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Relation of Circulating Osteoprotegerin Levels on Admission to Microvascular Obstruction After Primary Percutaneous Coronary Intervention
Relation of Circulating Osteoprotegerin Levels on Admission to Microvascular Obstruction After Primary Percutaneous Coronary Intervention Ayhan Erkol, MDa,*, Selcuk Pala, MDb, Cevat Kırma, MDb, Vecih Oduncu, MDb, Cihan Dündar, MDb, Akın Izgi, MDb, Kürsat Tigen, MDb, and C. Michael Gibson, MD, MSc Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, has recently been linked to atherosclerosis and development of postinfarction heart failure. This study was designed to assess the association between admission OPG levels and microvascular obstruction (MVO) in patients who underwent primary percutaneous coronary intervention (p-PCI). Plasma samples for OPG analysis were obtained <30 minutes after admission in 47 patients who underwent p-PCI. Angiographic no-reflow (Thrombolysis In Myocardial Infarction [TIMI] flow grade <3 or 3 with myocardial blush grade 0 or 1 after p-PCI) was assessed immediately after p-PCI. MVO was assessed and quantified by the intracoronary hemodynamic measure of index of microcirculatory resistance performed on day 4 or 5 after p-PCI. Patients with angiographic no-reflow had significantly higher OPG levels on admission. On multiple linear regression analysis, OPG ( ⴝ 0.412, p ⴝ 0.001) and B-type natriuretic peptide ( ⴝ 0.409, p ⴝ 0.001) levels were independently and directly associated with the index of microcirculatory resistance. In conclusion, plasma OPG levels on admission are strongly associated with MVO and significantly correlated with the degree of MVO after p-PCI. It remains to be established whether improvement of microvascular perfusion is feasible with therapeutic strategies aimed to decrease circulating OPG levels. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107:857– 862) Despite the successful restoration of normal epicardial flow, myocardial perfusion remains impaired in as many as 50% of patients with ST-segment elevation myocardial infarction (MI), a condition known as “no-reflow phenomenon” or microvascular obstruction (MVO).1 The prognostic value of the presence and the extent of MVO in patients after MI has been well demonstrated in previous studies.2,3 Thus, the identification of new tools for risk stratification to select patients at high risk for the no-reflow phenomenon is important. Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, acts as a decoy receptor for receptor activator of nuclear factor B ligand (RANKL) and interferes in its binding to cell surface receptor activator of nuclear factor B (RANK).4 Besides its important regulatory role in bone metabolism, endocrine function, and the immune system,5 the OPG–RANKL–RANK axis has also been linked to atherosclerosis.6 – 8 Despite the established link between the increased OPG levels and myocardial failure in post-MI patients,9 –11 whether OPG plays an independent pathophysiologic role in the progression of heart
a Department of Cardiology, Kocaeli Derince Education and Research Hospital, Kocaeli; bDepartment of Cardiology, Kartal Kosuyolu Heart Education and Research Hospital, Istanbul, Turkey; and cBeth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Manuscript received September 5, 2010; revised manuscript received and accepted October 30, 2010. *Corresponding author: Tel: 90-505-7924640; fax: 90-262-2335540. E-mail address: [email protected] (A. Erkol).
0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.10.071
failure or is merely a marker of the severity of ventricular dysfunction has not been clearly defined. We hypothesized that circulating OPG levels on admission are associated with reperfusion injury and MVO after primary percutaneous coronary intervention (p-PCI). To test this hypothesis, we measured OPG in plasma samples and used standard methods and intracoronary hemodynamic measures to assess microvascular perfusion in patients who underwent p-PCI. Methods Forty-seven patients with their first acute ST-segment elevation MIs who were admitted to Kartal Kosuyolu Heart Education and Research Hospital and scheduled to undergo p-PCI ⬍12 hours after the onset of symptoms were prospectively enrolled. Inclusion criteria were (1) typical ongoing ischemic chest pain for ⬎30 minutes and (2) STsegment elevation ⱖ0.1 mV in ⱖ2 contiguous leads or new left bundle branch block on initial electrocardiograph. Exclusion criteria were cardiogenic shock and/or clinical instability, previous ST-segment elevation MI, malignant lifethreatening diseases, the presence of an additional lesion causing ⬎50% narrowing distal to the culprit lesion, peripheral arterial disease, aortic aneurysm, chronic inflammatory disease, and renal failure. Preinfarction angina pectoris was defined as cardiac symptoms for ⬍30 minutes that occurred ⬍2 days before infarct onset. All patients received chewable aspirin 300 mg and a loading dose of clopidogrel 600 mg on admission to the emergency room. Written informed consent was obtained www.ajconline.org
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Table 1 Baseline demographics and clinical characteristics Characteristic Main characteristics Age (years) Body mass index (kg/m2) Men Diabetes mellitus Hypertension* Hypercholesterolemia† Current smoker Preinfarction angina pectoris Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Anterior MI Killip class ⱖII Initial ST elevation (mm) Wall motion score index Left ventricular ejection fraction (%) Medications Aspirin Clopidogrel Enoxaparin  blockers Statins Angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers Intravenous tirofiban Intracoronary tirofiban Laboratory tests Peak troponin I (pg/ml) B-type natriuretic peptide (pg/ml) C-reactive protein (mg/dl) Hemoglobin (g/dl) Neutrophil count (⫻109/L) Platelet count (⫻109/L)
All Patients (n ⫽ 47)
OPG ⬍ Median (n ⫽ 24)
OPG ⬎ Median (n ⫽ 23)
p Value
56 ⫾ 7.7 27 ⫾ 4.4 42 (89%) 7 (15%) 13 (28%) 4 (8.5%) 35 (75%) 28 (60%) 131 ⫾ 26 81 ⫾ 18 77 ⫾ 16 29 (62%) 7 (15%) 11 ⫾ 8 1.29 ⫾ 0.17 54 ⫾ 7.8
55 ⫾ 6.4 27 ⫾ 5.3 22 (92%) 4 (17%) 6 (25%) 2 (8.3%) 19 (79%) 12 (52%) 132 ⫾ 24 83 ⫾ 18 80 ⫾ 18 16 (67%) 3 (13%) 13 ⫾ 8 1.3 ⫾ 0.18 53 ⫾ 7.5
57 ⫾ 8.8 26 ⫾ 3.5 20 (87%) 3 (13%) 7 (30%) 2 (8.7%) 16 (70%) 16 (70%) 130 ⫾ 28 80 ⫾ 19 74 ⫾ 14 13 (57%) 4 (17%) 10 ⫾ 7 1.28 ⫾ 0.16 54 ⫾ 8.2
0.28 0.59 0.67 1.00 0.75 1.00 0.52 0.24 0.75 0.56 0.19 0.56 0.70 0.21 0.61 0.56
47 (100%) 47 (100%) 47 (100%) 42 (89%) 43 (92%) 37 (79%)
24 (100%) 24 (100%) 24 (100%) 22 (92%) 23 (96%) 19 (79%)
23 (100%) 23 (100%) 23 (100%) 20 (87%) 20 (87%) 18 (78%)
1.00 1.00 1.00 0.67 0.35 1.00
47 (100%) 24 (51%)
24 (100%) 12 (50%)
23 (100%) 12 (52%)
1.00 1.00
67 ⫾ 53 85 ⫾ 94 0.6 ⫾ 0.5 14 ⫾ 1.5 8.1 ⫾ 2.5 261 ⫾ 60
69 ⫾ 50 79 ⫾ 78 0.5 ⫾ 0.3 14 ⫾ 1.3 8.2 ⫾ 2.4 253 ⫾ 53
65 ⫾ 57 92 ⫾ 109 0.7 ⫾ 0.6 14 ⫾ 1.8 8 ⫾ 2.6 270 ⫾ 67
0.82 0.64 0.32 0.66 0.74 0.35
Data are expressed as mean ⫾ SD or as number (percentage). * Systolic blood pressure ⬎140 mm Hg and/or diastolic blood pressure ⬎90 mm Hg or receiving antihypertensive treatment. † Total cholesterol ⬎200 mg/dl and/or low-density lipoprotein cholesterol ⬎130 mg/dl or receiving lipid-lowering therapy.
