Scandinavian Cardiovascular Journal, 2014; 48: 209–215
ORIGINAL ARTICLE
High osteoprotegerin levels predict MACCE in STEMI patients, but are not associated with myocardial salvage
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METTE BJERRE1, KIM MUNK2, ASTRID DRIVSHOLM SLOTH2, SØREN STEEN NIELSEN3, ALLAN FLYVBJERG1 & HANS ERIK BØTKER2 1The
Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus C, Denmark, 2Department of Cardiology, Aarhus University Hospital, Aarhus C, Denmark, and 3Department of Nuclear Medicine, Hospital of South West Jutland, Esbjerg, Denmark
Abstract Objectives. High circulating levels of osteoprotegerin (OPG) carry prognostic impact in cohorts with various cardiovascular diagnoses. With the present study, we aim to investigate the role of OPG within the scale of myocardial damage. Design. This study includes 219 consecutive patients with acute ST-elevation myocardial infarction randomized to primary percutaneous coronary intervention (pPCI) or pPCI and remote ischemic per-conditioning. Salvage index via myocardial single-photon emission CT assessment (data available in 61% of the patients) was performed, and derived from Day 1 (myocardial area at risk) and Day 30 (final infarct size). Plasma OPG levels were measured using an in-house immunoassay. A combined end-point of all-mortality, myocardial infarction, stroke, readmission for heart failure and ischemic stroke/ transient ischemic attack (Major Adverse Cardiac and Cerebrovascular Events [MACCE]) was used for follow-up; 45 (38–48 months). Results. High OPG levels were associated with the severity of cardiovascular disease. During follow-up, OPG was a predictor of MACCE (unadjusted, HR: 2.1, 95% CI: 1.14–3.85, P 0.017). Adjustments for age, gender, and body mass index preserved the independent predictive power of OPG. However, OPG levels were neither associated with salvage index nor with the final infarct size. Remote ischemic per-conditioning had no effect on OPG levels. Conclusion. Despite absent association between OPG levels and the scale of myocardial damage, high OPG levels predict a significantly increased risk of MACCE. Key words: myocardial salvage index, OPG, STEMI
Introduction Arterial calcification is part of the atherosclerotic process leading to clinical cardiovascular disease. Recognizing associations between bone pathology and cardiovascular disease, osteoprotegerin (OPG), a glycoprotein involved in the regulation of bone metabolism, have attracted attention as a possible mediator of vascular calcification (1). OPG is produced by vascular endothelial and smooth muscle cells and secreted into the circulation (2). Several prognostic associations involving circulating OPG levels have been reported, both regarding risk of cardiovascular disease and of the subsequent risk of death and complications amongst patients with such conditions (3). In addition, OPG concentrations are positively correlated with coronary calcification,
vascular stiffness, and the presence of unstable atherosclerotic plaques (4,5). Highly elevated OPG levels have been reported in patients with ST-segment elevation myocardial infarction (STEMI) (6–8), and OPG is found to be a strong predictor for long-term mortality in patients with acute coronary syndromes (9) compared to that of patients with stable or chronic heart disease (10) (Bjerre et al., unpublished) and healthy individuals (11,12). Recently, high levels of OPG in STEMI patients, measured in plasma obtained within the first 24 h after reperfusion with percutaneous coronary intervention (PCI), were associated with the risk of developing larger infarcts (13,14). We have previously demonstrated a significant increase of myocardial salvage in patients treated with remote ischemic
Correspondence: Mette Bjerre, PhD, The Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Nørrebrogade 44, Building 3b, DK-8000 Aarhus C, Denmark. Tel: 45-7846-2168. Fax: 45-7846-2150. E-mail: [email protected] (Received 6 January 2014 ; revised 18 April 2014 ; accepted 21 April 2014 ) ISSN 1401-7431 print/ISSN 1651-2006 online © 2014 Informa Healthcare DOI: 10.3109/14017431.2014.917767
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per-conditioning as an adjunct to primary PCI (15). Considering this, we wanted to investigate whether the role of OPG, as a marker for future cardiac events is simply related to larger infarcts. Thus, the aim of the present study was to elucidate a potential association between plasma OPG measured at admission in STEMI patients (with and without per-conditioning) and myocardial salvage assessed using single-photon emission CT (SPECT) imaging. Furthermore, we wanted to evaluate OPG in terms of risk of Major Adverse Cardiac and Cerebrovascular Events (MACCE) during a follow-up period of 45 months (IQR: 38–48 months).
