Growth differentiation factor 15 in heart failure: An update

Current Heart Failure Reports

Volumn 9, Issue 4, 2012, Pages 337-345

  Wollert, Kai C ^a   Kempf, Tibor ^a  

^a HANNOVER MEDICAL SCHOOL   (Germany)

Author keywords

Acute coronary syndrome; Aging; Atherosclerosis; BNP; Diabetes; GDF 15; Heart failure; Incidence; Inflammation; Oxidative stress; P53; Prognosis; Renal function; Troponin

Indexed keywords

AMINO TERMINAL PRO BRAIN NATRIURETIC PEPTIDE; BIOLOGICAL MARKER; GROWTH DIFFERENTIATION FACTOR 15; PLACEBO; PROTEIN P53; TROPONIN T; VALSARTAN;

ACUTE CORONARY SYNDROME; ARTICLE; CARDIAC PATIENT; CARDIOMETABOLIC RISK; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CLINICAL DECISION MAKING; COMMUNITY LIVING; HEART FAILURE; HOSPITAL READMISSION; HUMAN; LEFT VENTRICULAR ASSIST DEVICE; PROGNOSIS; PROTEIN BLOOD LEVEL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PULMONARY HYPERTENSION;

BIOLOGICAL MARKERS; CARDIOVASCULAR DISEASES; GROWTH DIFFERENTIATION FACTOR 15; HEART FAILURE; HUMANS; PROGNOSIS;

EID: 84872174624     PISSN: 15469530     EISSN: 15469549     Source Type: Journal    
DOI: 10.1007/s11897-012-0113-9     Document Type: Article

References (91)