from all patients. The study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by our hospital ethics committee. All p-PCI procedures were performed by experienced interventional cardiologists through a femoral approach with a 7Fr guiding catheter. An intravenous bolus of unfractionated heparin at a dose of 70 U/kg body weight was administered. All patients received tirofiban as a glycoprotein IIb/IIIa inhibitor. Thrombus aspiration was recommended depending on relevant thrombus. In all patients, balloon predilatation was followed by stent implantation. Those patients with additional lesions causing ⬎50% narrowing distal to the culprit lesion were excluded after angiography. All patients were treated with maintenance doses of clopidogrel (75 mg/day for 12 months) and aspirin (300 mg for 30 days and then 100 mg indefinitely). Other guideline-based cardiac medications were administered at the maximum tolerated doses. Angiographic analysis included pre- and postprocedural Thrombolysis In Myocardial Infarction (TIMI) flow grade, corrected TIMI frame count,12 and myocardial blush grade.13 Visual assessments were performed offline by 2 blinded ob-
servers. Angiographic no-reflow was defined as TIMI flow grade ⬍ 3 or 3 with a myocardial blush grade of 0 or 1.1 All echocardiographic studies were performed and interpreted on the third day after MI by 2 experienced blinded sonographers. The left ventricular ejection fraction and wall motion score index were measured according to American Society of Echocardiography criteria.14 For OPG plasma level measurement, venous peripheral blood samples were drawn on admission, before the administration of any medication. Pyrogen-free blood collection tubes, with ethylenediaminetetraacetic acid as an anticoagulant, were centrifuged within 30 minutes (2,000 rpm for 10 minutes). Plasma was separated, aliquoted, and frozen at ⫺80°C until analysis. Plasma OPG was quantified in duplicate by using a commercially available in vitro enzyme-linked immunosorbent assay (RayBiotech, Norcross, Georgia) according to the manufacturer’s instructions. The intra-assay coefficient of variation was 4.1%. The lower limit of detection was 1 pg/ml. Plasma B-type natriuretic peptide (ADVIA Centaur Btype natriuretic peptide assay; Bayer Diagnostics, Tarry-
Coronary Artery Disease/Osteoprotegerin and No-Reflow After p-PCI
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Table 2 Angiographic characteristics and procedural results Characteristic Preprocedural characteristics Pain to balloon time (minutes) Culprit left anterior descending coronary artery Multivessel disease Baseline TIMI grade 0 or 1 Thrombus score 4 or 5 Number of stents Maximal inflation pressure (atm) Length of stent (mm) Use of thrombus aspirating device Minimal luminal diameter (mm) Mean residual stenosis (%) Side branch embolization Postprocedural results TIMI flow grade 2 3 Corrected TIMI frame count Myocardial blush grade 0 or 1 2 or 3 Angiographic no-reflow Second catheterization IMR ⬎30 U IMR (U) Coronary flow reserve
All Patients (n ⫽ 47)
OPG ⬍ Median (n ⫽ 24)
OPG ⬎ Median (n ⫽ 23)
p Value
201 ⫾ 98 28 (60%) 36 (77%) 47 (100%) 47 (100%) 1.23 ⫾ 0.47 16 (14–18) 25 (20–28) 6 (13%) 3 ⫾ 0.31 8.7 ⫾ 5.5 6 (13%)
200 ⫾ 94 15 (63%) 21 (88%) 24 (100%) 24 (100%) 1.16 ⫾ 0.38 16 (14–18) 22.5 (18–28) 3 (13%) 3 ⫾ 0.33 9.8 ⫾ 6.1 4 (17%)
202 ⫾ 105 13 (57%) 15 (65%) 23 (100%) 23 (100%) 1.3 ⫾ 0.56 16 (14–18) 25 (20–32) 3 (13%) 3.1 ⫾ 0.27 7.5 ⫾ 4.6 2 (8.7%)
0.92 0.77 0.09 1.00 1.00 0.40 0.31 0.47 1.00 0.24 0.20 0.67
6 (13%) 41 (87%) 23 ⫾ 9
1 (4%) 23 (96%) 20 ⫾ 5
5 (22%) 18 (78%) 25 ⫾ 11
16 (34%) 31 (66%) 17 (36%)
4 (17%) 20 (83%) 5 (21%)
12 (52%) 11 (48%) 12 (52%)
0.036
23 (49%) 31 ⫾ 14 2.1 ⫾ 0.7
7 (29%) 26 ⫾ 13 2.2 ⫾ 0.7
16 (70%) 36 ⫾ 14 1.9 ⫾ 0.6
0.009 0.013 0.18
0.09
0.04 0.01
Data are expressed as mean ⫾ SD, as median (interquartile range), or as number (percentage).