Methods Design and subjects This study involves patients enrolled in the “remote ischemic conditioning in STEMI” trial; a single-center randomized controlled trial at Aarhus University Hospital, Aarhus, Denmark. A detailed description of randomization and the study protocol has been described previously (15). Briefly, a total of 333 patients were assessed for eligibility and randomly assigned to receive either standard primary percutaneous coronary intervention (pPCI) (control group, n 167), or pPCI and remote ischemic conditioning (intervention group, n 166). Remote ischemia was performed through intermittent arm ischemia by four cycles of upper limb ischemia applied, using a standard upperarm blood pressure cuff inflated to 200 mmHg for 5 min and then deflated for 5 min. On arrival, 41 patients were excluded because they did not meet the study inclusion criteria, of note patients with previous myocardial infarction were included in the present study (15). After inclusion, 22 patients withdrew informed consent Plasma samples were not available or the amount of plasma was insufficient for OPG analysis in 51 patients, thus a total of 219 patients were included for OPG analysis (control group, n 105, intervention group, n 114). In a total of 134 patients (controls n 64, intervention group n 70) salvage index was obtained via myocardial SPECT assessment (16) derived from Day 1 (area at risk) and Day 30 (final infarct size). Informed consent was obtained from all patients. Primary PCI Primary PCI was performed according to international guidelines using the transfemoral, or the transradial approach when femoral access was not achievable. Prior to the PCI procedure, patients received 300 mg oral or intravenous aspirin, 600 mg oral clopidogrel, and 10,000 IU of unfractionated
heparin intravenously. During the intervention, and continuing as infusion for 12 h after the procedure, patients received the GP IIb-IIIa antagonist abciximab unless contraindicated. Patients were prescribed lifelong 75 mg aspirin daily and 75 mg clopidogrel daily for 12 months. Follow-up and study end-points Immediately before the reperfusion procedure, patients received 700 MBq ( 10%) 99Technetium-sestamibi intravenously to quantify myocardial area at risk of infarction. Within 8 h after injection, SPECT was performed with a high-resolution parallel-hole collimator dual-headed rotating camera (ADAC Laboratories, Forte, Milpitas, CA, USA). Myocardial area at risk was determined by calculating the area of the left ventricle containing lower counts than the normal mean limit for pixels according to the MIBIMIBI rest database (17), as described previously (15). Imaging data were analysed independently by two experienced nuclear cardiology readers using the automatic program Quantitative Perfusion SPECT (Cedars-Sinai Medical Center, Los Angeles, CA, USA). At the Day30-follow-up-visit, an identical protocol was used to quantify the final infarct size, apart from the radionuclide being injected after 15-min bed rest, and the SPECT being performed 1 h after the injection (15). Myocardial salvage was calculated as area at risk—final infarct size, and the salvage index was calculated ⎛(area at risk − final infarct size)⎞ ⎜ ⎟, area at risk ⎝ ⎠ comprising the percentage of fraction of myocardium at risk being salvaged. A salvage index of 1 indicates maximum treatment success, whereas a salvage index of 0 indicates no benefit from the treatment. The Killip class (18) was scored at admission and the New York Heart Association (NYHA) class of disease was scored at Day 30. A combined end-point of MACCE (all-cause mortality, myocardial infarction [MI], readmission for heart failure, and ischemic stroke/transient ischemic attack) was evaluated during the follow-up 45 months (IQR: 38–48 months). Information on all-cause mortality was obtained (N 219) from the Danish Civil Registration System and information on readmissions was obtained from the Danish National Patient Registry and confirmed with medical record review as described previously (19). Measurement of plasma OPG Peripheral arterial blood was drawn from the femoral sheath at the beginning of the PCI procedure, thereby
OPG does not predict myocardial salvage avoiding contamination with contrast fluid. EDTA plasma was obtained after 10-min centrifugation at 4°C and stored at 80°C. Plasma OPG concentrations were quantified by an in-house Time-Resolved Immunofluorometric Assay for detection of OPG (12). The limit of detection was 15 ng/L and, the intra- and inter-assay variations were below 5 and 9%, respectively.
assumptions in the models were evaluated and fulfilled. In the statistical tests p-values 0.05 or lesser were considered of statistical significance. Stata/IC (11.0) was used for the statistical analyses. Results Baseline characteristics The mean log[OPG] SD was 3.49 0.24, corresponding to 3,065 ng/L in the entire cohort. No difference in OPG levels was observed between the intervention and control group (3,005 ng/L vs. 3,131 ng/L, P 0.59), thus the groups were combined for the subsequent analysis. The OPG levels were significantly higher in women than in men (3,917 ng/L vs. 2,850 ng/L, P 0.0004) and a significant increase in concentration was seen with older age (P 0.00001). Patients were divided into two groups according to the median OPG (2,977 ng/L). Patients with high OPG levels were older, included a larger proportion of women and had a lower body-mass index. No difference in the history of diseases was observed (Table I)
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Statistical analysis Data showing a non-Gaussian distribution was logtransformed, among others OPG. Proportions were compared using χ2-test, continuous Gaussian distributed variables with Student’s t-test, and non-Gaussian distributed variables with the Mann–Whitney test. We tested associations between log-OPG and other baseline variables using univariate logistic or linear regression. Kaplan–Meier curves of high and low OPG levels (divided by the median) were constructed and compared using the log-rank test. Hazard ratios were calculated using Cox proportional hazard regression analyses. The linearity and proportional hazards
Table I. Baseline characteristics in patients divided according to OPG median. Low OPG (n 109) Randomized to intervention Age (years) Gender (male %) Body-mass index (BMI) (kg/m2) History of: Diabetes Hypertension Hypercholesterolemia PCI AMI Current smoker Medication: Aspirin Clopidogrel Heparin β-blocker ACE-inhibitor Digoxin Symptom-to-balloon time (min) LAD infarct (%) Vessels with significant Disease: 0 1 2 3 LVEF day one LVEF day 30 Pre procedural TIMI flow grade: 0 I II III
59 (54%) 60.3 10.5 92 (85%) 27.2 4.4 8 37 19 6 14 62
High OPG (n 110) 55 (50%) 66.9 10.8 77 (70%) 25.3 3.8
(7%) (34%) (17%) (6%) (13%) (57%)
15 47 28 11 13 55
21(19%) 2 (2%) 1 (1%) 14 (13%) 11 (10%) 1 (1%) 193 (143–298) 39 (36%) 0 70 19 14 43.8 50.2 57 6 11 28
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(0%) (68%) (18%) (14%) (41.8–45.8) (48.6–51.7) (56%) (6%) (10%) (26%)
P-value 0.54 0.00001 0.01 0.001
(14%) (43%) (26%) (10%) (12%) (50%)
0.13 0.18 0.15 0.21 0.82 0.34
33 6 2 18 24 3 210 53
(30%) (6%) (2%) (17%) (22%) (3%) (139–372) (48%)
0.06 0.15 0.56 0.43 0.01 0.31 0.52 0.05 0.33
3 73 23 11 41.3 48.4
(3%) (66%) (21%) (10%) (39.1–43.5) (46.1–50.7)
51 13 13 29
0.11 0.18 0.39
(48%) (12%) (12%) (27%)
The p-value is indicated as overalls vessels disease: P = 0.33. Data are presented as mean SD, number (%), or median (IQR). LAD, left anterior descending artery; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; AMI, acute myocardial infarct; TIMI, thrombolysis in myocardial infarction.