1. Shah AM, Mann DL. In search of new therapeutic targets and strategies for heart failure: recent advances in basic science. Lancet. 2011;378:704-12.
2. Strait JB, Lakatta EG. Aging-Associated cardiovascular changes and their relationship to heart failure. Heart Fail Clin. 2012;8:143-64.
3. Dhingra R, Vasan RS. Diabetes and the risk of heart failure. Heart Fail Clin. 2012;8:125-33.
4. Frohlich ED, Susic D. Pressure overload. Heart Fail Clin. 2012;8:21-32.
5. Ronco C, Haapio M, House AA, et al. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52:1527-39.
6. Anand IS. Anemia and chronic heart failure implications and treatment options. J Am Coll Cardiol. 2008;52:501-11.
7. Clark AL, Poole-Wilson PA, Coats AJ. Exercise limitation in chronic heart failure: central role of the periphery. J Am Coll Cardiol. 1996;28:1092-102.
8. Braunwald E. Biomarkers in heart failure. N Engl J Med. 2008;358:2148-59.
9. van Kimmenade RR, Januzzi JL. Emerging biomarkers in heart failure. Clin Chem. 2012;58:127-38.
10. Wollert KC. Tailored therapy for heart failure: the role of biomarkers. Eur Heart J. 2012, Epub ahead of print.
11. Kempf T, Wollert KC. Growth-differentiation factor-15 in heart failure. Heart Fail Clin. 2009;5:537-47.
12. Bootcov MR, Bauskin AR, Valenzuela SM, et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-β superfamily. Proc Natl Acad Sci U S A. 1997;94:11514-9. (Pubitemid 27451030)
13. Bauskin AR, Zhang HP, Fairlie WD, et al. The propeptide of macrophage inhibitory cytokine (MIC-1), a TGF-β superfamily member, acts as a quality control determinant for correctly folded MIC-1. EMBO J. 2000;19:2212-20.
14. Shi M, Zhu J, Wang R, et al. Latent TGF-β structure and activation. Nature. 2011;474:343-9.
15. Su AI, Wiltshire T, Batalov S, et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A. 2004;101:6062-7. (Pubitemid 38520528)
16. Kempf T, Eden M, Strelau J, et al. The transforming growth factor-β superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res. 2006;98:351-60.
17. 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;17:581-8. This study uncovers a major role for GDF-15 in controlling inflammatory cell recruitment by directly interfering with leukocyte integrin activation. Loss of this unique anti-inflammatory mechanism leads to fatal cardiac rupture after myocardial infarction in mice, thus attributing an adaptive function to GDF-15 in the context of acute ischemic injury.
18. Buitrago M, Lorenz K, Maass AH, et al. The transcriptional repressor Nab1 is a specific regulator of pathological cardiac hypertrophy. Nat Med. 2005;11:837-44.
19. Xu J, Kimball TR, Lorenz JN, 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;98:342-50.
20. Krusche CA, Holthofer B, Hofe V, et al. Desmoglein 2 mutant mice develop cardiac fibrosis and dilation. Basic Res Cardiol. 2011;106:617-33.
21. Clerk A, Kemp TJ, Zoumpoulidou G, Sugden PH. Cardiac myocyte gene expression profiling during H2O2-induced apoptosis. Physiol Genomics. 2007;29:118-27.
22. Frank D, Kuhn C, Brors B, et al. Gene expression pattern in biomechanically stretched cardiomyocytes: evidence for a stretch-specific gene program. Hypertension. 2008;51:309-18.
23. Widera C, Giannitsis E, Kempf T, et al. Identification of follistatinlike 1 by expression cloning as an activator of the growth differentiation factor 15 gene and a prognostic biomarker in acute coronary syndrome. Clin Chem. 2012;58:1233-41.
24. de Lemos JA, McGuire DK, Drazner MH. B-Type natriuretic peptide in cardiovascular disease. Lancet. 2003;362:316-22.
25. 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;318:325-33.
26. Bermudez B, Lopez S, Pacheco YM, et al. Influence of postprandial triglyceride-rich lipoproteins on lipid-mediated gene expression in smooth muscle cells of the human coronary artery. Cardiovasc Res. 2008;79:294-303.
27. Ferrari N, Pfeffer U. Dell'Eva R, et al.: The transforming growth factor-β family members bone morphogenetic protein-2 and macrophage inhibitory cytokine-1 as mediators of the antiangiogenic activity of N-(4-hydroxyphenyl)retinamide. Clin Cancer Res. 2005;11:4610-9. (Pubitemid 40825652)
28. Secchiero P, Corallini F, Gonelli A, et al. Antiangiogenic activity of the MDM2 antagonist nutlin-3. Circ Res. 2007;100:61-9. (Pubitemid 46066774)