town, New York) and serum C-reactive protein (IMMAGE nephelometer; Beckman Coulter, Inc., Fullerton, California) levels were measured ⬍1 hour after blood collection. Other biochemical and hemographic parameters were determined by our routine laboratory methods. Four to 5 days after p-PCI, all patients underwent repeat cardiac catheterization. For hemodynamic measurements, a guidewire tipped with pressure and temperature sensors (PressureWire 5 Sensor; Radi Medical Systems, Uppsala, Sweden) was positioned distal to the stented segment of the infarct-related artery. Intravenous adenosine (140 g/kg/ min) was used as the hyperemic agent. The hemodynamic measurements were performed, as previously described,2 by an independent and blinded interventionalist different from the one who performed p-PCI. Thermodilution-derived coronary flow reserve was calculated as the mean transit time at rest divided by the mean transit time during hyperemia. The index of microcirculatory resistance (IMR) was calculated by dividing the mean distal coronary pressure by the inverse of mean hyperemic transit time (multiplication of distal coronary pressure and mean hyperemic transit time). The Kolmogorov-Smirnov test was used to test the normality of distribution of continuous variables. Continuous variables with normal and non-normal distributions are expressed as mean ⫾ SD and median (interquartile range), respectively. Categorical variables are expressed as numbers and percentages of patients. Group means for continuous variables with normal and non-normal distributions were compared using Student’s t tests and Mann-Whitney U tests, respectively. Categorical variables were compared using chi-square tests or
Fischer’s exact tests, as appropriate. Finally, a multiple linear regression analysis was conducted using the IMR as the dependent variable to assess the relation between the OPG levels and the degree of MVO. Results The study population consisted of 47 patients (89% men, mean age 56 ⫾ 7.7 years, range 39 to 73) with ST-segment elevation MI who underwent p-PCI. Blood samples were obtained ⬍30 minutes after admission, before the administration of any medication. The mean time from symptom onset to blood collection was 165 ⫾ 94 minutes. The mean plasma OPG level was 114 ⫾ 105 pg/ml, with a median value of 81 pg/ml. The baseline clinical characteristics of the subgroups of patients, with OPG levels higher and lower than the median, were comparable (Table 1). There was no significant correlation between OPG levels and baseline characteristics, except for weak correlations between OPG and age (r ⫽ 0.32 p ⫽ 0.027), B-type natriuretic peptide (r ⫽ 0.298, p ⫽ 0.04), and C-reactive protein (r ⫽ 0.38, p ⫽ 0.04). Angiographic characteristics and procedural results for the 2 groups were comparable (Table 2). Time from symptom onset to p-PCI was 201 ⫾ 98 minutes. P-PCI was successful in all patients. Each patient received ⱖ1 stent. Most patients achieved TIMI grade 3 flow (87%). The incidence of angiographic no-reflow was 36%. The incidence of myocardial blush grade 0 or 1 (52% vs 17%, p ⫽ 0.01) and angiographic no-reflow (52% vs 21%, p ⫽ 0.03) was higher in patients with OPG levels higher
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Figure 1. Comparison of plasma OPG levels according to angiographic no-reflow. The central line and the box represent the median and interquartile range, respectively, and the error bars extend from the 10th to the 90th percentile. Table 3 Multiple linear regression Variable Constant OPG B-type natriuretic peptide

t
p Value
19.396 0.412 0.409
7.486 3.482 3.456
0.000 0.001 0.001
r2 ⫽ 0.438.
than the median on admission. Accordingly, patients with angiographic no-reflow had higher levels of OPG compared to patients with normal reflow (161 ⫾ 117 vs 87 ⫾ 88 pg/ml, p ⫽ 0.019; Figure 1). The corrected TIMI frame count was significantly higher in patients with OPG levels greater than the median (25 ⫾ 11 vs 20 ⫾ 5, p ⫽ 0.04), and there was a significant linear correlation between OPG levels and corrected TIMI frame count (r ⫽ 0.53, p ⫽ 0.001). The mean IMR was 31 ⫾ 14 U. Compared to patients with OPG levels less than the median on admission, the IMR was higher (36 ⫾ 14 vs 26 ⫾ 13, p ⫽ 0.013), and there was a trend toward lower coronary flow reserve (1.9 ⫾ 0.6 vs 2.2 ⫾ 0.7, p ⫽ 0.18) in patients with OPG levels higher than the median on admission. On multiple linear regression analysis, OPG ( ⫽ 0.412, p ⫽ 0.001) and B-type natriuretic peptide ( ⫽ 0.409, p ⫽ 0.001) levels were independently and directly associated with IMR (r2 ⫽ 0.438; Table 3). Discussion This is the first study reporting an association between plasma levels of OPG on admission and the no-reflow
phenomenon after p-PCI. There was a significant linear relation between OPG levels on admission and the degree of MVO quantified by the IMR. Elevated OPG levels are associated with the presence and severity of coronary artery disease.6 Circulating OPG levels were found to be increased in patients with unstable angina7 and in those with ST-segment elevation MI.8 Ueland et al9 identified OPG as a novel predictive marker for cardiovascular mortality and clinical events in post-MI patients with heart failure. Subsequently, serum OPG levels were found to be strongly predictive of long-term mortality and heart failure hospitalizations in patients with acute coronary syndromes.10 Likewise, in a recent study, OPG/tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) ratios on admission were significantly higher in patients with acute MI in whom heart failure developed on follow-up.11 Despite the established link between the increased OPG levels and myocardial failure,9 –11 whether OPG plays an independent pathophysiologic role in the progression of heart failure or is merely a marker of the severity of ventricular dysfunction has not been clearly defined. Because of its pleiotropic effects on the immune system, we hypothesized that circulating OPG levels on admission are associated with reperfusion injury and MVO after p-PCI. We verified our hypothesis and demonstrated the relation of pre-p-PCI admission OPG levels to MVO. This may be a potential mechanism for the previously established link between elevated OPG levels on admission and the development of heart failure in post-MI patients. However, larger studies are warranted to clearly define the association between admission OPG levels and left ventricular remodeling.