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OPG levels do not predict infarct size or myocardial salvage
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No significant correlation was found between OPG levels and area at risk, final infarct size, myocardial salvage, or salvage index (Figure 1). In contrast, we found that patients with high OPG levels had significantly larger area at risk (Table II). However, no differences in final infarct size, myocardial salvage or salvage index between groups with high or low OPG levels were seen. No gender difference was found when analysing area at risk, final infarct size, myocardial salvage, and salvage index. High OPG levels are associated with severity of cardiovascular disease The stage of heart failure was determined according to NYHA functional classification and 33% of the patients were classified as having slight or marked limitation of physical activity (NYHA class II or III). These patients had significantly higher OPG levels compared to patients without heart failure symptoms (NYHA class I; 3,281 ng/L vs. 2,734 ng/L, P 0.047). High OPG levels were also associated with disease severity (Killip Class 1 vs. 2; 2,969 ng/L vs. 4,011 ng/L, P 0.04). In addition, 6.9% of the patients with high OPG suffered from MACCE during the first 30-day-follow-up compared to only 1% of the patients with low OPG (P 0.03). Also, Left anterior descending artery infarcts were more
frequent in the group of patients with high OPG levels (P 0.05). However, the number of diseased vessels did not differ between groups of low and high OPG levels (Table I). Follow-up and survival analysis During a median follow-up time of 45 months (IQR: 38–48 months), 47 (21%) patients reached the combined endpoint of MACCE (death [n 13], MI [n 17], readmission for heart failure [n 9], and ischemic stroke/transient ischemic attack [n 8]). Log-rank test based on the Kaplan–Meier curves showed a significant association between high OPG and risk of poor outcome (Figure 2). This association was confirmed using the univariate Cox-analysis (HR: 2.1, 95% CI: 1.14–3.85, P 0.017). Importantly, OPG remained an independent predictor of MACCE after adjustment for age, gender, and bodymass index (HR: 2.0, 95% CI: 1.03–3.89, P 0.039); however, after adjustment for final infarct size and salvage index the association was attenuated (HR: 1.42, 95% CI: 0.69–2.95, P 0.34) or (HR: 1.94 95% CI: 0.87–4.33, P 0.11).
Discussion This study strongly suggests that increased circulating OPG levels are not directly involved in the myocardial damage after STEMI. Although we did not
Figure 1. Correlations between log OPG and area at risk, final infarct size, salvage, and salvage index. Hollow circles represent each patient and the fitted line is shown in black.
OPG does not predict myocardial salvage
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Table II. Size of myocardial area at risk, final infarct size, and derived salvage and salvage index according to OPG levels divided by median. Low OPG Patients (n) Salvage index Area at risk (% of left ventricle) Salvage (% of left ventricle) Final infarct size (% of left ventricle)
70 77 71 97
High OPG
Median (IQR) 0.65 24% 12% 6%
(0.42–0.89) (13–35) (5–23) (2–16)
Patients (n)
Median (IQR)
P-value
64 73 64 90
0.63 (0.39–0.92) 34% (24–43) 18% (11–26) 10% (12–23)
0.95 0.004 0.06 0.36
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Salvage: area at risk final infarct size. Salvage index: [(salvage)/area at risk].
observe an association between OPG levels and the final infarct size or the myocardial salvage index, patients with high values of OPG had an impaired outcome. The severity of the disease was enhanced in patients with increased OPG levels. Patients with increased OPG levels had larger area at risk, but this association disappeared after adjustment for age. As previously reported, pPCI and remote ischemic perconditioning as an adjunct treatment to pPCI resulted in increased myocardial salvage (15). Of note, no difference in OPG levels was found between the control and intervention group. Our results support the emerging evidence that OPG participates in the pathogenesis of vascular disease. Opposed to previous studies, this may indicate that OPG levels reflect otherwise adverse circumstances not directly related to the myocardial damage. However, a number of MACCEs were present in the group of patients without these evaluations. Consequently, the association between OPG and MACCE was attenuated, most likely due to lack of power, after adjustments for final infarct size and salvage index, even in the absence of a statistical association between OPG and either of them (Table II).
Figure 2. Unadjusted Kaplan–Meier plot for the combined endpoint MACCE (all-cause mortality, myocardial infarction, readmission for heart failure, and ischemic stroke/transient ischemic attack) according to OPG levels. The solid line represents low OPG levels (below median), and the dashed line represents high OPG levels (above median).
In contrast, an association between impaired myocardial salvage assessed by cardiac magnetic resonance imaging and high OPG levels ( 75th percentile) in STEMI patients was recently reported (13). Of note, the salvage index was markedly lower, as compared to our study, indicating that the patients had less benefit of treatment or larger infarcts. Similarly, in a group of STEMI-patients treated with PCI, high baseline OPG levels (reported as above 1,400 ng/L) were strongly associated with larger final infarct size, assessed by SPECT imaging, after 3 months of follow-up (14). These results contrast our findings, and in both studies the OPG levels are markedly lower compared with our present and previous findings (6). Salvage of threatened myocardium is the principal mechanism by which patients with AMI benefit from reperfusion. Quantification of myocardial salvage index rather than final infarct size eliminates the inter-individual variation (20). There is conflicting evidence about the impact of gender in myocardial salvage after STEMI (21,22). In our study we found no gender-based difference in salvage, area at risk or final infarct size. However, we did find significantly higher OPG levels in women compared with men. OPG is produced by a variety of tissues, including the vascular system, smooth muscle cells and endothelial cells (23), and high expression of OPG was found in inflammatory cells present in atherosclerotic plaques (24). Furthermore, OPG contributes to endothelial dysfunction (23). Notably, OPG acts as a decoy receptor competitively inhibiting RANK ligand and thus OPG is expected to counteract calcification. High OPG levels may thus be expected to prevent cardiovascular events. However, the precise mechanisms are still unknown. Increase in OPG concentration may be a response to, rather than a cause of, atherosclerosis or vascular calcification, perhaps representing an attempt to regulate the processes. Increased OPG levels are found in patients with diabetes and in patients who die (25,26). Thus, the OPG levels may just reflect extensive cardiovascular disease.
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Limitations Final infarct size and myocardial salvage index using myocardial SPECT assessment was only obtained in 85 and 61% of the patients, respectively, either due to withdrawal of informed consent, patients lost from dying, or to coronary artery bypass grafting rendering SPECT imaging impossible. Blood samples were only obtained at baseline prior to primary PCI.
7.
8.
9.
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Conclusion Despite absent association between OPG levels and the scale of myocardial damage, patients with high values of OPG had significantly increased risk of MACCE. This indicates that high OPG levels as a marker of future events may reflect something else critical than simply larger infarcts. Increase in the OPG concentration may be representing an attempt to regulate the processes or a marker of disease severity.
