Original Article http://dx.doi.org/10.4070/kcj.2012.42.7.464 Print ISSN 1738-5520 • On-line ISSN 1738-5555
Korean Circulation Journal
Serial Plasma Levels of Angiogenic Factors in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention Bo Hyun Kim, MS1, Young-Guk Ko, MD1, Ae-Young Her, MD2, Jung-Sun Kim, MD1, Ki-Chul Hwang, PhD1, Dong-Ho Shin, MD1, Byeong-Keuk Kim, MD1, Donghoon Choi, MD1, Jong-Won Ha, MD1, Myeong-Ki Hong, MD1, and Yangsoo Jang, MD1 1
Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University Health System, Seoul, Division of Cardiology, Kangwon National University Hospital, Chuncheon, Korea
2
Background and Objectives: Patients with acute myocardial infarction show varying degrees of collateral development. However, the relationships between angiogenic factors and degree of collaterals are not well known. Subjects and Methods: Fifty-nine patients (mean age, 59±10 years) with ST-segment elevation myocardial infarction (STEMI) underwent primary percutaneous coronary intervention (PCI). Patients were divided into one of 2 groups: group I (Rentrop collateral grade 0/1, n=34) or group II (grade 2/3, n=25). Plasma levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor (sFlt-1), angiopoietin (Ang)-2, and soluble Tie-2 at baseline, 24 and 48 hours after PCI were measured. Results: There were fewer diabetic patients and higher incidence of previous angina and multi-vessel disease in group II. Group II had a lower left ventricular ejection fraction and a trend toward longer pain-to-balloon time. Plasma levels of Ang-2, sFlt-1 were elevated prior to primary PCI and decreased after PCI, whereas plasma level of VEGF was relatively low initially, however rose after PCI. sTie-2 levels showed no significant interval change in group I, but decreased over time in group II. VEGF, sFlt-1, and Tie-2 levels did not differ between the groups at each time point. However, plasma levels of Ang-2 were higher in group I than in group II at baseline and at 48 hours. Conclusion: Presence of collaterals in STEMI patients undergoing primary PCI was associated with lesser rise in Ang-2 plasma level. VEGF showed a delayed response to acute ischemia compared to Ang-2. Clinical implications of our findings need to be investigated in further studies. (Korean Circ J 2012;42:464-470) KEY WORDS: Myocardial infarction; Angiogenesis modulating agents; Vascular endothelial growth factor; Angiopoietin-2.
Introduction Angiogenesis is the formation of new blood vessels from preexReceived: September 24, 2011 Revision Received: December 10, 2011 Accepted: February 6, 2012 Correspondence: Young-Guk Ko, MD, Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University Health System, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea Tel: 82-2-2228-8460 , Fax: 82-2-2227-7732 E-mail:
[email protected] • The authors have no financial conflicts of interest. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons. org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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isting blood vessels, whereas arteriogenesis is the enlarging of existing blood vessels to form collaterals.1) The exact molecular mechanisms that drive neovascularization remain still unclear. Vascular endothelial growth factor-A (or simply VEGF) is a growth factor involved in angiogenesis and arteriogenesis.2)3) VEGF binds to Vascular endothelial growth factor receptor (VEGFR-1/Flt-1) and VEGFR-2 (KDR/Flk-1), but with an approximate 10-fold higher affinity for VEGFR-1.2)3) Whereas VEGFR-2 mediates almost all of the known cellular responses to VEGF, VEGFR-1 is thought to modulate VEGFR-2 signaling.4) Angiopoietin (Ang)-1 and Ang-2 function as regulators of angiogenesis and arteriogenesis.5-8) Both Angs bind to the extracellular domain of the Tie-2 receptor of endothelial cells.5)6) Whereas Ang-2 destabilizes the vessel to make it sensitive to angiogenic growth factors such as VEGF, Ang-1 promotes vascular stabilization and counteracts VEGF-induced angiogenesis.5)6) Soluble forms of Copyright © 2012 The Korean Society of Cardiology
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both VEGFR-1 and Tie-2 are produced and secreted into the circulation, where they can bind their respective growth factors and inhibit angiogenesis.9-11) Whereas soluble VEGFR-1 (sFlt-1) is produced by alternative splicing of the VEGFR-1 gene, soluble Tie-2 is the result of proteolytic cleavage from the full-length membranebound receptor.9)10) The presence of collateral circulation in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) has been reported to be associated with smaller infarct size and more preserved left ventricular function.12) Sudden ischemia elicited by myocardial infarction induces a compensatory response to improve myocardial perfusion by angiogenesis and arteriogenesis.13) However, well developed collateral arteries are observed only in a minority of patients at the time of primary PCI.14) Reasons for considerable interindividual variability in the extent of collateral formation remain uncertain. The purpose of the present study was to investigate the relationship between degree of collateral circulation and plasma levels of factors that regulate angiogenesis and arteriogenesis.
Subjects and Methods Study subjects A total of 59 consecutive patients (mean age, 59±10 years) with ST-segment elevation myocardial infarct (STEMI) from the registry of the Infarction Prognosis Study, a prospective AMI cohort study at the Severance Cardiovascular Hospital, who underwent successful primary PCI within 12 hours of pain onset during the period between July, 2007 and October 2008 were enrolled in this study. The Infarction Prognosis Study was approved by the hospital institutional review board and performed according to good clinical practice standards. Written informed consent was obtained from each patient before enrollment. The diagnosis of STEMI was based on acute typical chest pain with electrocardiogram findings (ST-segment elevation of ≥0.2 mV in precordial leads and ≥0.1 mV in limb leads), and elevated cardiac troponin T >0.01 ng/mL. All subjects showed a total or subtotal occlusion of the infarct-related artery with Thrombolysis in Myocardial Infarction (TIMI) flow of 0 or 1 on coronary angiography prior to primary PCI. We excluded patients with the following: a past history of old myocardial infarction, having undergone a previous coronary artery bypass surgery, chronic total occlusion, renal failure (serum creatinine >2.0 mg/dL) and presence of significant stenosis in non-infarct related arteries requiring additional revascularization. Grading of coronary collaterals and primary percutaneous coronary intervention All patients received loading doses of 250 mg aspirin, 600 mg www.e-kcj.org
clopidogrel, and 70 IU/kg of intravenous heparin before primary PCI. Right and left coronary angiography was performed via femoral artery using standard Judkins technique. Degrees of coronary artery stenosis and collateral circulation were estimated visually by 2 independent cardiologists who were blinded to the clinical information of patients. Coronary collateral flow was graded according to the Rentrop scoring system15) as follows: 0, no filling of any collateral vessels; 1, filling of side branches of the artery to be perfused by collateral vessels without visualization of the epicardial segment; 2, partial filling of the epicardial artery by collateral vessels; and 3, complete filling of the epicardial artery by collateral vessels. If collateral circulation to the infarct territory was developed from more than 1 location, the site with the highest grade was taken into account. All PCIs were performed using a standard technique. A successful PCI was defined as a final TIMI grade 3 flow of the infarct-related artery with