29. Nickel N, Jonigk D, Kempf T, et al. GDF-15 is abundantly expressed in plexiform lesions in patients with pulmonary arterial hypertension and affects proliferation and apoptosis of pulmonary endothelial cells. Respir Res. 2011;12:62.
30. Ding Q, Mracek T, Gonzalez-Muniesa P, et al. Identification of macrophage inhibitory cytokine-1 in adipose tissue and its secretion as an adipokine by human adipocytes. Endocrinology. 2009;150:1688-96.
31. de Jager SC, Bermudez B, Bot I, et al. Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J Exp Med. 2011;208:217-25.
32. Lok SI, 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. doi:10.1093/eurjhf/ hfs120. This study shows that the GDF-15 levels in patients with advanced nonischemic HF decrease substantially after left ventricular assist device implantation, indicating that even large increases in GDF-15 are, to some extent, reversible and responsive to a potentially life-saving therapeutic intervention.
33. Heger J, Schiegnitz E, von Waldthausen D, et al. Growth differentiation factor 15 acts anti-Apoptotic and pro-hypertrophic in adult cardiomyocytes. J Cell Physiol. 2010;224:120-6.
34. Kempf T, Horn-Wichmann R, Brabant G, et al. Circulating concentrations of growth-differentiation factor 15 in apparently healthy elderly individuals and patients with chronic heart failure as assessed by a new immunoradiometric sandwich assay. Clin Chem. 2007;53:284-91.
35. Rohatgi A, Patel P, Das SR, 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;58:172-82. This large population-based study shows that the circulating levels of GDF-15 are independently related to coronary artery calcium, all-cause mortality, and cardiovascular mortality in community-dwelling individuals without known cardiovascular disease.
36. Kempf T, Sinning JM, Quint A, et al. Growth-differentiation factor-15 for risk stratification in patients with stable and unstable coronary heart disease: results from the AtheroGene study. Circ Cardiovasc Genet. 2009;2:286-92.
37. Kempf T, von Haehling S, Peter T, et al. Prognostic utility of growth differentiation factor-15 in patients with chronic heart failure. J Am Coll Cardiol. 2007;50:1054-60.
38. Anand IS, Kempf T, Rector TS, et al. Serial measurement of growth-differentiation factor-15 in heart failure: relation to disease severity and prognosis in the Valsartan Heart Failure Trial. Circulation. 2010;122:1387-95. This study presents the largest experience with GDF-15 in heart failure and identifies GDF-15 as an independent prognostic biomarker. The GDF-15 levels increase over time, indicating that GDF-15 reflects a pathophysiological axis that is not completely addressed by the therapies prescribed in Val-HeFT.
39. Stahrenberg R, Edelmann F, Mende M, et al. The novel biomarker growth differentiation factor 15 in heart failure with normal ejection fraction. Eur J Heart Fail. 2010;12:1309-16. This study shows that GDF-15 levels in heart failure with preserved ejection fraction are similar to those in heart failure with reduced ejection fraction. The diagnostic properties of GDF-15 for detecting heart failure with preserved ejection fraction were at least as good as those of NT-proBNP, and a combination of both markers significantly improved diagnostic accuracy.
40. Zimmers TA, Jin X, Hsiao EC, et al. Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury. Shock. 2005;23:543-8. (Pubitemid 40677428)
41. Zimmers TA, Jin X, Hsiao EC, et al. Growth differentiation factor-15: induction in liver injury through p53 and tumor necrosis factorindependent mechanisms. J Surg Res. 2006;130:45-51.
42. Melanson BD, Bose R, Hamill JD, et al. The role of mRNA decay in p53-induced gene expression. RNA. 2011;17:2222-34.
43. Baek SJ, Horowitz JM, Eling TE. Molecular cloning and characterization of human nonsteroidal anti-inflammatory drug-Activated gene promoter. Basal transcription is mediated by Sp1 and Sp3. J Biol Chem. 2001;276:33384-92.
44. Kannan K, Amariglio N, Rechavi G, Givol D. Profile of gene expression regulated by induced p53: connection to the TGF-β family. FEBS Lett. 2000;470:77-82.
45. Li PX, Wong J, Ayed A, et al. Placental transforming growth factor-β is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression. J Biol Chem. 2000;275:20127-35.
46. Tan M, Wang Y, Guan K, Sun Y. PTGF-β, a type β transforming growth factor (TGF-β) superfamily member, is a p53 target gene that inhibits tumor cell growth via TGF-β signaling pathway. Proc Natl Acad Sci U S A. 2000;97:109-14.