Acknowledgments From the Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University we would like to thank Lisa Buus, for invaluable technical assistance and Karin Ø. Kristensen for linguistic guidance.
10.
11.
12.
13.
14.
Declaration of interest: The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
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References
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1. Reid P, Holen I. Pathophysiological roles of osteoprotegerin (OPG). Eur J Cell Biol. 2009;88:1–17. 2. Hofbauer LC, Shui C, Riggs BL, Dunstan CR, Spelsberg TC, O’Brien T, Khosla S. Effects of immunosuppressants on receptor activator of NF-kappaB ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells. Biochem Biophys Res Commun. 2001;280:334–9. 3. Montagnana M, Lippi G, Danese E, Guidi GC. The role of osteoprotegerin in cardiovascular disease. Ann Med. 2013;45:254–64. 4. Nybo M, Rasmussen LM. The capability of plasma osteoprotegerin as a predictor of cardiovascular disease: a systematic literature review. Eur J Endocrinol. 2008; 159:603–8. 5. Montecucco F, Steffens S, Mach F. The immune response is involved in atherosclerotic plaque calcification: could the RANKL/RANK/OPG system be a marker of plaque instability? Clin Dev Immunol. 2007;2007:75805. 6. Pedersen S, Mogelvang R, Bjerre M, Frystyk J, Flyvbjerg A, Galatius S, et al. Osteoprotegerin predicts long-term outcome
17.
18.
19.
20. 21.
in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Cardiology. 2012;123:31–8. Crisafulli A, Micari A, Altavilla D, Saporito F, Sardella A, Passaniti M, et al. Serum levels of osteoprotegerin and RANKL in patients with ST elevation acute myocardial infarction. Clin Sci (Lond). 2005;109:389–95. Canga A, Durakoglugil ME, Erdogan T, Kirbas A, Yilmaz A, Cicek Y, et al. Elevated serum osteoprotegerin levels predict in-hospital major adverse cardiac events in patients with ST elevation myocardial infarction. J Cardiol. 2012; 60:355–60. Omland T, Ueland T, Jansson AM, Persson A, Karlsson T, Smith C, et al. Circulating osteoprotegerin levels and longterm prognosis in patients with acute coronary syndromes. J Am Coll Cardiol. 2008;51:627–33. Roysland R, Bonaca MP, Omland T, Sabatine M, Murphy SA, Scirica BM, et al. Osteoprotegerin and cardiovascular mortality in patients with non-ST elevation acute coronary syndromes. Heart. 2012;98:786–91. Vik A, Mathiesen EB, Brox J, Wilsgaard T, Njolstad I, Jorgensen L, Hansen JB. Serum osteoprotegerin is a predictor for incident cardiovascular disease and mortality in a general population: the Tromso Study. J Thromb Haemost. 2011;9:638–44. Mogelvang R, Haahr-Pedersen S, Bjerre M, Frystyk J, Iversen A, Galatius S, et al. Osteoprotegerin improves risk detection by traditional cardiovascular risk factors and hsCRP. Heart. 2013;99:106–10. Fuernau G, Zaehringer S, Eitel I, de Waha S, Droppa M, Desch S, et al. Osteoprotegerin in ST-elevation myocardial infarction: prognostic impact and association with markers of myocardial damage by magnetic resonance imaging. Int J Cardiol. 2013;167:2134–9. Andersen GO, Knudsen EC, Aukrust P, Yndestad A, Oie E, Muller C, et al. Elevated serum osteoprotegerin levels measured early after acute ST-elevation myocardial infarction predict final infarct size. Heart. 2011;97:460–5. Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010;375:727–34. Ndrepepa G, Mehilli J, Schwaiger M, Schuhlen H, Nekolla S, Martinoff S, et al. Prognostic value of myocardial salvage achieved by reperfusion therapy in patients with acute myocardial infarction. J Nucl Med. 2004;45:725–9. Kaltoft A, Nielsen SS, Terkelsen CJ, Bottcher M, Lassen JF, Krusell LR, et al. Scintigraphic evaluation of routine filterwire distal protection in percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: a randomized controlled trial. J Nucl Cardiol. 2009;16:784–91. Killip T III, Kimball JT. Treatment of myocardial infarction in a coronary care unit. A two year experience with 250 patients. Am J Cardiol. 1967;20:457–64. Sloth AD, Schmidt MR, Munk K, Kharbanda RK, Redington AN, Schmidt M, et al. Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J. 2014;35:168–75. Botker HE, Kaltoft AK, Pedersen SF, Kim WY. Measuring myocardial salvage. Cardiovasc Res. 2012;94:266–75. Eitel I, Desch S, de Waha S, Fuernau G, Gutberlet M, Schuler G, Thiele H. Sex differences in myocardial salvage
OPG does not predict myocardial salvage
Scand Cardiovasc J Downloaded from informahealthcare.com by Kainan University on 04/28/15 For personal use only.
and clinical outcome in patients with acute reperfused STelevation myocardial infarction: advances in cardiovascular imaging. Circ Cardiovasc Imaging. 2012;5:119–26. 22. Canali E, Masci P, Bogaert J, Bucciarelli Ducci C, Francone M, McAlindon E, et al. Impact of gender differences on myocardial salvage and post-ischaemic left ventricular remodelling after primary coronary angioplasty: new insights from cardiovascular magnetic resonance. Eur Heart J Cardiovasc Imaging. 2012;13:948–53. 23. Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res. 2004;95:1046–57.
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24. Vik A, Mathiesen EB, Noto AT, Sveinbjornsson B, Brox J, Hansen JB. Serum osteoprotegerin is inversely associated with carotid plaque echogenicity in humans. Atherosclerosis. 2007;191:128–34. 25. Jorsal A, Tarnow L, Flyvbjerg A, Parving HH, Rossing P, Rasmussen LM. Plasma osteoprotegerin levels predict cardiovascular and all-cause mortality and deterioration of kidney function in type 1 diabetic patients with nephropathy. Diabetologia. 2008;51:2100–7. 26. Reinhard H, Lajer M, Gall MA, Tarnow L, Parving HH, Rasmussen LM, et al. Osteoprotegerin and mortality in type 2 diabetic patients. Diabetes Care. 2010;33:2561–6.
