Circulating Angiopoietins-1 and -2, Angiopoietin Receptor Tie-2 and Vascular Endothelial Growth Factor-A as Biomarkers of Acute Myocardial Infarction: a Prospective Nested Case-Control Study

BMC Cardiovascular Disorders

Norman Orentreich¹  Joseph H Vogelman¹  Evangelos Hytopoulos²  Charles P Quesenberry³  Edward R McCluskey²  Jeanne A Darbinian³  Bruce H Phelps²  Carlos Iribarren³ 

[1] Orentreich Foundation for the Advancement of Science, Inc., 855 Route 301, Cold Spring-on-Hudson, NY 10516, USA;Aviir, Inc., 2463 Faber Place, Palo Alto, CA 94303, USA;Kaiser Permanente Division of Research, 2000 Broadway, Oakland, CA 94612, USA

关键词: epidemiology;    acute myocardial infarction;    angiogenesis;   

Others  :  1085963
DOI  :  10.1186/1471-2261-11-31

 received in 2010-08-18, accepted in 2011-06-14,  发布年份 2011

【 摘 要 】

Background

Angiogenesis is up-regulated in myocardial ischemia. However, limited data exist assessing the value of circulating angiogenic biomarkers in predicting future incidence of acute myocardial infarction (AMI). Our aim was to examine the association between circulating levels of markers of angiogenesis with risk of incident acute myocardial infarction (AMI) in men and women.

Methods

We performed a case-control study (nested within a large cohort of persons receiving care within Kaiser Permanente of Northern California) including 695 AMI cases and 690 controls individually matched on age, gender and race/ethnicity.

Results

Median [inter-quartile range] serum concentrations of vascular endothelial growth factor-A (VEGF-A; 260 [252] vs. 235 [224] pg/mL; p = 0.01) and angiopoietin-2 (Ang-2; 1.18 [0.66] vs. 1.05 [0.58] ng/mL; p < 0.0001) were significantly higher in AMI cases than in controls. By contrast, endothelium-specific receptor tyrosine kinase (Tie-2; 14.2 [3.7] vs. 14.0 [3.1] ng/mL; p = 0.07) and angiopoietin-1 levels (Ang-1; 33.1 [13.6] vs. 32.5 [12.7] ng/mL; p = 0.52) did not differ significantly by case-control status. After adjustment for educational attainment, hypertension, diabetes, smoking, alcohol consumption, body mass index, LDL-C, HDL-C, triglycerides and C-reactive protein, each increment of 1 unit of Ang-2 as a Z score was associated with 1.17-fold (95 percent confidence interval, 1.02 to 1.35) increased odds of AMI, and the upper quartile of Ang-2, relative to the lowest quartile, was associated with 1.63-fold (95 percent confidence interval, 1.09 to 2.45) increased odds of AMI.

Conclusions

Our data support a role of Ang-2 as a biomarker of incident AMI independent of traditional risk factors.