Coronary Artery Disease/Osteoprotegerin and No-Reflow After p-PCI
Reperfusion injury, as well as distal atherothrombotic embolization, in situ thrombosis, and vasospasm, plays a significant role in the pathogenesis of no-reflow.15 Reperfusion markedly enhances the infiltration of coronary microcirculation by neutrophils and platelets.16 The essential initiating step, adhesion of neutrophils to the vascular endothelial cells, is followed by activation, diapedesis, and extravascular migration into surrounding myocytes.17 Besides causing microvascular plugs, these neutrophils release degradative enzymes and oxygen free radicals that can directly cause tissue and endothelial damage.18 Previous studies have shown that OPG increases the adhesion of neutrophils to the endothelial cells. Mangan et al19 demonstrated a linear increase in adhesion molecules when human umbilical vein endothelial cells were incubated with increasing concentrations of OPG and tumor necrosis factor–␣ in vitro. Likewise, Zauli et al20 demonstrated that OPG markedly and rapidly increases leukocyte-endothelial interactions in vitro and in vivo. Moreover, the greatest effect was observed at concentrations of OPG similar to the levels observed in patients with cardiovascular diseases. It could therefore be hypothesized that pre-PCI increased OPG levels might exacerbate reperfusion injury by increasing the initial leukocyte infiltration of the microcirculation. In addition to standard angiographic and electrocardiographic methods, we used guidewires tipped with pressure and temperature sensors to evaluate microvascular function and measured IMR. Cardiac magnetic resonance imaging is the reference method to identify and directly quantify MVO. We did not perform cardiac magnetic resonance imaging for the assessment of MVO. However, IMR has been proved to be a strong predictor of MVO after ST-segment elevation MI.2 Moreover, a recent study demonstrated that IMR was higher in patients with MVO on cardiac magnetic resonance imaging, and IMR independently predicted left ventricular function and infarct volume.21 The mean IMR in our study was 31 ⫾ 14 U, with a median value of 30 U, which is close to the median IMR value of 32 U2 and the optimal IMR cut-off value of 33 U22 found in previous studies to predict left ventricular remodeling. The mean IMR was 22 U in a previous study including patients with no obvious microvascular dysfunction.23 The extent of microvascular dysfunction changes, particularly within the first 48 hours after reperfusion, and stabilizes 2 days to 1 week after reperfusion.24,25 Therefore, we performed these measurements 4 to 5 days after p-PCI to increase their predictive value. In contrast to previous studies,26,27 we did not find a significant association between plasma B-type natriuretic peptide levels and angiographic no-reflow. However, there was a significant linear relation between B-type natriuretic peptide levels and IMR. Thus, B-type natriuretic peptide may identify those patients with MVO despite early angiographic success. This study was carried out in a relatively limited number of patients. However, we evaluated microvascular function not only by multiple standard measures but also by quantitative and objective indexes to test our hypothesis. Measurement of biomarkers only once in each participant and absence of markers of oxidative stress to support our hy-
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pothesis merit consideration. Circulating OPG may not fully reflect the activity of OPG at the tissue level. Finally, we did not measure the RANKL levels, but OPG may be a more reliable and stable marker of OPG–RANKL–RANK axis activity than RANKL and RANK.28 1. Niccoli G, Burzotta F, Galiuto L, Crea F. Myocardial no-reflow in humans. J Am Coll Cardiol 2009;54:281–292. 2. Fearon WF, Shah M, Ng M, Brinton T, Wilson A, Tremmel JA, Schnittger I, Lee DP, Vagelos RH, Fitzgerald PJ, Yock PG, Yeung AC. Predictive value of the index of microcirculatory resistance in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2008;51:560 –565. 3. Galiuto L, Garramone B, Scarà A, Rebuzzi AG, Crea F, La Torre G, Funaro S, Madonna M, Fedele F, Agati L; AMICI Investigators. The extent of microvascular damage during myocardial contrast echocardiography is superior to other known indexes of post-infarct reperfusion in predicting left ventricular remodeling: results of the multicenter AMICI study. J Am Coll Cardiol 2008;51:552–559. 4. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337–342. 5. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89:309 –319. 6. Jono S, Ikari Y, Shioi A, Mori K, Miki T, Hara K, Nishizawa Y. Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 2002;106:1192–1194. 7. Sandberg WJ, Yndestad A, Øie E, Smith C, Ueland T, Ovchinnikova O, Robertson AK, Müller F, Semb AG, Scholz H, Andreassen AK, Gullestad L, Damås JK, Frøland SS, Hansson GK, Halvorsen B, Aukrust P. Enhanced T-cell expression of RANK ligand in acute coronary syndrome: possible role in plaque destabilization. Arterioscler Thromb Vasc Biol 2006;26:857– 863. 8. Crisafulli A, Micari A, Altavilla D, Saporito F, Sardella A, Passaniti M, Raffa S, D’anneo G, Lucà F, Mioni C, Arrigo F, Squadrito F. Serum levels of osteoprotegerin and RANKL in patients with ST elevation acute myocardial infarction. Clin Sci (Lond) 2005;109:389 – 395. 9. Ueland T, Jemtland R, Godang K, Kjekshus J, Hognestad A, Omland T, Squire IB, Gullestad L, Bollerslev J, Dickstein K, Aukrust P. Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction. J Am Coll Cardiol 2004;44:1970 –1976. 10. Omland T, Ueland T, Jansson AM, Persson A, Karlsson T, Smith C, Herlitz J, Aukrust P, Hartford M, Caidahl K. Circulating osteoprotegerin levels and long-term prognosis in patients with acute coronary syndromes. J Am Coll Cardiol 2008;51:627– 633. 11. Secchiero P, Corallini F, Beltrami AP, Ceconi C, Bonasia V, Di Chiara A, Ferrari R, Zauli G. An imbalanced OPG/TRAIL ratio is associated to severe acute myocardial infarction. Atherosclerosis 2010;210:274 – 277. 12. Gibson CM, Murphy SA, Rizzo MJ, Ryan KA, Marble SJ, McCabe CH, Cannon CP, Van de Werf F, Braunwald E. The relationship between the TIMI frame count and clinical outcomes after thrombolytic administration. Circulation 1999;99:1945–1950. 13. van ’t Hof AWJ, Liem A, Suryapranata H, Hoorntje JC, de Boer MJ, Zijlstra F. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Circulation 1998;97:2302–2306. 14. Gottdiener JS, Bednarz J, Devereux R, Gardin J, Klein A, Manning WJ, Morehead A, Kitzman D, Oh J, Quinones M, Schiller NB, Stein JH, Weissman NJ. American Society of Echocardiography recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr 2004;17:1086 –1119. 15. Prasad A, Stone GW, Holmes DR, Gersh B. Reperfusion injury, microvascular dysfunction, and cardioprotection: the “dark side” of reperfusion. Circulation 2009;120:2105–2112. 16. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357:1121–1135.