ORIGINAL ARTICLE
High osteoprotegerin levels predict MACCE in STEMI patients, but are not associated with myocardial salvage
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METTE BJERRE1, KIM MUNK2, ASTRID DRIVSHOLM SLOTH2, SØREN STEEN NIELSEN3, ALLAN FLYVBJERG1 & HANS ERIK BØTKER2 1The
Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus C, Denmark, 2Department of Cardiology, Aarhus University Hospital, Aarhus C, Denmark, and 3Department of Nuclear Medicine, Hospital of South West Jutland, Esbjerg, Denmark
Abstract Objectives. High circulating levels of osteoprotegerin (OPG) carry prognostic impact in cohorts with various cardiovascular diagnoses. With the present study, we aim to investigate the role of OPG within the scale of myocardial damage. Design. This study includes 219 consecutive patients with acute ST-elevation myocardial infarction randomized to primary percutaneous coronary intervention (pPCI) or pPCI and remote ischemic per-conditioning. Salvage index via myocardial single-photon emission CT assessment (data available in 61% of the patients) was performed, and derived from Day 1 (myocardial area at risk) and Day 30 (final infarct size). Plasma OPG levels were measured using an in-house immunoassay. A combined end-point of all-mortality, myocardial infarction, stroke, readmission for heart failure and ischemic stroke/ transient ischemic attack (Major Adverse Cardiac and Cerebrovascular Events [MACCE]) was used for follow-up; 45 (38–48 months). Results. High OPG levels were associated with the severity of cardiovascular disease. During follow-up, OPG was a predictor of MACCE (unadjusted, HR: 2.1, 95% CI: 1.14–3.85, P 0.017). Adjustments for age, gender, and body mass index preserved the independent predictive power of OPG. However, OPG levels were neither associated with salvage index nor with the final infarct size. Remote ischemic per-conditioning had no effect on OPG levels. Conclusion. Despite absent association between OPG levels and the scale of myocardial damage, high OPG levels predict a significantly increased risk of MACCE. Key words: myocardial salvage index, OPG, STEMI
Introduction Arterial calcification is part of the atherosclerotic process leading to clinical cardiovascular disease. Recognizing associations between bone pathology and cardiovascular disease, osteoprotegerin (OPG), a glycoprotein involved in the regulation of bone metabolism, have attracted attention as a possible mediator of vascular calcification (1). OPG is produced by vascular endothelial and smooth muscle cells and secreted into the circulation (2). Several prognostic associations involving circulating OPG levels have been reported, both regarding risk of cardiovascular disease and of the subsequent risk of death and complications amongst patients with such conditions (3). In addition, OPG concentrations are positively correlated with coronary calcification,
vascular stiffness, and the presence of unstable atherosclerotic plaques (4,5). Highly elevated OPG levels have been reported in patients with ST-segment elevation myocardial infarction (STEMI) (6–8), and OPG is found to be a strong predictor for long-term mortality in patients with acute coronary syndromes (9) compared to that of patients with stable or chronic heart disease (10) (Bjerre et al., unpublished) and healthy individuals (11,12). Recently, high levels of OPG in STEMI patients, measured in plasma obtained within the first 24 h after reperfusion with percutaneous coronary intervention (PCI), were associated with the risk of developing larger infarcts (13,14). We have previously demonstrated a significant increase of myocardial salvage in patients treated with remote ischemic
Correspondence: Mette Bjerre, PhD, The Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Nørrebrogade 44, Building 3b, DK-8000 Aarhus C, Denmark. Tel: 45-7846-2168. Fax: 45-7846-2150. E-mail: [email protected] (Received 6 January 2014 ; revised 18 April 2014 ; accepted 21 April 2014 ) ISSN 1401-7431 print/ISSN 1651-2006 online © 2014 Informa Healthcare DOI: 10.3109/14017431.2014.917767
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per-conditioning as an adjunct to primary PCI (15). Considering this, we wanted to investigate whether the role of OPG, as a marker for future cardiac events is simply related to larger infarcts. Thus, the aim of the present study was to elucidate a potential association between plasma OPG measured at admission in STEMI patients (with and without per-conditioning) and myocardial salvage assessed using single-photon emission CT (SPECT) imaging. Furthermore, we wanted to evaluate OPG in terms of risk of Major Adverse Cardiac and Cerebrovascular Events (MACCE) during a follow-up period of 45 months (IQR: 38–48 months).
