID-19: A Course Through Stormy Waters. Med. Surg. J. Rev. Med. Chir. 2020, 124, 351–362. [Google Scholar]
- Lionte, C.; Sorodoc, V.; Haliga, R.E.; Bologa, C.; Ceasovschih, A.; Petris, O.R.; Coman, A.E.; Stoica, A.; Sirbu, O.; Puha, G.; et al. Inflammatory and Cardiac Biomarkers in Relation with Post-Acute COVID-19 and Mortality: What We Know after Successive Pandemic Waves. Diagnostics 2022, 12, 1373. [Google Scholar] [CrossRef]
- Anand, I.S.; Kempf, T.; Rector, T.S.; Tapken, H.; Allhoff, T.; Jantzen, F.; Kuskowski, M.; Cohn, J.N.; Drexler, H.; Wollert, K.C. Serial measurement of growth-differentiation factor-15 in heart failure: Relation to disease severity and prognosis in the valsartan heart failure trial. Circulation 2010, 122, 1387–1395. [Google Scholar] [CrossRef] [Green Version]
- Bouabdallaoui, N.; Claggett, B.; Zile, M.R.; McMurray, J.J.V.; O’Meara, E.; Packer, M.; Prescott, M.F.; Swedberg, K.; Solomon, S.D.; Rouleau, J.L. PARADIGM-HF Investigators and Committees. Growth differentiation factor-15 is not modified by sacubitril/valsartan and is an independent marker of risk in patients with heart failure and reduced ejection fraction: The PARADIGM-HF trial. Eur. J. Heart Fail. 2018, 20, 1701–1709. [Google Scholar] [CrossRef] [Green Version]
- Eggers, K.M.; Kempf, T.; Wallentin, L.; Wollert, K.C.; Lind, L. Change in growth differentiation factor 15 concentrations over time independently predicts mortality in community-dwelling elderly individuals. Clin. Chem. 2013, 59, 1091–1098. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lourenço, P.; Cunha, F.M.; Ferreira-Coimbra, J.; Barroso, I.; Guimarães, J.T.; Bettencourt, P. Dynamics of growth differentiation factor 15 in acute heart failure. ESC Heart Fail. 2021, 8, 2527–2534. [Google Scholar] [CrossRef] [PubMed]
- Bonaca, M.P.; Morrow, D.A.; Braunwald, E.; Cannon, C.P.; Jiang, S.; Breher, S.; Sabatine, M.S.; Kempf, T.; Wallentin, L.; Wollert, K.C. Growth differentiation factor-15 and risk of recurrent events in patients stabilized after acute coronary syndrome: Observations from PROVE IT-TIMI 22. Arterioscler. Thromb. Vasc. Biol. 2011, 31, 203–210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rehman, S.U.; Mueller, T.; Januzzi, J.L. Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure. J. Am. Coll. Cardiol. 2008, 52, 1458–1465. [Google Scholar] [CrossRef]
- Grande, D.; Leone, M.; Rizzo, C.; Terlizzese, P.; Parisi, G.; Gioia, M.I.; Leopizzi, T.; Segreto, A.; Guida, P.; Romito, R.; et al. A Multiparametric Approach Based on NT-proBNP, ST2, and Galectin3 for Stratifying One Year Prognosis of Chronic Heart Failure Outpatients. J. Cardiovasc. Dev. Dis. 2017, 4, 9. [Google Scholar] [CrossRef]
- Dupuy, A.M.; Curinier, C.; Kuster, N.; Huet, F.; Leclercq, F.; Davy, J.M.; Cristol, J.P.; Roubille, F. Multi-Marker Strategy in Heart Failure: Combination of ST2 and CRP Predicts Poor Outcome. PLoS ONE 2016, 11, e0157159. [Google Scholar] [CrossRef]