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17. Bekkers SC, Yazdani SK, Virmani R, Waltenberger J. MVO: underlying pathophysiology and clinical diagnosis. J Am Coll Cardiol 2010; 55:1649 –1660. 18. Ambrosio G, Tritto I. Reperfusion injury: experimental evidence and clinical implications. Am Heart J 1999;138:69 –75. 19. Mangan SH, Campenhout AV, Rush C, Golledege J. Osteoprotegerin upregulates endothelial cell adhesion molecule response to tumour necrosis factor-a associated with induction of angiopoietin-2. Cardiovasc Res 2007;76:494 –505. 20. Zauli G, Corallini F, Bossi F, Fischetti F, Durigutto P, Celeghini C, Tedesco F, Secchiero P. Osteoprotegerin increases leukocyte adhesion to endothelial cells both in vitro and in vivo. Blood 2007;110:536 – 43. 21. McGeoch R, Watkins S, Berry C, Steedman T, Davie A, Byrne J, Hillis S, Lindsay M, Robb S, Dargie H, Oldroyd K. The index of microcirculatory resistance measured acutely predicts the extent and severity of myocardial infarction in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv 2010;3:715–722. 22. Lim HS, Yoon MH, Tahk SJ, Yang HM, Choi BJ, Choi SY, Sheen SS, Hwang GS, Kang SJ, Shin JH. Usefulness of the index of microcirculatory resistance for invasively assessing myocardial viability immediately after primary angioplasty for anterior myocardial infarction. Eur Heart J 2009;30:2854 –2860. 23. Aarnoudse W, Fearon WF, Manoharan G, Geven M, van de Vosse F, Rutten M, De Bruyne B, Pijls NH. Epicardial stenosis severity
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does not affect minimal microcirculatory resistance. Circulation 2004;110:2137–2142. Wu KC, Kim RJ, Bluemke DA, Rochitte CE, Zerhouni EA, Becker LC, Lima JA. Quantification and time course of MVO by contrastenhanced echocardiography and magnetic resonance imaging following acute myocardial infarction and reperfusion. J Am Coll Cardiol 1998;32:1756 –1764. Galiuto L, Gabrielli FA, Lombardo A, La Torre G, Scarà A, Rebuzzi AG, Crea F. Reversible microvascular dysfunction coupled with persistent myocardial dysfunction: implications for post-infarct left ventricular remodelling. Heart 2007;93:565–571. Grabowski M, Filipiak KJ, Karpinski G, Wretowski D, Rdzanek A, Huczek Z, Horszczaruk GJ, Kochman J, Rudowski R, Opolski G. Serum B-type natriuretic peptide levels on admission predict not only short-term death but also angiographic success of procedure in patients with acute ST-elevation myocardial infarction treated with primary angioplasty. Am Heart J 2004;148:655– 662. Jeong YH, Kim WJ, Park DW, Choi BR, Lee SW, Kim YH, Lee CW, Hong MK, Kim JJ, Park SW, Park SJ. Serum B-type natriuretic peptide on admission can predict the “no-reflow” phenomenon after primary drug-eluting stent implantation for ST-segment elevation myocardial infarction. Int J Cardiol 2010;141:175–181. Venuraju SM, Yerramasu A, Corder R, Lahiri A. Osteoprotegerin as a predictor of coronary artery disease and cardiovascular mortality and morbidity. J Am Coll Cardiol 2010;55:2049 –2061.
a Department of Cardiology, Kocaeli Derince Education and Research Hospital, Kocaeli; bDepartment of Cardiology, Kartal Kosuyolu Heart Education and Research Hospital, Istanbul, Turkey; and cBeth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Manuscript received September 5, 2010; revised manuscript received and accepted October 30, 2010. *Corresponding author: Tel: 90-505-7924640; fax: 90-262-2335540. E-mail address: [email protected] (A. Erkol).
0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.10.071
failure or is merely a marker of the severity of ventricular dysfunction has not been clearly defined. We hypothesized that circulating OPG levels on admission are associated with reperfusion injury and MVO after primary percutaneous coronary intervention (p-PCI). To test this hypothesis, we measured OPG in plasma samples and used standard methods and intracoronary hemodynamic measures to assess microvascular perfusion in patients who underwent p-PCI. Methods Forty-seven patients with their first acute ST-segment elevation MIs who were admitted to Kartal Kosuyolu Heart Education and Research Hospital and scheduled to undergo p-PCI ⬍12 hours after the onset of symptoms were prospectively enrolled. Inclusion criteria were (1) typical ongoing ischemic chest pain for ⬎30 minutes and (2) STsegment elevation ⱖ0.1 mV in ⱖ2 contiguous leads or new left bundle branch block on initial electrocardiograph. Exclusion criteria were cardiogenic shock and/or clinical instability, previous ST-segment elevation MI, malignant lifethreatening diseases, the presence of an additional lesion causing ⬎50% narrowing distal to the culprit lesion, peripheral arterial disease, aortic aneurysm, chronic inflammatory disease, and renal failure. Preinfarction angina pectoris was defined as cardiac symptoms for ⬍30 minutes that occurred ⬍2 days before infarct onset. All patients received chewable aspirin 300 mg and a loading dose of clopidogrel 600 mg on admission to the emergency room. Written informed consent was obtained www.ajconline.org
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Table 1 Baseline demographics and clinical characteristics Characteristic Main characteristics Age (years) Body mass index (kg/m2) Men Diabetes mellitus Hypertension* Hypercholesterolemia† Current smoker Preinfarction angina pectoris Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min) Anterior MI Killip class ⱖII Initial ST elevation (mm) Wall motion score index Left ventricular ejection fraction (%) Medications Aspirin Clopidogrel Enoxaparin  blockers Statins Angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers Intravenous tirofiban Intracoronary tirofiban Laboratory tests Peak troponin I (pg/ml) B-type natriuretic peptide (pg/ml) C-reactive protein (mg/dl) Hemoglobin (g/dl) Neutrophil count (⫻109/L) Platelet count (⫻109/L)