Methods Design and subjects This study involves patients enrolled in the “remote ischemic conditioning in STEMI” trial; a single-center randomized controlled trial at Aarhus University Hospital, Aarhus, Denmark. A detailed description of randomization and the study protocol has been described previously (15). Briefly, a total of 333 patients were assessed for eligibility and randomly assigned to receive either standard primary percutaneous coronary intervention (pPCI) (control group, n 167), or pPCI and remote ischemic conditioning (intervention group, n 166). Remote ischemia was performed through intermittent arm ischemia by four cycles of upper limb ischemia applied, using a standard upperarm blood pressure cuff inflated to 200 mmHg for 5 min and then deflated for 5 min. On arrival, 41 patients were excluded because they did not meet the study inclusion criteria, of note patients with previous myocardial infarction were included in the present study (15). After inclusion, 22 patients withdrew informed consent Plasma samples were not available or the amount of plasma was insufficient for OPG analysis in 51 patients, thus a total of 219 patients were included for OPG analysis (control group, n 105, intervention group, n 114). In a total of 134 patients (controls n 64, intervention group n 70) salvage index was obtained via myocardial SPECT assessment (16) derived from Day 1 (area at risk) and Day 30 (final infarct size). Informed consent was obtained from all patients. Primary PCI Primary PCI was performed according to international guidelines using the transfemoral, or the transradial approach when femoral access was not achievable. Prior to the PCI procedure, patients received 300 mg oral or intravenous aspirin, 600 mg oral clopidogrel, and 10,000 IU of unfractionated
heparin intravenously. During the intervention, and continuing as infusion for 12 h after the procedure, patients received the GP IIb-IIIa antagonist abciximab unless contraindicated. Patients were prescribed lifelong 75 mg aspirin daily and 75 mg clopidogrel daily for 12 months. Follow-up and study end-points Immediately before the reperfusion procedure, patients received 700 MBq ( 10%) 99Technetium-sestamibi intravenously to quantify myocardial area at risk of infarction. Within 8 h after injection, SPECT was performed with a high-resolution parallel-hole collimator dual-headed rotating camera (ADAC Laboratories, Forte, Milpitas, CA, USA). Myocardial area at risk was determined by calculating the area of the left ventricle containing lower counts than the normal mean limit for pixels according to the MIBIMIBI rest database (17), as described previously (15). Imaging data were analysed independently by two experienced nuclear cardiology readers using the automatic program Quantitative Perfusion SPECT (Cedars-Sinai Medical Center, Los Angeles, CA, USA). At the Day30-follow-up-visit, an identical protocol was used to quantify the final infarct size, apart from the radionuclide being injected after 15-min bed rest, and the SPECT being performed 1 h after the injection (15). Myocardial salvage was calculated as area at risk—final infarct size, and the salvage index was calculated ⎛(area at risk − final infarct size)⎞ ⎜ ⎟, area at risk ⎝ ⎠ comprising the percentage of fraction of myocardium at risk being salvaged. A salvage index of 1 indicates maximum treatment success, whereas a salvage index of 0 indicates no benefit from the treatment. The Killip class (18) was scored at admission and the New York Heart Association (NYHA) class of disease was scored at Day 30. A combined end-point of MACCE (all-cause mortality, myocardial infarction [MI], readmission for heart failure, and ischemic stroke/transient ischemic attack) was evaluated during the follow-up 45 months (IQR: 38–48 months). Information on all-cause mortality was obtained (N 219) from the Danish Civil Registration System and information on readmissions was obtained from the Danish National Patient Registry and confirmed with medical record review as described previously (19). Measurement of plasma OPG Peripheral arterial blood was drawn from the femoral sheath at the beginning of the PCI procedure, thereby
OPG does not predict myocardial salvage avoiding contamination with contrast fluid. EDTA plasma was obtained after 10-min centrifugation at 4°C and stored at 80°C. Plasma OPG concentrations were quantified by an in-house Time-Resolved Immunofluorometric Assay for detection of OPG (12). The limit of detection was 15 ng/L and, the intra- and inter-assay variations were below 5 and 9%, respectively.
assumptions in the models were evaluated and fulfilled. In the statistical tests p-values 0.05 or lesser were considered of statistical significance. Stata/IC (11.0) was used for the statistical analyses. Results Baseline characteristics The mean log[OPG] SD was 3.49 0.24, corresponding to 3,065 ng/L in the entire cohort. No difference in OPG levels was observed between the intervention and control group (3,005 ng/L vs. 3,131 ng/L, P 0.59), thus the groups were combined for the subsequent analysis. The OPG levels were significantly higher in women than in men (3,917 ng/L vs. 2,850 ng/L, P 0.0004) and a significant increase in concentration was seen with older age (P 0.00001). Patients were divided into two groups according to the median OPG (2,977 ng/L). Patients with high OPG levels were older, included a larger proportion of women and had a lower body-mass index. No difference in the history of diseases was observed (Table I)
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Statistical analysis Data showing a non-Gaussian distribution was logtransformed, among others OPG. Proportions were compared using χ2-test, continuous Gaussian distributed variables with Student’s t-test, and non-Gaussian distributed variables with the Mann–Whitney test. We tested associations between log-OPG and other baseline variables using univariate logistic or linear regression. Kaplan–Meier curves of high and low OPG levels (divided by the median) were constructed and compared using the log-rank test. Hazard ratios were calculated using Cox proportional hazard regression analyses. The linearity and proportional hazards
Table I. Baseline characteristics in patients divided according to OPG median. Low OPG (n 109) Randomized to intervention Age (years) Gender (male %) Body-mass index (BMI) (kg/m2) History of: Diabetes Hypertension Hypercholesterolemia PCI AMI Current smoker Medication: Aspirin Clopidogrel Heparin β-blocker ACE-inhibitor Digoxin Symptom-to-balloon time (min) LAD infarct (%) Vessels with significant Disease: 0 1 2 3 LVEF day one LVEF day 30 Pre procedural TIMI flow grade: 0 I II III
59 (54%) 60.3 10.5 92 (85%) 27.2 4.4 8 37 19 6 14 62
High OPG (n 110) 55 (50%) 66.9 10.8 77 (70%) 25.3 3.8
(7%) (34%) (17%) (6%) (13%) (57%)
15 47 28 11 13 55
21(19%) 2 (2%) 1 (1%) 14 (13%) 11 (10%) 1 (1%) 193 (143–298) 39 (36%) 0 70 19 14 43.8 50.2 57 6 11 28
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(0%) (68%) (18%) (14%) (41.8–45.8) (48.6–51.7) (56%) (6%) (10%) (26%)
P-value 0.54 0.00001 0.01 0.001
(14%) (43%) (26%) (10%) (12%) (50%)
0.13 0.18 0.15 0.21 0.82 0.34
33 6 2 18 24 3 210 53
(30%) (6%) (2%) (17%) (22%) (3%) (139–372) (48%)
0.06 0.15 0.56 0.43 0.01 0.31 0.52 0.05 0.33
3 73 23 11 41.3 48.4
(3%) (66%) (21%) (10%) (39.1–43.5) (46.1–50.7)
51 13 13 29
0.11 0.18 0.39
(48%) (12%) (12%) (27%)
The p-value is indicated as overalls vessels disease: P = 0.33. Data are presented as mean SD, number (%), or median (IQR). LAD, left anterior descending artery; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; AMI, acute myocardial infarct; TIMI, thrombolysis in myocardial infarction.