- Hao, J.; Cheang, I.; Zhang, L.; Wang, K.; Wang, H.M.; Wu, Q.Y.; Zhou, Y.L.; Zhou, F.; Xu, D.J.; Zhang, H.F.; et al. Growth differentiation factor-15 combined with N-terminal prohormone of brain natriuretic peptide increase 1-year prognosis prediction value for patients with acute heart failure: A prospective cohort study. Chin. Med. J. 2019, 132, 2278–2285. [Google Scholar] [CrossRef]
- Wettersten, N.; Maisel, A. Role of Cardiac Troponin Levels in Acute Heart Failure. Card. Fail. Rev. 2015, 1, 102–106. [Google Scholar] [CrossRef]
- Gherasim, L. Troponins in Heart Failure–a Perpetual Challenge. Maedica 2019, 14, 371–377. [Google Scholar]
- Mehra, M.R.; Uber, P.A.; Park, M.H.; Scott, R.L.; Ventura, H.O.; Harris, B.C.; Frohlich, E.D. Obesity and suppressed B-type natriuretic peptide levels in heart failure. J. Am. Coll. Cardiol. 2004, 43, 1590–1595. [Google Scholar] [CrossRef] [PubMed]
Characteristics | Total (N = 173) | Acute HF (N = 120) | Control Group (N = 53) | p-Value | ||||||
---|---|---|---|---|---|---|---|---|---|---|
Min | Mean ± STD | Max | Min | Mean ± STD | Max | Min | Mean ± STD | Max | ||
Age (years) | 18 | 65 ± 13.3 | 94 | 18 | 66.4 ± 15.3 | 94 | 30 | 64 ± 11.9 | 85 | 0.526 |
Mortality rate: N (%) | 21 (12.1%) | 21 (17.5%) | 0 (0%) | <0.001 | ||||||
Gender | 0.438 | |||||||||
Male: N, (%) | 104 (60%) | 71 (59.20%) | 33 (62.30%) | |||||||
Female: N, (%) | 69 (40%) | 49 (40.80%) | 20 (37.70%) | |||||||
Smoking: N, (%) | 67 (38.7%) | 48 (40%) | 19 (35.8%) | 0.605 | ||||||
Alcohol abuse: N, (%) | 97 (56.1%) | 75 (62.5%) | 22 (41.5%) | 0.012 | ||||||
Arterial hypertension: N, (%) | 94 (54.3%) | 60 (50%) | 34 (64.2%) | 0.085 | ||||||
Ischemic heart disease: N, (%) | 76 (43.9%) | 59 (49.2%) | 17 (32%) | 0.037 | ||||||
Diabetes mellitus N, (%) | 29 (16.8%) | 22 (18.3%) | 7 (13.2%) | 0.406 | ||||||
Obesity (BMI > 30 kg/m2): N, (%) | 49 (28.3%) | 42 (35%) | 7 (13.2%) | 0.003 | ||||||
Anemia N, (%) | 47 (27.2%) | 35 (29.2%) | 12 (22.7%) | 0.377 | ||||||
COVID-19: N, (%) | 13 (7.5%) | 8 (6.7%) | 5 (9.4%) | 0.241 |
Total (N = 173) | Acute HF (N = 120) | Control Group (N = 53) | p-Value | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Characteristics | Min | Mean ± STD | Max | Min | Mean ± STD | Max | Min | Mean ± STD | Max | |
LV ejection fraction (%) | 10% | 39.4 ± 14.4 | 72% | 10% | 33.8 ± 13.9% | 61 % | 38% | 52.2 ± 15.7 | 72% | 0.017 |
LV end-diastolic diameter (mm) N, (%) | 30 | 52.7 ± 8.2 | 75 | 32 | 55.1 ± 8.6 | 75 | 30 | 47.3 ± 7.7 | 63 | 0.033 |
Hemoglobin (g/dL) | 7.20 | 13.3 ± 2.1 | 33.7 | 7.20 | 13.2 ± 2.4 | 33.7 | 9.60 | 13.5 ± 1.9 | 18.40 | 0.069 |
Hematocrit (%) | 22.20 | 39.5 ± 9.7 | 56.3 | 22.20 | 39.5 ± 8.9 | 56.3 | 29.2 | 39.4 ± 11.2 | 52.70 | 0.909 |
Leukocytes (×109/L) | 1.20 | 9.5 ± 1.3 | 30.2 | 4.10 | 10.2 ± 1.34 | 25.2 | 1.2 | 7.9 ± 1.2 | 30.18 | 0.044 |
Platelets (×103/μL) | 37 | 266 ± 43 | 2630 | 37 | 270 ± 45 | 2630 | 37 | 253 ± 42 | 595 | 0.245 |