All Patients (n ⫽ 47)
OPG ⬍ Median (n ⫽ 24)
OPG ⬎ Median (n ⫽ 23)
p Value
56 ⫾ 7.7 27 ⫾ 4.4 42 (89%) 7 (15%) 13 (28%) 4 (8.5%) 35 (75%) 28 (60%) 131 ⫾ 26 81 ⫾ 18 77 ⫾ 16 29 (62%) 7 (15%) 11 ⫾ 8 1.29 ⫾ 0.17 54 ⫾ 7.8
55 ⫾ 6.4 27 ⫾ 5.3 22 (92%) 4 (17%) 6 (25%) 2 (8.3%) 19 (79%) 12 (52%) 132 ⫾ 24 83 ⫾ 18 80 ⫾ 18 16 (67%) 3 (13%) 13 ⫾ 8 1.3 ⫾ 0.18 53 ⫾ 7.5
57 ⫾ 8.8 26 ⫾ 3.5 20 (87%) 3 (13%) 7 (30%) 2 (8.7%) 16 (70%) 16 (70%) 130 ⫾ 28 80 ⫾ 19 74 ⫾ 14 13 (57%) 4 (17%) 10 ⫾ 7 1.28 ⫾ 0.16 54 ⫾ 8.2
0.28 0.59 0.67 1.00 0.75 1.00 0.52 0.24 0.75 0.56 0.19 0.56 0.70 0.21 0.61 0.56
47 (100%) 47 (100%) 47 (100%) 42 (89%) 43 (92%) 37 (79%)
24 (100%) 24 (100%) 24 (100%) 22 (92%) 23 (96%) 19 (79%)
23 (100%) 23 (100%) 23 (100%) 20 (87%) 20 (87%) 18 (78%)
1.00 1.00 1.00 0.67 0.35 1.00
47 (100%) 24 (51%)
24 (100%) 12 (50%)
23 (100%) 12 (52%)
1.00 1.00
67 ⫾ 53 85 ⫾ 94 0.6 ⫾ 0.5 14 ⫾ 1.5 8.1 ⫾ 2.5 261 ⫾ 60
69 ⫾ 50 79 ⫾ 78 0.5 ⫾ 0.3 14 ⫾ 1.3 8.2 ⫾ 2.4 253 ⫾ 53
65 ⫾ 57 92 ⫾ 109 0.7 ⫾ 0.6 14 ⫾ 1.8 8 ⫾ 2.6 270 ⫾ 67
0.82 0.64 0.32 0.66 0.74 0.35
Data are expressed as mean ⫾ SD or as number (percentage). * Systolic blood pressure ⬎140 mm Hg and/or diastolic blood pressure ⬎90 mm Hg or receiving antihypertensive treatment. † Total cholesterol ⬎200 mg/dl and/or low-density lipoprotein cholesterol ⬎130 mg/dl or receiving lipid-lowering therapy.
from all patients. The study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by our hospital ethics committee. All p-PCI procedures were performed by experienced interventional cardiologists through a femoral approach with a 7Fr guiding catheter. An intravenous bolus of unfractionated heparin at a dose of 70 U/kg body weight was administered. All patients received tirofiban as a glycoprotein IIb/IIIa inhibitor. Thrombus aspiration was recommended depending on relevant thrombus. In all patients, balloon predilatation was followed by stent implantation. Those patients with additional lesions causing ⬎50% narrowing distal to the culprit lesion were excluded after angiography. All patients were treated with maintenance doses of clopidogrel (75 mg/day for 12 months) and aspirin (300 mg for 30 days and then 100 mg indefinitely). Other guideline-based cardiac medications were administered at the maximum tolerated doses. Angiographic analysis included pre- and postprocedural Thrombolysis In Myocardial Infarction (TIMI) flow grade, corrected TIMI frame count,12 and myocardial blush grade.13 Visual assessments were performed offline by 2 blinded ob-
servers. Angiographic no-reflow was defined as TIMI flow grade ⬍ 3 or 3 with a myocardial blush grade of 0 or 1.1 All echocardiographic studies were performed and interpreted on the third day after MI by 2 experienced blinded sonographers. The left ventricular ejection fraction and wall motion score index were measured according to American Society of Echocardiography criteria.14 For OPG plasma level measurement, venous peripheral blood samples were drawn on admission, before the administration of any medication. Pyrogen-free blood collection tubes, with ethylenediaminetetraacetic acid as an anticoagulant, were centrifuged within 30 minutes (2,000 rpm for 10 minutes). Plasma was separated, aliquoted, and frozen at ⫺80°C until analysis. Plasma OPG was quantified in duplicate by using a commercially available in vitro enzyme-linked immunosorbent assay (RayBiotech, Norcross, Georgia) according to the manufacturer’s instructions. The intra-assay coefficient of variation was 4.1%. The lower limit of detection was 1 pg/ml. Plasma B-type natriuretic peptide (ADVIA Centaur Btype natriuretic peptide assay; Bayer Diagnostics, Tarry-
Coronary Artery Disease/Osteoprotegerin and No-Reflow After p-PCI
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Table 2 Angiographic characteristics and procedural results Characteristic Preprocedural characteristics Pain to balloon time (minutes) Culprit left anterior descending coronary artery Multivessel disease Baseline TIMI grade 0 or 1 Thrombus score 4 or 5 Number of stents Maximal inflation pressure (atm) Length of stent (mm) Use of thrombus aspirating device Minimal luminal diameter (mm) Mean residual stenosis (%) Side branch embolization Postprocedural results TIMI flow grade 2 3 Corrected TIMI frame count Myocardial blush grade 0 or 1 2 or 3 Angiographic no-reflow Second catheterization IMR ⬎30 U IMR (U) Coronary flow reserve
All Patients (n ⫽ 47)
OPG ⬍ Median (n ⫽ 24)
OPG ⬎ Median (n ⫽ 23)
p Value
201 ⫾ 98 28 (60%) 36 (77%) 47 (100%) 47 (100%) 1.23 ⫾ 0.47 16 (14–18) 25 (20–28) 6 (13%) 3 ⫾ 0.31 8.7 ⫾ 5.5 6 (13%)
200 ⫾ 94 15 (63%) 21 (88%) 24 (100%) 24 (100%) 1.16 ⫾ 0.38 16 (14–18) 22.5 (18–28) 3 (13%) 3 ⫾ 0.33 9.8 ⫾ 6.1 4 (17%)
202 ⫾ 105 13 (57%) 15 (65%) 23 (100%) 23 (100%) 1.3 ⫾ 0.56 16 (14–18) 25 (20–32) 3 (13%) 3.1 ⫾ 0.27 7.5 ⫾ 4.6 2 (8.7%)
0.92 0.77 0.09 1.00 1.00 0.40 0.31 0.47 1.00 0.24 0.20 0.67
6 (13%) 41 (87%) 23 ⫾ 9
1 (4%) 23 (96%) 20 ⫾ 5
5 (22%) 18 (78%) 25 ⫾ 11
16 (34%) 31 (66%) 17 (36%)
4 (17%) 20 (83%) 5 (21%)
12 (52%) 11 (48%) 12 (52%)
0.036
23 (49%) 31 ⫾ 14 2.1 ⫾ 0.7
7 (29%) 26 ⫾ 13 2.2 ⫾ 0.7
16 (70%) 36 ⫾ 14 1.9 ⫾ 0.6
0.009 0.013 0.18
0.09
0.04 0.01
Data are expressed as mean ⫾ SD, as median (interquartile range), or as number (percentage).