【 授权许可】

   
2011 Iribarren et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Helisch A, Schaper W: Arteriogenesis: the development and growth of collateral arteries. Microcirculation 2003, 10:83-97.
• [2]Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J: Vascular-specific growth factors and blood vessel formation. Nature 2000, 407:242-8.
• [3]Rissanen TT, Vajanto I, Hiltunen MO, Rutanen J, Kettunen MI, Niemi M, Leppanen P, Turunen MP, Markkanen JE, Arve K, Alhava E, Kauppinen RA, Yla-Herttuala S: Expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 (KDR/Flk-1) in ischemic skeletal muscle and its regeneration. Am J Pathol 2002, 160:1393-403.
• [4]Hashimoto E, Ogita T, Nakaoka T, Matsuoka R, Takao A, Kira Y: Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart. Am J Physiol 1994, 267:H1948-54.
• [5]Inoue M, Itoh H, Ueda M, Naruko T, Kojima A, Komatsu R, Doi K, Ogawa Y, Tamura N, Takaya K, Igaki T, Yamashita J, Chun TH, Masatsugu K, Becker AE, Nakao K: Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: possible pathophysiological significance of VEGF in progression of atherosclerosis. Circulation 1998, 98:2108-16.
• [6]Ladoux A, Frelin C: Hypoxia is a strong inducer of vascular endothelial growth factor mRNA expression in the heart. Biochem Biophys Res Commun 1993, 195:1005-10.
• [7]O'Brien ER, Garvin MR, Dev R, Hinohara T, Simpson JB, Schwartz SM: Angiogenesis in human coronary atherosclerotic plaques. Am J Pathol 1994, 145:883-94.
• [8]Tenaglia AN, Peters KG, Sketch MH, Annex BH: Neovascularization in atherectomy specimens from patients with unstable angina: implications for pathogenesis of unstable angina. Am Heart J 1998, 135:10-4.
• [9]Ferrara N: Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res 2000, 55:15-35.
• [10]Yla-Herttuala S, Rissanen TT, Vajanto I, Hartikainen J: Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J Am Coll Cardiol 2007, 49:1015-26.
• [11]Lee KW, Lip GY, Blann AD: Plasma angiopoietin-1, angiopoietin-2, angiopoietin receptor tie-2, and vascular endothelial growth factor levels in acute coronary syndromes. Circulation 2004, 110:2355-60.
• [12]Heeschen C, Dimmeler S, Hamm CW, Boersma E, Zeiher AM, Simoons ML: Prognostic significance of angiogenic growth factor serum levels in patients with acute coronary syndromes. Circulation 2003, 107:524-30.
• [13]Eaton CB, Gramling R, Parker DR, Roberts MB, Lu B, Ridker PM: Prospective association of vascular endothelial growth factor-A (VEGF-A) with coronary heart disease mortality in southeastern New England. Atherosclerosis 2008, 200:221-7.
• [14]Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD: Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 1996, 87:1171-80.
• [15]Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD: Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997, 277:55-60.
• [16]Peters KG, Kontos CD, Lin PC, Wong AL, Rao P, Huang L, Dewhirst MW, Sankar S: Functional significance of Tie2 signaling in the adult vasculature. Recent Prog Horm Res 2004, 59:51-71.
• [17]Visconti RP, Richardson CD, Sato TN: Orchestration of angiogenesis and arteriovenous contribution by angiopoietins and vascular endothelial growth factor (VEGF). Proc Natl Acad Sci USA 2002, 99:8219-24.
• [18]Fukuhara S, Sako K, Noda K, Nagao K, Miura K, Mochizuki N: Tie2 is tied at the cell-cell contacts and to extracellular matrix by angiopoietin-1. Exp Mol Med 2009, 41:133-9.
• [19]Patel JV, Lim HS, Varughese GI, Hughes EA, Lip GY: Angiopoietin-2 levels as a biomarker of cardiovascular risk in patients with hypertension. Ann Med 2008, 40:215-22.
• [20]Collen MF: Automated multiphasic health testing. Implementation of a system. Hospitals 1971, 45:49-58.
• [21]Collen MF: Periodic health evaluations: the multiphasic approach. Internist 1981, 22:13-5.
• [22]Collen MF, Rubin L, Neyman J, Dantzig GB, Baer RM, Siegelaub AB: Automated Multiphasic Screening and Diagnosis. Am J Public Health Nations Health 1964, 54:741-50.
• [23]Robins JM, Gail MH, Lubin JH: More on "Biased selection of controls for case-control analyses of cohort studies". Biometrics 1986, 42:293-9.
• [24]Krieger N: Overcoming the absence of socioeconomic data in medical records: validation and application of a census-based methodology. Am J Public Health 1992, 82:703-10.
• [25]Karter AJ, Ferrara A, Liu JY, Moffet HH, Ackerson LM, Selby JV: Ethnic disparities in diabetic complications in an insured population. Jama 2002, 287:2519-27.
• [26]Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB: Prediction of coronary heart disease using risk factor categories. Circulation 1998, 97:1837-47.
• [27]Gupta R, Tongers J, Losordo DW: Human studies of angiogenic gene therapy. Circ Res 2009, 105:724-36.
• [28]Chae JK, Kim I, Lim ST, Chung MJ, Kim WH, Kim HG, Ko JK, Koh GY: Coadministration of angiopoietin-1 and vascular endothelial growth factor enhances collateral vascularization. Arterioscler Thromb Vasc Biol 2000, 20:2573-8.
• [29]Peters KG: Vascular endothelial growth factor and the angiopoietins: working together to build a better blood vessel. Circ Res 1998, 83(3):342-3.
• [30]Sigala F, Savvari P, Liontos M, Sigalas P, Pateras IS, Papalampros A, Basdra EK, Kolettas E, Kotsinas A, Papavassiliou AG, Gorgoulis VG: Increased expression of bFGF is associated with carotid atherosclerotic plaques instability engaging the NF-kappaB pathway. J Cell Mol Med 2010, in press.
• [31]Moulton KS, Heller E, Konerding MA, Flynn E, Palinski W, Folkman J: Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation 1999, 99:1726-32.
• [32]Matsunaga T, Chilian WM, March K: Angiostatin is negatively associated with coronary collateral growth in patients with coronary artery disease. Am J Physiol Heart Circ Physiol 2005, 288:H2042-6.
• [33]Pencina MJ, D'Agostino RB, D'Agostino RB, Vasan RS: Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008, 27:157-72.