Blood glucose (mg/dL) | 63 | 142.5 ± 37.1 | 582 | 63 | 149.2 ± 33.4 | 582 | 73 | 128.1 ± 41.8 | 388 | 0.111 |
Total bilirubin (mg/dL) | 0.09 | 1 ± 0.2 | 5.02 | 0.10 | 1.2 ± 0.2 | 5.02 | 0.1 | 0.5 ± 0.2 | 1.12 | <0.001 |
Sodium (mmol/L) | 121 | 138.3 ± 12.6 | 147 | 121 | 137.8 ± 14.1 | 147 | 122 | 141.1 ± 8.5 | 147 | 0.002 |
Potassium (mmol/L) | 2.90 | 4.5 ± 0.8 | 6.3 | 2.90 | 4.6 ± 0.9 | 6.30 | 3.20 | 4.3 ± 0.7 | 5.60 | 0.009 |
Creatinine (mg/dL) | 0.60 | 1.2 ± 0.3 | 4.0 | 0.60 | 1.2 ± 0.3 | 4.01 | 0.7 | 1 ± 0.2 | 3.78 | 0.029 |
Total cholesterol (mg/dL) | 63 | 164.2 ± 51.2 | 331 | 63 | 161.1 ± 51.9 | 331 | 90 | 173.3 ± 49.3 | 285 | 0.109 |
LDL-cholesterol (mg/dL) | 33 | 109.2 ± 33.4 | 255 | 33 | 106.6 ± 35.6 | 255 | 53 | 124.6 ± 31.2 | 197 | 0.253 |
HDL-cholesterol (mg/dL) | 12 | 41.7 ± 16.5 | 111 | 12 | 40 ± 15.9 | 111 | 36 | 52.4 ± 17.7 | 76 | <0.001 |
Beta-blockers | 148 (85.6%) | 99 (82.5%) | 49 (92.5%) | 0.087 | ||||||
Inhibitors of the RAS | 121 (70%) | 77 (64.2%) | 44 (83.1%) | 0.012 | ||||||
Loop-diuretics | 119 (68.8%) | 102 (85%) | 17 (32.1%) | <0.001 | ||||||
Mineralocorticoid receptor antagonist | 92 (53.2%) | 83 (69.2%) | 9 (17%) | <0.001 |
Biomarker | Total = 173 | Acute HF = 120 | Controls = 53 | p-Value |
---|---|---|---|---|
GDF-15 (ng/L) | 439 (199–786) | 596 (305–904) | 216 (139–305) | <0.01 |
NT-proBNP (pg/mL) | 3757 (1827–9764) | 5440 (2812–12791) | 107.80 (41.30–325.25) | <0.01 |
hs-Troponin (ng/L) | 31.01 (7.03–104.80) | 38.25 (12.45–179.50) | 2.26 (1.14–5.43) | <0.01 |
Parameter | GDF−15 | |
---|---|---|
r | p−Value | |
LVEF | −0.117 | 0.125 |
LVEDD | −0.021 | 0.873 |
LAVI | 0.142 | 0.085 |
E/e’ | 0.191 | 0.038 |
sPAP | 0.188 | 0.046 |
NT−proBNP | 0.264 | 0.004 |
hs−Troponin | 0.035 | 0.752 |
C−reactive protein | 0.177 | 0.047 |
Hemoglobin | −0.095 | 0.101 |
Leukocytes | 0.065 | 0.468 |
Serum creatinine | 0.224 | 0.014 |
Sodium | −0.250 | 0.006 |
Potassium | 0.165 | 0.03 |
Total bilirubin | 0.376 | <0.001 |
ALT | 0.188 | 0.035 |
AST | 0.302 | <0.001 |
Total cholesterol | −0.423 | <0.001 |
LDL−cholesterol | −0.370 | <0.001 |
HDL−cholesterol | −0.242 | 0.011 |
BMI | −0.051 | 0.579 |
Age | 0.166 | 0.07 |
Male gender | 0.089 | 0.332 |
Alcohol abuse | −0.018 | 0.844 |
Smoking | 0.070 | 0.499 |
Diabetes mellitus | 0.170 | 0.063 |
Arterial hypertension | −0.056 | 0.545 |
Ischemic heart disease | 0.016 | 0.861 |
Systolic blood pressure | −0.194 | 0.035 |
Diastolic blood pressure | −0.157 | 0.061 |
Heart rate | −0.031 | 0.755 |
Pulmonary crackles | 0.306 | <0.001 |
Peripheral edema | 0.316 | <0.001 |
Lactate level | 0.301 | <0.001 |
Inotropic support | 0.256 | 0.005 |
Length of hospital stay | 0.189 | 0.042 |
In−hospital mortality | 0.283 | <0.001 |
30−days mortality | 0.375 | <0.001 |
BIOMARKER | AUC | Std. Error | Asymptotic 95% Confidence Interval | p-Value | |
---|---|---|---|---|---|
Lower Bound | Upper Bound | ||||
