冠心病患者血浆GDF-15水平与三年预后的关系研究
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摘要
目的
GDF-15为一种新发现的TGF-β超家族成员,巨噬细胞激活,心肌细胞、血管内皮细胞和平滑肌细胞等心血管系统细胞在缺血刺激和氧化应激下GDF-15表达增高,GDF-15为一种分泌型蛋白,急性冠脉综合症和慢性心衰患者血浆GDF-15水平升高。体外和动物实验已证实GDF-15是一种心血管保护因子,而大多数临床研究表明GDF-15水平增高与心血管疾病的不良预后相关。本研究关注冠状动脉粥样硬化性心脏病前期病变、稳定性病变及UAP患者血浆GDF-15水平及其与传统心血管危险因素的关系,同时探讨GDF-15循环水平与预后的相关性。
方法
入组未发生过急性心肌梗死的初次行冠脉造影检查的患者,按照冠脉造影结果分为非CAD组和CAD组,同时排除陈旧心梗、心衰、重要脏器损伤、急慢性感染、结缔组织疾病和肿瘤患者。记录其入院临床生化指标和造影结果并采集血样测定GDF-15水平,对所有患者进行电话随访和病历随访,记录终点事件及发生时间,进行统计分析。.
结果
非CAD组患者血浆HDL-C明显高丁CAD组,男性比例明显低于CAD组,血糖异常比例明显低于CAD组；UAP组患者冠脉病变程度明显重于SAP组；非CAD组、SAP组、UAP组患者血浆GDF-15水平依次升高：血浆GDF-15水平与年龄、血糖异常、冠脉病变程度呈显著正相关。BMI、HGB、GDF-15水平与入院行冠脉造影检查的非心梗患者的预后独立相关；冠脉病变程度与CAD患者一年预后独立相关；非CAD患者血浆GDF-15水平大于1200ng/L组预后较差；血糖异常进展者基础GDF-15水平高：GDF-15水平大于900ng/L的CAD患者接受介入治疗可明显获益。
结论
GDF-15与传统心血管危险因素和冠脉病变程度相关,其水平升高提示患者无终点事件生存率低并更容易进展为血糖异常,GDF-15可作为心血管疾病危险分层的生物标记物指导CAD患者的治疗选择。
Background
Growth differentiation factor15(GDF-15) is a member of the transforming growth factor-β cytokine superfamily. It is induced in the cardiovascular cells by many risk factors of coronary artery disease. Circulating levels of GDF-15may relate to these risk factors and provide prognostic information in patients with coronary atherosclerotic heart disease.
Methods and Result
Blood samples were obtained after CAG from158patients without acute myocyte infarction. GDF-15levels were determined by enzyme linked immuno-sorbent assay. Clinical and biochemical informations were recorded and all patientes were followed up. Circulating levels of GDF-15positively related to age, diabetes and Gensini score of the coronary artery. Patients with higher level of GDF-15had a worse prognose during following-up. A significant interaction existed between GDF-15level on admission and the effect of treatment strategy on the primary composite end point.
Conclusions
GDF-15is a potential tool for risk stratification and therapeutic decision making in patients with coronary atherosclerotic heart disease. A prospective randomized trial is needed to validate these findings.
GDF-15为一种新发现的TGF-β超家族成员,巨噬细胞激活,心肌细胞、血管内皮细胞和平滑肌细胞等心血管系统细胞在缺血刺激和氧化应激下GDF-15表达增高,GDF-15为一种分泌型蛋白,急性冠脉综合症和慢性心衰患者血浆GDF-15水平升高。体外和动物实验已证实GDF-15是一种心血管保护因子,而大多数临床研究表明GDF-15水平增高与心血管疾病的不良预后相关。本研究关注冠状动脉粥样硬化性心脏病前期病变、稳定性病变及UAP患者血浆GDF-15水平及其与传统心血管危险因素的关系,同时探讨GDF-15循环水平与预后的相关性。
方法
入组未发生过急性心肌梗死的初次行冠脉造影检查的患者,按照冠脉造影结果分为非CAD组和CAD组,同时排除陈旧心梗、心衰、重要脏器损伤、急慢性感染、结缔组织疾病和肿瘤患者。记录其入院临床生化指标和造影结果并采集血样测定GDF-15水平,对所有患者进行电话随访和病历随访,记录终点事件及发生时间,进行统计分析。.