47. Yang H, Filipovic Z, Brown D, et al. Macrophage inhibitory cytokine-1: a novel biomarker for p53 pathway activation. Mol Cancer Ther. 2003;2:1023-9.
48. Osada M, Park HL, Park MJ, et al. A p53-Type response element in the GDF15 promoter confers high specificity for p53 activation. Biochem Biophys Res Commun. 2007;354:913-8. (Pubitemid 46216219)
49. Albertoni M, Shaw PH, Nozaki M, et al. Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1. Oncogene. 2002;21:4212-9. (Pubitemid 34753827)
50. Minamino T, Orimo M, Shimizu I, et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med. 2009;15:1082-7.
51. Ahima RS. Connecting obesity, aging and diabetes. Nat Med. 2009;15:996-7.
52. Reinhardt HC, Schumacher B. The p53 network: cellular and systemic DNA damage responses in aging and cancer. Trends Genet. 2012;28:128-36.
53. Wang JC, Bennett M. Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res. 2012;111:245-59.
54. Moslehi J, DePinho RA, Sahin E. Telomeres and mitochondria in the aging heart. Circ Res. 2012;110:1226-37.
55. Sahin E, Colla S, Liesa M, et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature. 2011;470:359-65.
56. Sano M, Minamino T, Toko H, et al. p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature. 2007;446:444-8. (Pubitemid 46474597)
57. Shimizu I, Yoshida Y, Katsuno T, et al. p53-induced adipose tissue inflammation is critically involved in the development of insulin resistance in heart failure. Cell Metab. 2012;15:51-64.
58. Daniels LB, Clopton P, Laughlin GA, et al. Growthdifferentiation factor-15 is a robust, independent predictor of 11-year mortality risk in community-dwelling older adults: the Rancho Bernardo Study. Circulation. 2011;123:2101-10. This population-based study in older adults without known heart disease identifies GDF-15 as a robust predictor of all-cause, cardiovascular, and noncardiovascular mortality, adding incremental value to traditional risk factors, NT-proBNP, and CRP.
59. Lind L, Wallentin L, Kempf T, 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;30:2346-53.
60. Eggers KM, Kempf T, Lagerqvist B, et al. Growth-differentiation factor-15 for long-Term risk prediction in patients stabilized after an episode of non-ST-segment-elevation acute coronary syndrome. Circ Cardiovasc Genet. 2010;3:88-96.
61. Wollert KC, Kempf T, Peter T, et al. Prognostic value of growthdifferentiation factor-15 in patients with non-ST-elevation acute coronary syndrome. Circulation. 2007;115:962-71.
62. Wollert KC, Kempf T, Lagerqvist B, et al. Growth differentiation factor 15 for risk stratification and selection of an invasive treatment strategy in non ST-elevation acute coronary syndrome. Circulation. 2007;116:1540-8. (Pubitemid 47511417)
63. 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;28:2858-65.
64. Khan SQ, Ng K, Dhillon O, et al. Growth differentiation factor-15 as a prognostic marker in patients with acute myocardial infarction. Eur Heart J. 2009;30:1057-65.
65. Dostalova I, Roubicek T, Bartlova M, et al. Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: the influence of very low calorie diet. Eur J Endocrinol. 2009;161:397-404.
66. Vila G, Riedl M, Anderwald C, et al. The relationship between insulin resistance and the cardiovascular biomarker growth differentiation factor-15 in obese patients. Clin Chem. 2011;57:309-16.
67. Kempf T, Guba-Quint A, Torgerson J, et al. Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese non-diabetic individuals: results from the XENDOS trial. Eur J Endocrinol. 2012. doi:10.1530/EJE-12-0466.
68. Schledzewski K, Geraud C, Arnold B, et al. Deficiency of liver sinusoidal scavenger receptors stabilin-1 and ;2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors. J Clin Invest. 2011;121:703-14.
69. Duong Van Huyen JP, Cheval L, Bloch-Faure M, et al. GDF15 triggers homeostatic proliferation of acid-secreting collecting duct cells. J Am Soc Nephrol. 2008;19:1965-74.
70. Simonson MS, Tiktin M, Debanne SM, et al. The renal transcriptome of db/db mice identifies putative urinary biomarker proteins in patients with type 2 diabetes: a pilot study. Am J Physiol Renal Physiol. 2012;302:F820-9.