GDF-15 (ng/L) | 0.883 | 0.028 | 0.828 | 0.938 | <0.01 |
NT-proBNP (pg/mL) | 0.976 | 0.013 | 0.952 | 1.000 | <0.01 |
hs-Troponin (ng/L) | 0.839 | 0.054 | 0.733 | 0.944 | <0.01 |
Criterion | Concentration (ng/L) | Se | Sp |
---|---|---|---|
Se = Sp | 306 | 0.750 | 0.755 |
Youden’s index (max Se + Sp) | 314 | 0.750 | 0.776 |
High-mortality risk cut-off | 618 | 0.483 | 0.867 |
Chi-Square | df | p-Value | |
---|---|---|---|
Log Rank (Mantel-Cox) | 7.075 | 1 | 0.008 |
Test of equality of survival distributions for the different levels of GDF-15. |
Biomarkers | GDF-15 < 596 ng/L | GDF-15 > 596 ng/L | p-Value | |
---|---|---|---|---|
Mortality (%) | ||||
NT-proBNP < 5440 pg/mL | 7.3% | 25% | <0.01 | |
NT-proBNP > 5440 pg/mL | 10.5% | 40% | <0.01 |
Model | R | R2 | Adjusted R2 | Std. Error of the Estimate | p-Value | Durbin-Watson |
---|---|---|---|---|---|---|
0.375 a | 0.141 | 0.133 | 0.385 | <0.001 | ||
1 | 0.438 b | 0.192 | 0.178 | 0.375 | <0.001 | |
2 | 0.451 c | 0.203 | 0.183 | 0.374 | <0.001 | 1.822 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Miftode, R.-S.; Constantinescu, D.; Cianga, C.-M.; Petris, A.-O.; Costache, I.-I.; Mitu, O.; Miftode, I.-L.; Mitu, I.; Timpau, A.-S.; Duca, S.-T.; et al. A Rising Star of the Multimarker Panel: Growth Differentiation Factor-15 Levels Are an Independent Predictor of Mortality in Acute Heart Failure Patients Admitted to an Emergency Clinical Hospital from Eastern Europe. Life 2022, 12, 1948. https://doi.org/10.3390/life12121948
Miftode R-S, Constantinescu D, Cianga C-M, Petris A-O, Costache I-I, Mitu O, Miftode I-L, Mitu I, Timpau A-S, Duca S-T, et al. A Rising Star of the Multimarker Panel: Growth Differentiation Factor-15 Levels Are an Independent Predictor of Mortality in Acute Heart Failure Patients Admitted to an Emergency Clinical Hospital from Eastern Europe. Life. 2022; 12(12):1948. https://doi.org/10.3390/life12121948
Chicago/Turabian StyleMiftode, Radu-Stefan, Daniela Constantinescu, Corina-Maria Cianga, Antoniu-Octavian Petris, Irina-Iuliana Costache, Ovidiu Mitu, Ionela-Larisa Miftode, Ivona Mitu, Amalia-Stefana Timpau, Stefania-Teodora Duca, and et al. 2022. "A Rising Star of the Multimarker Panel: Growth Differentiation Factor-15 Levels Are an Independent Predictor of Mortality in Acute Heart Failure Patients Admitted to an Emergency Clinical Hospital from Eastern Europe" Life 12, no. 12: 1948. https://doi.org/10.3390/life12121948
APA StyleMiftode, R.-S., Constantinescu, D., Cianga, C.-M., Petris, A.-O., Costache, I.-I., Mitu, O., Miftode, I.-L., Mitu, I., Timpau, A.-S., Duca, S.-T., Costache, A.-D., Cianga, P., & Serban, I.-L. (2022). A Rising Star of the Multimarker Panel: Growth Differentiation Factor-15 Levels Are an Independent Predictor of Mortality in Acute Heart Failure Patients Admitted to an Emergency Clinical Hospital from Eastern Europe. Life, 12(12), 1948. https://doi.org/10.3390/life12121948