town, New York) and serum C-reactive protein (IMMAGE nephelometer; Beckman Coulter, Inc., Fullerton, California) levels were measured ⬍1 hour after blood collection. Other biochemical and hemographic parameters were determined by our routine laboratory methods. Four to 5 days after p-PCI, all patients underwent repeat cardiac catheterization. For hemodynamic measurements, a guidewire tipped with pressure and temperature sensors (PressureWire 5 Sensor; Radi Medical Systems, Uppsala, Sweden) was positioned distal to the stented segment of the infarct-related artery. Intravenous adenosine (140 g/kg/ min) was used as the hyperemic agent. The hemodynamic measurements were performed, as previously described,2 by an independent and blinded interventionalist different from the one who performed p-PCI. Thermodilution-derived coronary flow reserve was calculated as the mean transit time at rest divided by the mean transit time during hyperemia. The index of microcirculatory resistance (IMR) was calculated by dividing the mean distal coronary pressure by the inverse of mean hyperemic transit time (multiplication of distal coronary pressure and mean hyperemic transit time). The Kolmogorov-Smirnov test was used to test the normality of distribution of continuous variables. Continuous variables with normal and non-normal distributions are expressed as mean ⫾ SD and median (interquartile range), respectively. Categorical variables are expressed as numbers and percentages of patients. Group means for continuous variables with normal and non-normal distributions were compared using Student’s t tests and Mann-Whitney U tests, respectively. Categorical variables were compared using chi-square tests or
Fischer’s exact tests, as appropriate. Finally, a multiple linear regression analysis was conducted using the IMR as the dependent variable to assess the relation between the OPG levels and the degree of MVO. Results The study population consisted of 47 patients (89% men, mean age 56 ⫾ 7.7 years, range 39 to 73) with ST-segment elevation MI who underwent p-PCI. Blood samples were obtained ⬍30 minutes after admission, before the administration of any medication. The mean time from symptom onset to blood collection was 165 ⫾ 94 minutes. The mean plasma OPG level was 114 ⫾ 105 pg/ml, with a median value of 81 pg/ml. The baseline clinical characteristics of the subgroups of patients, with OPG levels higher and lower than the median, were comparable (Table 1). There was no significant correlation between OPG levels and baseline characteristics, except for weak correlations between OPG and age (r ⫽ 0.32 p ⫽ 0.027), B-type natriuretic peptide (r ⫽ 0.298, p ⫽ 0.04), and C-reactive protein (r ⫽ 0.38, p ⫽ 0.04). Angiographic characteristics and procedural results for the 2 groups were comparable (Table 2). Time from symptom onset to p-PCI was 201 ⫾ 98 minutes. P-PCI was successful in all patients. Each patient received ⱖ1 stent. Most patients achieved TIMI grade 3 flow (87%). The incidence of angiographic no-reflow was 36%. The incidence of myocardial blush grade 0 or 1 (52% vs 17%, p ⫽ 0.01) and angiographic no-reflow (52% vs 21%, p ⫽ 0.03) was higher in patients with OPG levels higher
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Figure 1. Comparison of plasma OPG levels according to angiographic no-reflow. The central line and the box represent the median and interquartile range, respectively, and the error bars extend from the 10th to the 90th percentile. Table 3 Multiple linear regression Variable Constant OPG B-type natriuretic peptide

t
p Value
19.396 0.412 0.409
7.486 3.482 3.456
0.000 0.001 0.001
r2 ⫽ 0.438.
than the median on admission. Accordingly, patients with angiographic no-reflow had higher levels of OPG compared to patients with normal reflow (161 ⫾ 117 vs 87 ⫾ 88 pg/ml, p ⫽ 0.019; Figure 1). The corrected TIMI frame count was significantly higher in patients with OPG levels greater than the median (25 ⫾ 11 vs 20 ⫾ 5, p ⫽ 0.04), and there was a significant linear correlation between OPG levels and corrected TIMI frame count (r ⫽ 0.53, p ⫽ 0.001). The mean IMR was 31 ⫾ 14 U. Compared to patients with OPG levels less than the median on admission, the IMR was higher (36 ⫾ 14 vs 26 ⫾ 13, p ⫽ 0.013), and there was a trend toward lower coronary flow reserve (1.9 ⫾ 0.6 vs 2.2 ⫾ 0.7, p ⫽ 0.18) in patients with OPG levels higher than the median on admission. On multiple linear regression analysis, OPG ( ⫽ 0.412, p ⫽ 0.001) and B-type natriuretic peptide ( ⫽ 0.409, p ⫽ 0.001) levels were independently and directly associated with IMR (r2 ⫽ 0.438; Table 3). Discussion This is the first study reporting an association between plasma levels of OPG on admission and the no-reflow
phenomenon after p-PCI. There was a significant linear relation between OPG levels on admission and the degree of MVO quantified by the IMR. Elevated OPG levels are associated with the presence and severity of coronary artery disease.6 Circulating OPG levels were found to be increased in patients with unstable angina7 and in those with ST-segment elevation MI.8 Ueland et al9 identified OPG as a novel predictive marker for cardiovascular mortality and clinical events in post-MI patients with heart failure. Subsequently, serum OPG levels were found to be strongly predictive of long-term mortality and heart failure hospitalizations in patients with acute coronary syndromes.10 Likewise, in a recent study, OPG/tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) ratios on admission were significantly higher in patients with acute MI in whom heart failure developed on follow-up.11 Despite the established link between the increased OPG levels and myocardial failure,9 –11 whether OPG plays an independent pathophysiologic role in the progression of heart failure or is merely a marker of the severity of ventricular dysfunction has not been clearly defined. Because of its pleiotropic effects on the immune system, we hypothesized that circulating OPG levels on admission are associated with reperfusion injury and MVO after p-PCI. We verified our hypothesis and demonstrated the relation of pre-p-PCI admission OPG levels to MVO. This may be a potential mechanism for the previously established link between elevated OPG levels on admission and the development of heart failure in post-MI patients. However, larger studies are warranted to clearly define the association between admission OPG levels and left ventricular remodeling.