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OPG levels do not predict infarct size or myocardial salvage
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No significant correlation was found between OPG levels and area at risk, final infarct size, myocardial salvage, or salvage index (Figure 1). In contrast, we found that patients with high OPG levels had significantly larger area at risk (Table II). However, no differences in final infarct size, myocardial salvage or salvage index between groups with high or low OPG levels were seen. No gender difference was found when analysing area at risk, final infarct size, myocardial salvage, and salvage index. High OPG levels are associated with severity of cardiovascular disease The stage of heart failure was determined according to NYHA functional classification and 33% of the patients were classified as having slight or marked limitation of physical activity (NYHA class II or III). These patients had significantly higher OPG levels compared to patients without heart failure symptoms (NYHA class I; 3,281 ng/L vs. 2,734 ng/L, P 0.047). High OPG levels were also associated with disease severity (Killip Class 1 vs. 2; 2,969 ng/L vs. 4,011 ng/L, P 0.04). In addition, 6.9% of the patients with high OPG suffered from MACCE during the first 30-day-follow-up compared to only 1% of the patients with low OPG (P 0.03). Also, Left anterior descending artery infarcts were more
frequent in the group of patients with high OPG levels (P 0.05). However, the number of diseased vessels did not differ between groups of low and high OPG levels (Table I). Follow-up and survival analysis During a median follow-up time of 45 months (IQR: 38–48 months), 47 (21%) patients reached the combined endpoint of MACCE (death [n 13], MI [n 17], readmission for heart failure [n 9], and ischemic stroke/transient ischemic attack [n 8]). Log-rank test based on the Kaplan–Meier curves showed a significant association between high OPG and risk of poor outcome (Figure 2). This association was confirmed using the univariate Cox-analysis (HR: 2.1, 95% CI: 1.14–3.85, P 0.017). Importantly, OPG remained an independent predictor of MACCE after adjustment for age, gender, and bodymass index (HR: 2.0, 95% CI: 1.03–3.89, P 0.039); however, after adjustment for final infarct size and salvage index the association was attenuated (HR: 1.42, 95% CI: 0.69–2.95, P 0.34) or (HR: 1.94 95% CI: 0.87–4.33, P 0.11).
Discussion This study strongly suggests that increased circulating OPG levels are not directly involved in the myocardial damage after STEMI. Although we did not
Figure 1. Correlations between log OPG and area at risk, final infarct size, salvage, and salvage index. Hollow circles represent each patient and the fitted line is shown in black.
OPG does not predict myocardial salvage
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Table II. Size of myocardial area at risk, final infarct size, and derived salvage and salvage index according to OPG levels divided by median. Low OPG Patients (n) Salvage index Area at risk (% of left ventricle) Salvage (% of left ventricle) Final infarct size (% of left ventricle)
70 77 71 97
High OPG
Median (IQR) 0.65 24% 12% 6%
(0.42–0.89) (13–35) (5–23) (2–16)
Patients (n)
Median (IQR)
P-value
64 73 64 90
0.63 (0.39–0.92) 34% (24–43) 18% (11–26) 10% (12–23)
0.95 0.004 0.06 0.36
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Salvage: area at risk final infarct size. Salvage index: [(salvage)/area at risk].
observe an association between OPG levels and the final infarct size or the myocardial salvage index, patients with high values of OPG had an impaired outcome. The severity of the disease was enhanced in patients with increased OPG levels. Patients with increased OPG levels had larger area at risk, but this association disappeared after adjustment for age. As previously reported, pPCI and remote ischemic perconditioning as an adjunct treatment to pPCI resulted in increased myocardial salvage (15). Of note, no difference in OPG levels was found between the control and intervention group. Our results support the emerging evidence that OPG participates in the pathogenesis of vascular disease. Opposed to previous studies, this may indicate that OPG levels reflect otherwise adverse circumstances not directly related to the myocardial damage. However, a number of MACCEs were present in the group of patients without these evaluations. Consequently, the association between OPG and MACCE was attenuated, most likely due to lack of power, after adjustments for final infarct size and salvage index, even in the absence of a statistical association between OPG and either of them (Table II).
Figure 2. Unadjusted Kaplan–Meier plot for the combined endpoint MACCE (all-cause mortality, myocardial infarction, readmission for heart failure, and ischemic stroke/transient ischemic attack) according to OPG levels. The solid line represents low OPG levels (below median), and the dashed line represents high OPG levels (above median).
In contrast, an association between impaired myocardial salvage assessed by cardiac magnetic resonance imaging and high OPG levels ( 75th percentile) in STEMI patients was recently reported (13). Of note, the salvage index was markedly lower, as compared to our study, indicating that the patients had less benefit of treatment or larger infarcts. Similarly, in a group of STEMI-patients treated with PCI, high baseline OPG levels (reported as above 1,400 ng/L) were strongly associated with larger final infarct size, assessed by SPECT imaging, after 3 months of follow-up (14). These results contrast our findings, and in both studies the OPG levels are markedly lower compared with our present and previous findings (6). Salvage of threatened myocardium is the principal mechanism by which patients with AMI benefit from reperfusion. Quantification of myocardial salvage index rather than final infarct size eliminates the inter-individual variation (20). There is conflicting evidence about the impact of gender in myocardial salvage after STEMI (21,22). In our study we found no gender-based difference in salvage, area at risk or final infarct size. However, we did find significantly higher OPG levels in women compared with men. OPG is produced by a variety of tissues, including the vascular system, smooth muscle cells and endothelial cells (23), and high expression of OPG was found in inflammatory cells present in atherosclerotic plaques (24). Furthermore, OPG contributes to endothelial dysfunction (23). Notably, OPG acts as a decoy receptor competitively inhibiting RANK ligand and thus OPG is expected to counteract calcification. High OPG levels may thus be expected to prevent cardiovascular events. However, the precise mechanisms are still unknown. Increase in OPG concentration may be a response to, rather than a cause of, atherosclerosis or vascular calcification, perhaps representing an attempt to regulate the processes. Increased OPG levels are found in patients with diabetes and in patients who die (25,26). Thus, the OPG levels may just reflect extensive cardiovascular disease.
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Limitations Final infarct size and myocardial salvage index using myocardial SPECT assessment was only obtained in 85 and 61% of the patients, respectively, either due to withdrawal of informed consent, patients lost from dying, or to coronary artery bypass grafting rendering SPECT imaging impossible. Blood samples were only obtained at baseline prior to primary PCI.
7.
8.
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Conclusion Despite absent association between OPG levels and the scale of myocardial damage, patients with high values of OPG had significantly increased risk of MACCE. This indicates that high OPG levels as a marker of future events may reflect something else critical than simply larger infarcts. Increase in the OPG concentration may be representing an attempt to regulate the processes or a marker of disease severity.
