Acute coronary syndrome (ACS) is a group of clinical syndromes caused by acute myocardial ischemia, including ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina (UA). Currently, the clinical diagnosis of ACS relies on three key factors: clinical data (such as medical history, age, symptoms, etc.), electrocardiogram (ECG), and cardiac biomarkers (cTn, MyO, CK-MB, NT-proBNP, etc.). However, diagnosing UA patients and some NSTEMI patients can be challenging due to the absence of characteristic electrocardiogram dynamic evolution seen in STEMI patients. This is particularly true in cases with mild symptoms or no obvious chest pain and negative detection of myocardial injury markers. Recent studies have highlighted the potential clinical value and availability of growth differentiation factor 15 (GDF-15) as a new cardiac biomarker closely associated with the occurrence and prognosis of ACS [1]. However, further investigation is needed to fully understand its role in ACS. This article aims to review the clinical application value of GDF-15 in acute coronary syndrome.

Shuangxi Wang, Renqing Zeng, Xianfa Liu. Research Status of Growth Differentation Factor-15 in Acute Coronary Syndrome. Frontiers in Medical Science Research (2024), Vol. 6, Issue 2: 133-139. https://doi.org/10.25236/FMSR.2024.060220.

[1] Krintus M, Kozinski M, Kubica J, et al. Critical appraisal of inflammatory markers in cardiovascular risk stratification. Crit Rev Clin Lab Sci, 2014, 51(5): 263-279.

[2] Wischhusen J, Melero I, Fridman W H. Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint. Front Immunol, 2020, 11: 951.

[3] Bootcov Mr B A, Valenzuela Sm, Moore Ag, Bansal M, He Xy, Zhang Hp, Donnellan M, Mahler S, Pryor K, Walsh Bj, Nicholson Rc, Fairlie Wd, Por Sb, Robbins Jm, Breit Sn.. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily.. Proc Natl Acad Sci USA, 1997 94(21): 11514-11519.

[4] Kempf T, Eden M, Strelau J, et al. The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res, 2006, 98(3): 351-360.

[5] Wollert K C, Kempf T, Wallentin L. Growth Differentiation Factor 15 as a Biomarker in Cardiovascular Disease. Clin Chem, 2017, 63(1): 140-151.

[6] Kato E T, Morrow D A, Guo J, et al. Growth differentiation factor 15 and cardiovascular risk: individual patient meta-analysis. Eur Heart J, 2023, 44(4): 293-300.

[7] De Jager S C, Bermudez B, Bot I, et al. Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J Exp Med, 2011, 208(2): 217-225.

[8] Rohatgi A, Patel P, Das S R, et al. Association of growth differentiation factor-15 with coronary atherosclerosis and mortality in a young, multiethnic population: observations from the Dallas Heart Study. Clin Chem, 2012, 58(1): 172-182.

[9] Kehl D W, Iqbal N, Fard A, et al. Biomarkers in acute myocardial injury. Transl Res, 2012, 159(4): 252-264.

[10] Sandoval Y, Lewis B R, Mehta R A, et al. Rapid Exclusion of Acute Myocardial Injury and Infarction With a Single High-Sensitivity Cardiac Troponin T in the Emergency Department: A Multicenter United States Evaluation. Circulation, 2022, 145(23): 1708-1719.

[11] Koninckx R, Daniels A, Windmolders S, et al. The cardiac atrial appendage stem cell: a new and promising candidate for myocardial repair. Cardiovasc Res, 2013, 97(3): 413-423.

[12] Rochette L, Dogon G, Zeller M, et al. GDF15 and Cardiac Cells: Current Concepts and New Insights. Int J Mol Sci, 2021, 22(16).

[13] Mazagova M, Buikema H, Landheer S W, et al. Growth differentiation factor 15 impairs aortic contractile and relaxing function through altered caveolar signaling of the endothelium. Am J Physiol Heart Circ Physiol, 2013, 304(5): H709-18.

[14] Lok S I, Winkens B, Goldschmeding 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(11): 1249-1256.

[15] Kempf T, Zarbock A, Widera C, et al. GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med, 2011, 17(5): 581-588.

[16] Xu J, Kimball T R, Lorenz J N, et al. GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circ Res, 2006, 98(3): 342-350.

[17] Mo Q, Zhuo L, Liao Z, et al. Serum GDF-15 Predicts In-Hospital Mortality and Arrhythmic Risks in Patients With Acute Myocardial Infarction. Clin Appl Thromb Hemost, 2022, 28: 10760296211063875.

[18] Wang J, Zhang T, Xu F, et al. GDF-15 at admission predicts cardiovascular death, heart failure, and bleeding outcomes in patients with CAD. ESC Heart Fail, 2023, 10(5): 3123-3132.

[19] Welsh P, Kimenai D M, Marioni R E, et al. Reference ranges for GDF-15, and risk factors associated with GDF-15, in a large general population cohort. Clin Chem Lab Med, 2022, 60(11): 1820-1829.

[20] Zhang S, Dai D, Wang X, et al. Growth differentiation factor-15 predicts the prognoses of patients with acute coronary syndrome: a meta-analysis. BMC Cardiovasc Disord, 2016, 16: 82.