71. Bonaca MP, Morrow DA, Braunwald E, et al. Growth differentiation factor-15 and risk of recurrent events in patients stabilized after acute coronary syndrome: observations from PROVE ITTIMI 22. Arterioscler Thromb Vasc Biol. 2011;31:203-10. This large study in patients with acute coronary syndrome shows that predischarge levels of GDF-15 are associated with the future risks of heart failure, recurrent myocardial infarction, and death independently of clinical predictors, BNP, and CRP.
72. Lindahl B, Lindback J, Jernberg T, et al. Serial analyses of Nterminal pro-B-Type natriuretic peptide in patients with non-STsegment elevation acute coronary syndromes: a Fragmin and fast Revascularisation during In Stability in Coronary artery disease (FRISC)-II substudy. J Am Coll Cardiol. 2005;45:533-41.
73. Manhenke C, Orn S, von Haehling S, et al. Clustering of 37 circulating biomarkers by exploratory factor analysis in patients following complicated acute myocardial infarction. Int J Cardiol. 2011, Epub ahead of print.
74. 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;108:955-8.
75. Bernheim SM, Grady JN, Lin Z, et al. National patterns of riskstandardized mortality and readmission for acute myocardial infarction and heart failure. Update on publicly reported outcomes measures based on the 2010 release. Circ Cardiovasc Qual Outcomes. 2010;3:459-67.
76. Wang TJ, Wollert KC, Larson MG, et al. Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study. Circulation. 2012, first published on August 20 2012 as doi:10.1161/CIRCULATIONAHA.112. 129437. As is shown in this study, GDF-15 predicts the future risk of heart failure in apparently healthy individuals from the community even in the context of BNP and established clinical risk factors.
77. Brown DA, Breit SN, Buring J, et al. Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study. Lancet. 2002;359:2159-63.
78. Wiklund FE, Bennet AM, Magnusson PK, et al. Macrophage inhibitory cytokine-1 (MIC-1/GDF15): a new marker of all-cause mortality. Aging Cell. 2010;9:1057-64.
79. Widera C, Pencina MJ, 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;33:1095-104.
80. Foley PW, Stegemann B, Ng K, et al. Growth differentiation factor-15 predicts mortality and morbidity after cardiac resynchronization therapy. Eur Heart J. 2009;30:2749-57.
81. Lankeit M, Kempf T, Dellas C, et al. Growth differentiation factor-15 for prognostic assessment of patients with acute pulmonary embolism. Am J Respir Crit Care Med. 2008;177:1018-25. This study identifies GDF-15 as a prognostic biomarker in acute pulmonary embolism. The ability of GDF-15 to identify patients who experienced complications during the first 30 days was superior to that of NT-proBNP. GDF-15, but not NT-proBNP, added prognostic information to an echocardiographic assessment of right ventricular function.
82. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123:1788-830.
83. Nickel N, Kempf T, Tapken H, et al. Growth differentiation factor-15 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178:534-41. This study identifies GDF-15 as an independent prognostic biomarker in patients with idiopathic pulmonary arterial hypertension and right-sided heart failure. Changes in GDF-15 over time after initiation of medical therapy were tracking changes in functional status.
84. Richards AM, Troughton RW. Use of natriuretic peptides to guide and monitor heart failure therapy. Clin Chem. 2012;58:62-71.
85. Frankenstein L, Remppis A, Frankenstein J, et al. Reference change values and determinants of variability of NT-proANP and GDF15 in stable chronic heart failure. Basic Res Cardiol. 2009;104:731-8.
86. Frankenstein L, Remppis A, Frankenstein J, et al. Variability of Nterminal probrain natriuretic peptide in stable chronic heart failure and its relation to changes in clinical variables. Clin Chem. 2009;55:923-9.
87. Miller LW, Pagani FD, Russell SD, et al. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med. 2007;357:885-96.
88. Kato TS, Chokshi A, Singh P, et al. Effects of continuous-flow versus pulsatile-flow left ventricular assist devices on myocardial unloading and remodeling. Circ Heart Fail. 2011;4:546-53.
89. Munzel T, Gori T, Bruno RM, Taddei S. Is oxidative stress a therapeutic target in cardiovascular disease? Eur Heart J. 2010;31:2741-8.
90. Heymans S, Hirsch E, Anker SD, et al. Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2009;11:119-29.
91. Wang X, Yang X, Sun K, et al. The haplotype of the growthdifferentiation factor 15 gene is associated with left ventricular hypertrophy in human essential hypertension. Clin Sci. 2010;118:137-45.