Acknowledgments From the Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University we would like to thank Lisa Buus, for invaluable technical assistance and Karin Ø. Kristensen for linguistic guidance.
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Declaration of interest: The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
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References
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1. Reid P, Holen I. Pathophysiological roles of osteoprotegerin (OPG). Eur J Cell Biol. 2009;88:1–17. 2. Hofbauer LC, Shui C, Riggs BL, Dunstan CR, Spelsberg TC, O’Brien T, Khosla S. Effects of immunosuppressants on receptor activator of NF-kappaB ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells. Biochem Biophys Res Commun. 2001;280:334–9. 3. Montagnana M, Lippi G, Danese E, Guidi GC. The role of osteoprotegerin in cardiovascular disease. Ann Med. 2013;45:254–64. 4. Nybo M, Rasmussen LM. The capability of plasma osteoprotegerin as a predictor of cardiovascular disease: a systematic literature review. Eur J Endocrinol. 2008; 159:603–8. 5. Montecucco F, Steffens S, Mach F. The immune response is involved in atherosclerotic plaque calcification: could the RANKL/RANK/OPG system be a marker of plaque instability? Clin Dev Immunol. 2007;2007:75805. 6. Pedersen S, Mogelvang R, Bjerre M, Frystyk J, Flyvbjerg A, Galatius S, et al. Osteoprotegerin predicts long-term outcome
17.
18.
19.
20. 21.
in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Cardiology. 2012;123:31–8. Crisafulli A, Micari A, Altavilla D, Saporito F, Sardella A, Passaniti M, et al. Serum levels of osteoprotegerin and RANKL in patients with ST elevation acute myocardial infarction. Clin Sci (Lond). 2005;109:389–95. Canga A, Durakoglugil ME, Erdogan T, Kirbas A, Yilmaz A, Cicek Y, et al. Elevated serum osteoprotegerin levels predict in-hospital major adverse cardiac events in patients with ST elevation myocardial infarction. J Cardiol. 2012; 60:355–60. Omland T, Ueland T, Jansson AM, Persson A, Karlsson T, Smith C, et al. Circulating osteoprotegerin levels and longterm prognosis in patients with acute coronary syndromes. J Am Coll Cardiol. 2008;51:627–33. Roysland R, Bonaca MP, Omland T, Sabatine M, Murphy SA, Scirica BM, et al. Osteoprotegerin and cardiovascular mortality in patients with non-ST elevation acute coronary syndromes. Heart. 2012;98:786–91. Vik A, Mathiesen EB, Brox J, Wilsgaard T, Njolstad I, Jorgensen L, Hansen JB. Serum osteoprotegerin is a predictor for incident cardiovascular disease and mortality in a general population: the Tromso Study. J Thromb Haemost. 2011;9:638–44. Mogelvang R, Haahr-Pedersen S, Bjerre M, Frystyk J, Iversen A, Galatius S, et al. Osteoprotegerin improves risk detection by traditional cardiovascular risk factors and hsCRP. Heart. 2013;99:106–10. Fuernau G, Zaehringer S, Eitel I, de Waha S, Droppa M, Desch S, et al. Osteoprotegerin in ST-elevation myocardial infarction: prognostic impact and association with markers of myocardial damage by magnetic resonance imaging. Int J Cardiol. 2013;167:2134–9. Andersen GO, Knudsen EC, Aukrust P, Yndestad A, Oie E, Muller C, et al. Elevated serum osteoprotegerin levels measured early after acute ST-elevation myocardial infarction predict final infarct size. Heart. 2011;97:460–5. Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010;375:727–34. Ndrepepa G, Mehilli J, Schwaiger M, Schuhlen H, Nekolla S, Martinoff S, et al. Prognostic value of myocardial salvage achieved by reperfusion therapy in patients with acute myocardial infarction. J Nucl Med. 2004;45:725–9. Kaltoft A, Nielsen SS, Terkelsen CJ, Bottcher M, Lassen JF, Krusell LR, et al. Scintigraphic evaluation of routine filterwire distal protection in percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: a randomized controlled trial. J Nucl Cardiol. 2009;16:784–91. Killip T III, Kimball JT. Treatment of myocardial infarction in a coronary care unit. A two year experience with 250 patients. Am J Cardiol. 1967;20:457–64. Sloth AD, Schmidt MR, Munk K, Kharbanda RK, Redington AN, Schmidt M, et al. Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J. 2014;35:168–75. Botker HE, Kaltoft AK, Pedersen SF, Kim WY. Measuring myocardial salvage. Cardiovasc Res. 2012;94:266–75. Eitel I, Desch S, de Waha S, Fuernau G, Gutberlet M, Schuler G, Thiele H. Sex differences in myocardial salvage
OPG does not predict myocardial salvage
Scand Cardiovasc J Downloaded from informahealthcare.com by Kainan University on 04/28/15 For personal use only.
and clinical outcome in patients with acute reperfused STelevation myocardial infarction: advances in cardiovascular imaging. Circ Cardiovasc Imaging. 2012;5:119–26. 22. Canali E, Masci P, Bogaert J, Bucciarelli Ducci C, Francone M, McAlindon E, et al. Impact of gender differences on myocardial salvage and post-ischaemic left ventricular remodelling after primary coronary angioplasty: new insights from cardiovascular magnetic resonance. Eur Heart J Cardiovasc Imaging. 2012;13:948–53. 23. Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res. 2004;95:1046–57.
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24. Vik A, Mathiesen EB, Noto AT, Sveinbjornsson B, Brox J, Hansen JB. Serum osteoprotegerin is inversely associated with carotid plaque echogenicity in humans. Atherosclerosis. 2007;191:128–34. 25. Jorsal A, Tarnow L, Flyvbjerg A, Parving HH, Rossing P, Rasmussen LM. Plasma osteoprotegerin levels predict cardiovascular and all-cause mortality and deterioration of kidney function in type 1 diabetic patients with nephropathy. Diabetologia. 2008;51:2100–7. 26. Reinhard H, Lajer M, Gall MA, Tarnow L, Parving HH, Rasmussen LM, et al. Osteoprotegerin and mortality in type 2 diabetic patients. Diabetes Care. 2010;33:2561–6.