[21] BATRA G, Lindbäck J, BECKER R C, et al. Biomarker-Based Prediction of Recurrent Ischemic Events in Patients With Acute Coronary Syndromes. J Am Coll Cardiol, 2022, 80(18): 1735-1747.

[22] Daniels L B, Clopton P, Laughlin G A, et al. Growth-differentiation factor-15 is a robust, independent predictor of 11-year mortality risk in community-dwelling older adults: the Rancho Bernardo Study. Circulation, 2011, 123(19): 2101-2110.

[23] Wollert K C, Kempf T, Peter T, et al. Prognostic value of growth-differentiation factor-15 in patients with non-ST-elevation acute coronary syndrome. Circulation, 2007, 115(8): 962-971.

[24] Schlittenhardt D, Schober A, Strelau J, et al. Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions. Cell Tissue Res, 2004, 318(2): 325-333.

[25] Woo K S. Perusal of risk stratification of acute myocardial infarction for half a century. Eur Heart J, 2009, 30(9): 1030-1032.

[26] GÜRgöze M T, Akkerhuis K M, Oemrawsingh R M, et al. Serially measured high-sensitivity cardiac troponin T, N-terminal-pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and growth differentiation factor 15 for risk assessment after acute coronary syndrome: the BIOMArCS cohort. Eur Heart J Acute Cardiovasc Care, 2023, 12(7): 451-461.

[27] Peiro O M, Garcia-Osuna A, Ordonez-Llanos J, et al. Long-term prognostic value of growth differentiation factor-15 in acute coronary syndromes. Clin Biochem, 2019, 73: 62-69.

[28] Bonaca M P, Morrow D A, Braunwald E, et al. 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(1): 203-210.

[29] Buljubasic N, Vroegindewey M M, Oemrawsingh R M, et al. Temporal Pattern of Growth Differentiation Factor-15 Protein After Acute Coronary Syndrome (From the BIOMArCS Study). Am J Cardiol, 2019, 124(1): 8-13.

[30] Batra G, Renlund H, Kunadian V, et al. Effects of early myocardial reperfusion and perfusion on myocardial necrosis/dysfunction and inflammation in patients with ST-segment and non-ST-segment elevation acute coronary syndrome: results from the PLATelet inhibition and patients Outcomes (PLATO) trial. Eur Heart J Acute Cardiovasc Care, 2022, 11(4): 336-349.

[31] Wallentin L, Lindhagen L, Ärnström E, et al. Early invasive versus non-invasive treatment in patients with non-ST-elevation acute coronary syndrome (FRISC-II): 15 year follow-up of a prospective, randomised, multicentre study. The Lancet, 2016, 388(10054): 1903-1911.

[32] Valgimigli M, Bueno H, Byrne R A, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J, 2018, 39(3): 213-260.

[33] Hagstrom E, James S K, Bertilsson M, et al. Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study. Eur Heart J, 2016, 37(16): 1325-1333.

[34] Wallentin L, Hijazi Z, Andersson U, et al. Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation, 2014, 130(21): 1847-1858.

[35] Lindholm D, Hagstrom E, James S K, et al. Growth Differentiation Factor 15 at 1 Month After an Acute Coronary Syndrome Is Associated With Increased Risk of Major Bleeding. J Am Heart Assoc, 2017, 6(4).

[36] Wallentin L, Lindholm D, Siegbahn A, et al. Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non–ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization. Circulation, 2014, 129(3): 293-303.

[37] Kimmoun A, Cotter G, Davison B, et al. Safety, Tolerability and efficacy of Rapid Optimization, helped by NT-proBNP and GDF-15, of Heart Failure therapies (STRONG-HF): rationale and design for a multicentre, randomized, parallel-group study. Eur J Heart Fail, 2019, 21(11): 1459-1467.

[38] Dominguez-Rodriguez A, Abreu-Gonzalez P, Avanzas P. Relation of growth-differentiation factor 15 to left ventricular remodeling in ST-segment elevation myocardial infarction. Am J Cardiol, 2011, 108(7): 955-958.

[39] Stahrenberg R, Edelmann F, Mende M, et al. The novel biomarker growth differentiation factor 15 in heart failure with normal ejection fraction. European Journal of Heart Failure, 2014, 12(12): 1309-1316.

[40] Santhanakrishnan R, Chong J P C, Ng T P, 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. European Journal of Heart Failure, 2014, 14(12): 1338-1347.

[41] Eggers K M, Kempf T, Venge P, et al. Improving long-term risk prediction in patients with acute chest pain: the Global Registry of Acute Coronary Events (GRACE) risk score is enhanced by selected nonnecrosis biomarkers. Am Heart J, 2010, 160(1): 88-94.

[42] Widera C, Pencina M J, Meisner A, et al. Adjustment of the GRACE score by growth differentiation factor 15 enables a more accurate appreciation of risk in non-ST-elevation acute coronary syndrome. Eur Heart J, 2012, 33(9): 1095-1104.

[43] Kempf T, Bjorklund E, Olofsson S, et al. Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction. Eur Heart J, 2007, 28(23): 2858-2865.