结果
非CAD组患者血浆HDL-C明显高丁CAD组,男性比例明显低于CAD组,血糖异常比例明显低于CAD组；UAP组患者冠脉病变程度明显重于SAP组；非CAD组、SAP组、UAP组患者血浆GDF-15水平依次升高：血浆GDF-15水平与年龄、血糖异常、冠脉病变程度呈显著正相关。BMI、HGB、GDF-15水平与入院行冠脉造影检查的非心梗患者的预后独立相关；冠脉病变程度与CAD患者一年预后独立相关；非CAD患者血浆GDF-15水平大于1200ng/L组预后较差；血糖异常进展者基础GDF-15水平高：GDF-15水平大于900ng/L的CAD患者接受介入治疗可明显获益。
结论
GDF-15与传统心血管危险因素和冠脉病变程度相关,其水平升高提示患者无终点事件生存率低并更容易进展为血糖异常,GDF-15可作为心血管疾病危险分层的生物标记物指导CAD患者的治疗选择。
Background
Growth differentiation factor15(GDF-15) is a member of the transforming growth factor-β cytokine superfamily. It is induced in the cardiovascular cells by many risk factors of coronary artery disease. Circulating levels of GDF-15may relate to these risk factors and provide prognostic information in patients with coronary atherosclerotic heart disease.
Methods and Result
Blood samples were obtained after CAG from158patients without acute myocyte infarction. GDF-15levels were determined by enzyme linked immuno-sorbent assay. Clinical and biochemical informations were recorded and all patientes were followed up. Circulating levels of GDF-15positively related to age, diabetes and Gensini score of the coronary artery. Patients with higher level of GDF-15had a worse prognose during following-up. A significant interaction existed between GDF-15level on admission and the effect of treatment strategy on the primary composite end point.
Conclusions
GDF-15is a potential tool for risk stratification and therapeutic decision making in patients with coronary atherosclerotic heart disease. A prospective randomized trial is needed to validate these findings.
引文
1. Bootcov MR, Bauskin AR, Valenzuela SM, et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A 1997;94:11514-9.
2. Bootcov MR, Bauskin AR, Valenzuela SM, et al.3) MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A 1997;94:11514-9.
3. Burt DW, Law AS.7) Evolution of the transforming growth factor-beta superfamily. Prog Growth Factor Res 1994;5:99-118.
4. Ozkaynak E, Schnegelsberg PN, Jin DF, et al.6) Osteogenic protein-2. A new member of the transforming growth factor-beta superfamily expressed early in embryogenesis. J Biol Chem 1992;267:25220-7.
5. Lawton LN, Bonaldo MF, Jelenc PC, et al.4) Identification of a novel member of the TGF-beta superfamily highly expressed in human placenta. Gene 1997;203:17-26.
6. Moore AG, Brown DA, Fairlie WD, et al. The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J Clin Endocrinol Metab 2000;85:4781-8.
7. 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.
8. Hsiao EC, Koniaris LG, Zimmers-Koniaris T, Sebald SM, Huynh TV, Lee SJ. Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury. Mol Cell Biol 2000;20:3742-51.
9. 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.
10. Zimmers TA, Jin X, Hsiao EC, McGrath SA, Esquela AF, Koniaris LG. Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury. Shock 2005;23:543-8.
11. Schober A, Bottner M, Strelau J, et al. Expression of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in the perinatal, adult, and injured rat brain. J Comp Neurol 2001;439:32-45.
12. 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.
13. 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;98:351-60.
14. Ferrari N, Pfeffer U, Dell'Eva R, Ambrosini C, Noonan DM, Albini A. The transforming growth factor-beta 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.
15. Secchiero P, Corallini F, Gonelli A, et al. Antiangiogenic activity of the MDM2 antagonist nutlin-3. Circ Res 2007; 100:61-9.
16. 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.
17. 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.
18. Wollert KC, Kempf T, Peter T, et al.9 Prognostic value of growth-differentiation factor-15 in patients with non-ST-elevation acute coronary syndrome. Circulation 2007;115:962-71.
19. 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.
20. Khan SQ, Ng K, Dhillon O, et al.10 Growth differentiation factor-15 as a prognostic marker in patients with acute myocardial infarction. Eur Heart J 2009;30:1057-65.
21. 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.
22. Khot UN, Khot MB, Bajzer CT, et al.1 Prevalence of conventional risk factors in patients with coronary heart disease. JAMA 2003;290:898-904.
23. 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.
24. Kim JH, Kim KY, Jeon JH, et al. Adipocyte culture medium stimulates production of macrophage inhibitory cytokine 1 in MDA-MB-231 cells. Cancer Lett 2008;261:253-62.
25. Kempf T, Bjorklund E, Olofsson S, et al.8 Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction. Eur Heart J 2007;28:2858-65.
26. Johnen H, Lin S, Kuffner T, et al. Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. Nat Med 2007;13:1333-40.
1. Bootcov MR, Bauskin AR, Valenzuela SM, et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A 1997;94:11514-9.
2. Bootcov MR, Bauskin AR, Valenzuela SM, et al.3) MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A 1997;94:11514-9.
3. Burt DW, Law AS.7) Evolution of the transforming growth factor-beta superfamily. Prog Growth Factor Res 1994;5:99-118.
4. Ozkaynak E, Schnegelsberg PN, Jin DF, et al.6) Osteogenic protein-2. A new member of the transforming growth factor-beta superfamily expressed early in embryogenesis. J Biol Chem 1992;267:25220-7.