Coronary Artery Disease/Osteoprotegerin and No-Reflow After p-PCI
Reperfusion injury, as well as distal atherothrombotic embolization, in situ thrombosis, and vasospasm, plays a significant role in the pathogenesis of no-reflow.15 Reperfusion markedly enhances the infiltration of coronary microcirculation by neutrophils and platelets.16 The essential initiating step, adhesion of neutrophils to the vascular endothelial cells, is followed by activation, diapedesis, and extravascular migration into surrounding myocytes.17 Besides causing microvascular plugs, these neutrophils release degradative enzymes and oxygen free radicals that can directly cause tissue and endothelial damage.18 Previous studies have shown that OPG increases the adhesion of neutrophils to the endothelial cells. Mangan et al19 demonstrated a linear increase in adhesion molecules when human umbilical vein endothelial cells were incubated with increasing concentrations of OPG and tumor necrosis factor–␣ in vitro. Likewise, Zauli et al20 demonstrated that OPG markedly and rapidly increases leukocyte-endothelial interactions in vitro and in vivo. Moreover, the greatest effect was observed at concentrations of OPG similar to the levels observed in patients with cardiovascular diseases. It could therefore be hypothesized that pre-PCI increased OPG levels might exacerbate reperfusion injury by increasing the initial leukocyte infiltration of the microcirculation. In addition to standard angiographic and electrocardiographic methods, we used guidewires tipped with pressure and temperature sensors to evaluate microvascular function and measured IMR. Cardiac magnetic resonance imaging is the reference method to identify and directly quantify MVO. We did not perform cardiac magnetic resonance imaging for the assessment of MVO. However, IMR has been proved to be a strong predictor of MVO after ST-segment elevation MI.2 Moreover, a recent study demonstrated that IMR was higher in patients with MVO on cardiac magnetic resonance imaging, and IMR independently predicted left ventricular function and infarct volume.21 The mean IMR in our study was 31 ⫾ 14 U, with a median value of 30 U, which is close to the median IMR value of 32 U2 and the optimal IMR cut-off value of 33 U22 found in previous studies to predict left ventricular remodeling. The mean IMR was 22 U in a previous study including patients with no obvious microvascular dysfunction.23 The extent of microvascular dysfunction changes, particularly within the first 48 hours after reperfusion, and stabilizes 2 days to 1 week after reperfusion.24,25 Therefore, we performed these measurements 4 to 5 days after p-PCI to increase their predictive value. In contrast to previous studies,26,27 we did not find a significant association between plasma B-type natriuretic peptide levels and angiographic no-reflow. However, there was a significant linear relation between B-type natriuretic peptide levels and IMR. Thus, B-type natriuretic peptide may identify those patients with MVO despite early angiographic success. This study was carried out in a relatively limited number of patients. However, we evaluated microvascular function not only by multiple standard measures but also by quantitative and objective indexes to test our hypothesis. Measurement of biomarkers only once in each participant and absence of markers of oxidative stress to support our hy-
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pothesis merit consideration. Circulating OPG may not fully reflect the activity of OPG at the tissue level. Finally, we did not measure the RANKL levels, but OPG may be a more reliable and stable marker of OPG–RANKL–RANK axis activity than RANKL and RANK.28 1. Niccoli G, Burzotta F, Galiuto L, Crea F. Myocardial no-reflow in humans. J Am Coll Cardiol 2009;54:281–292. 2. Fearon WF, Shah M, Ng M, Brinton T, Wilson A, Tremmel JA, Schnittger I, Lee DP, Vagelos RH, Fitzgerald PJ, Yock PG, Yeung AC. Predictive value of the index of microcirculatory resistance in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2008;51:560 –565. 3. Galiuto L, Garramone B, Scarà A, Rebuzzi AG, Crea F, La Torre G, Funaro S, Madonna M, Fedele F, Agati L; AMICI Investigators. The extent of microvascular damage during myocardial contrast echocardiography is superior to other known indexes of post-infarct reperfusion in predicting left ventricular remodeling: results of the multicenter AMICI study. J Am Coll Cardiol 2008;51:552–559. 4. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337–342. 5. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89:309 –319. 6. Jono S, Ikari Y, Shioi A, Mori K, Miki T, Hara K, Nishizawa Y. Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 2002;106:1192–1194. 7. Sandberg WJ, Yndestad A, Øie E, Smith C, Ueland T, Ovchinnikova O, Robertson AK, Müller F, Semb AG, Scholz H, Andreassen AK, Gullestad L, Damås JK, Frøland SS, Hansson GK, Halvorsen B, Aukrust P. Enhanced T-cell expression of RANK ligand in acute coronary syndrome: possible role in plaque destabilization. Arterioscler Thromb Vasc Biol 2006;26:857– 863. 8. Crisafulli A, Micari A, Altavilla D, Saporito F, Sardella A, Passaniti M, Raffa S, D’anneo G, Lucà F, Mioni C, Arrigo F, Squadrito F. Serum levels of osteoprotegerin and RANKL in patients with ST elevation acute myocardial infarction. Clin Sci (Lond) 2005;109:389 – 395. 9. Ueland T, Jemtland R, Godang K, Kjekshus J, Hognestad A, Omland T, Squire IB, Gullestad L, Bollerslev J, Dickstein K, Aukrust P. Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction. J Am Coll Cardiol 2004;44:1970 –1976. 10. Omland T, Ueland T, Jansson AM, Persson A, Karlsson T, Smith C, Herlitz J, Aukrust P, Hartford M, Caidahl K. Circulating osteoprotegerin levels and long-term prognosis in patients with acute coronary syndromes. J Am Coll Cardiol 2008;51:627– 633. 11. Secchiero P, Corallini F, Beltrami AP, Ceconi C, Bonasia V, Di Chiara A, Ferrari R, Zauli G. An imbalanced OPG/TRAIL ratio is associated to severe acute myocardial infarction. Atherosclerosis 2010;210:274 – 277. 12. Gibson CM, Murphy SA, Rizzo MJ, Ryan KA, Marble SJ, McCabe CH, Cannon CP, Van de Werf F, Braunwald E. The relationship between the TIMI frame count and clinical outcomes after thrombolytic administration. Circulation 1999;99:1945–1950. 13. van ’t Hof AWJ, Liem A, Suryapranata H, Hoorntje JC, de Boer MJ, Zijlstra F. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Circulation 1998;97:2302–2306. 14. Gottdiener JS, Bednarz J, Devereux R, Gardin J, Klein A, Manning WJ, Morehead A, Kitzman D, Oh J, Quinones M, Schiller NB, Stein JH, Weissman NJ. American Society of Echocardiography recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr 2004;17:1086 –1119. 15. Prasad A, Stone GW, Holmes DR, Gersh B. Reperfusion injury, microvascular dysfunction, and cardioprotection: the “dark side” of reperfusion. Circulation 2009;120:2105–2112. 16. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357:1121–1135.
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