5. Lawton LN, Bonaldo MF, Jelenc PC, et al.4) Identification of a novel member of the TGF-beta superfamily highly expressed in human placenta. Gene 1997;203:17-26.
6. Moore AG, Brown DA, Fairlie WD, et al. The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J Clin Endocrinol Metab 2000;85:4781-8.
7. Schlittenhardt D, Schober A, Strelau J, et al. Inv.olvement 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.
8. Hsiao EC, Koniaris LG, Zimmers-Koniaris T, Sebald SM, Huynh TV, Lee SJ. Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury. Mol Cell Biol 2000;20:3742-51.
9. 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.
10. Zimmers TA. Jin X. Hsiao EC. McGrath SA. Esquela AF. Koniaris LG. Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury. Shock 2005;23:543-8.
11. Schober A, Bottner M, Strelau J, et al. Expression of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in the perinatal, adult, and injured rat brain. J Comp Neurol 2001;439:32-45.
12. 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.
13. 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;98:351-60.
14. Ferrari N, Pfeffer U, Dell'Eva R, Ambrosini C, Noonan DM, Albini A. The transforming growth factor-beta 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.
15. Secchiero P, Corallini F, Gonelli A, et al. Antiangiogenic activity of the MDM2 antagonist nutlin-3. Circ Res 2007; 100:61-9.
16. 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.
17. 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.
18. Wollert KC, Kempf T, Peter T, et al.9 Prognostic value of growth-differentiation factor-15 in patients with non-ST-elevation acute coronary syndrome. Circulation 2007; 115:962-71.
19. 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.
20. Khan SQ, Ng K, Dhillon O, et al.10 Growth differentiation factor-15 as a prognostic marker in patients with acute myocardial infarction. Eur Heart J 2009;30:1057-65.
21. 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.
22. Khot UN, Khot MB, Bajzer CT, et al.1 Prevalence of conventional risk factors in patients with coronary heart disease. JAMA 2003;290:898-904.
23. 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.
24. Kim JH, Kim KY, Jeon JH, et al. Adipocyte culture medium stimulates production of macrophage inhibitory cytokine 1 in MDA-MB-231 cells. Cancer Lett 2008;261:253-62.
25. 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.
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2. Bootcov MR, Bauskin AR, Valenzuela SM, et al.3) MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A 1997;94:11514-9.
3. Burt DW, Law AS.7) Evolution of the transforming growth factor-beta superfamily. Prog Growth Factor Res 1994;5:99-118.
4. Ozkaynak E, Schnegelsberg PN, Jin DF, et al.6) Osteogenic protein-2. A new member of the transforming growth factor-beta superfamily expressed early in embryogenesis. J Biol Chem 1992;267:25220-7.
5. Lawton LN, Bonaldo MF, Jelenc PC, et al.4) Identification of a novel member of the TGF-beta superfamily highly expressed in human placenta. Gene 1997;203:17-26.
6. Moore AG, Brown DA, Fairlie WD, et al. The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J Clin Endocrinol Metab 2000;85:4781-8.
7. 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.
8. Hsiao EC, Koniaris LG, Zimmers-Koniaris T, Sebald SM, Huynh TV, Lee SJ. Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury. Mol Cell Biol 2000;20:3742-51.
9. 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.
10. Zimmers TA, Jin X, Hsiao EC, McGrath SA, Esquela AF, Koniaris LG. Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury. Shock 2005;23:543-8.
11. Schober A, Bottner M, Strelau J, et al. Expression of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in the perinatal, adult, and injured rat brain. J Comp Neurol 2001;439:32-45.
12. 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.
13. 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;98:351-60.
14. Ferrari N, Pfeffer U, Dell'Eva R, Ambrosini C, Noonan DM, Albini A. The transforming growth factor-beta 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.
15. Secchiero P, Corallini F, Gonelli A, et al. Antiangiogenic activity of the MDM2 antagonist nutlin-3. Circ Res 2007; 100:61-9.
16. 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.
17. 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.
18. Wollert KC, Kempf T, Peter T, et al.9 Prognostic value of growth-differentiation factor-15 in patients with non-ST-elevation acute coronary syndrome. Circulation 2007;115:962-71.
19. 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.
20. Khan SQ, Ng K, Dhillon O, et al.10 Growth differentiation factor-15 as a prognostic marker in patients with acute myocardial infarction. Eur Heart J 2009;30:1057-65.
21. 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.
22. Khot UN, Khot MB, Bajzer CT, et al.1 Prevalence of conventional risk factors in patients with coronary heart disease. JAMA 2003;290:898-904.
23. 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.
24. Kim JH, Kim KY, Jeon JH, et al. Adipocyte culture medium stimulates production of macrophage inhibitory cytokine 1 in MDA-MB-231 cells. Cancer Lett 2008;261:253-62.
25. Kempf T, Bjorklund E, Olofsson S, et al.8 Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction. Eur Heart J 2007;28:2858-65.
26. Johnen H, Lin S, Kuffner T, et al. Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. Nat Med 2007;13:1333-40.
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