- Email: [email protected]
Long-term prognostic value of preprocedural adiponectin levels in patients undergoing percutaneous coronary intervention
Letters to the Editor
cannot be confirmed as a higher frequency of conduction abnormalities in arrhythmogenic cardiomyopathy can be definitely excluded. These findings correspond to fibrofatty lesions in Tabib's work possibly representing true conduction abnormalities within arrhythmogenic cardiomyopathy usually sparing the conduction system. References [1] Tabib A, Loire R, Chalabreysse L, et al. Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia. Circulation 2003;108:3000–5. [2] Quarta G, Syrris P, Ashworth M, et al. Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy. Eur Heart J 2012;33:1128–36. [3] Taylor M, Graw S, Sinagra G, et al. Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Circulation 2011;124:876–85. [4] Marshall W, Furey M, Larsen B, et al. Correspondence to: right ventricular cardiomyopathy and sudden death in young people. N Eng J Med 1988;319:174–5.
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[5] Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 2010;31:806–14. [6] Peters S, Trümmel M, Koehler B. Special features of right bundle branch block in patients with arrhythmogenic right ventricular cardfiomyopathy/dysplasia. Int J Cardiol 2012;157:102–3. [7] Peters S, Trümmel M, Koehler B. QRS fragmentation in standard ECG as a diagnostic marker of arrhythmogenic right ventricular dysplasia–cardiomyopathy. Heart Rhythm 2008;5:1417–21. [8] Vasawala SC, Finn C, Delpriore J, et al. Prospective study of cardiac sarcoid mimicking arrhythmogenic right ventricular dysplasia. J Cardiovasc Electrophysiol 2009;20:473–6. [9] Martini B, Nava A, Thiene G, et al. Ventricular fibrillation without apparent heart disease: description of six cases. Am Heart J 1989;118:1203–9. [10] Hodgkinson KA, Parfrey PS, Bassett AS, et al. The impact of implantable cardioverterdefibrillator therapy on survival in autosomal-dominant arrhythmogenic right ventricular cardiomyopathy (ARVD5). J Am Coll Cardiol 2005;45:400–8. [11] Von Tintelen JP, Van Gelder IC, Asimaki A, et al. Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missence mutation in the DES gene. Heart Rhythm 2009;6:1574–83.
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.07.093
Long-term prognostic value of preprocedural adiponectin levels in patients undergoing percutaneous coronary intervention☆ Cédric Delhaye a,⁎, Natalia Kpogbemabou a,b, Thomas Modine a, Gilles Lemesle a, Bart Staels c, Michael Mahmoudi d, Anne Tailleux c, Gérald Luc e, Christophe Bauters a,b, Jean-Marc Lablanche a,b, Arnaud Sudre a a
Hôpital Cardiologique, CHRU de Lille, boulevard Pr Leclercq, 59037 Lille cedex, France Faculté de médecine, Université de Lille 2, 59045 Lille, France c Inserm, U1011, F-59000, Lille, France; Université Lille 2, F-59000, Lille, France; Institut Pasteur de Lille, F-59019, Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France d University of Surrey, Guilford, Surrey, GU2-7XH, UK e EA 2694, Laboratoire de Santé Publique, 59045 Lille cedex; Faculté des Sciences Pharmaceutiques et Biologiques, Université de Lille 2, 59006 Lille, France b
a r t i c l e
i n f o
Article history: Received 4 July 2013 Accepted 8 July 2013 Available online 15 August 2013 Keywords: Adiponectin Percutaneous coronary intervention Outcome
Adiponectin, an adipocyte-derived protein, is considered to possess cardioprotective properties mainly through antiinflammatory and anti-atherogenic mechanisms [1]. Low levels of adiponectin have thus been suspected to be associated with an increased risk of coronary artery disease (CAD) and acute coronary syndrome (ACS) in several though not all studies [2]. In patients presenting with manifest CAD, an inverse association has been suggested; high rather than low adiponectin levels may be associated with adverse outcomes and death [3–6]. In those presenting with
☆ Funding: INTERREG III, FEDER project EEC. ⁎ Corresponding author. Tel.: +33 320445301; fax: +33 320444898. E-mail address: [email protected] (C. Delhaye).
acute ST elevation myocardial infarction (STEMI), adiponectin has been shown to be a predictor of all cause mortality or cardiovascular death at long follow-up [5]. However, there is currently limited data regarding the long-term prognostic value of adiponectin in patients undergoing percutaneous coronary intervention (PCI) outside the setting of STEMI. Furthermore, the relationship between adiponectin and stent-related complication such as restenosis has not been explored. This study was design to examine these issues. Between March 2006 and September 2007, we constructed a prospective cardiovascular registry of 477 patients who underwent PCI for stable angina and non-ST-elevation ACS and for whom total plasma adiponectin were systematically assessed at the time of the procedure. Patients presenting with a STEMI were not included. Each patient gave informed consent. This study has received authorization from the local Patient Protection Committee. The authors of this manuscript certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. Circulating levels of plasma total adiponectin were determined with a multiplex bioassay using commercially available kit from Linco Research Inc. (Billerica, MA, USA; Human cardiovascular disease panel 1 multiplex immunoassay). PCI with bare metal or drug-eluting stent (DES) implantation was performed using conventional techniques. Aspirin and clopidogrel were systematically used before the procedure and thereafter. The median follow-up was 3.7 years [interquartile range = 3.4–4.2years]. The primary end point was defined as either all-
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Letters to the Editor
Table 1 Baseline characteristics stratified by adiponectin tertile. Total (N = 477)
Tertile1 (n = 159), Adipo b 15.25 μg/ml
Tertile2 (n = 159), 15.25 b Adipo b 20.12
Tertile3 (n = 159), Adipo N 20.12 μg/ml
r
P
Age (year) Male gender, n (%) Diabetes mellitus, n (%)b Systemic hypertension, n (%) Current smoker, n (%) Hypercholesterolemia, n (%)c Body mass index (kg/m2) Previous CAD, n (%)d
62.5 ± 11 399 (83.6) 148 (31.0) 280 (58.7) 137 (28.7) 395 (82.8) 27.6 ± 4.4 266 (55.8)
59.6 ± 10 139 (87.4) 53 (33.3) 93 (58.5) 50 (31.4) 138 (86.8) 28.4 ± 4.1 98 (61.6)
63.1 ± 11 140 (88.1) 49 (30.8) 92 (57.9) 48 (30.2) 131 (82.4) 27.8 ± 4.4 95 (59.7)
64.7 ± 11 120 (75.5) 46 (28.9) 95 (59.7) 39 (24.5) 126 (79.2) 26.4 ± 4.5 73 (45.9)
0.20
b 0.001 b 0.001 0.607 0.696 0.080 0.010 b 0.001 0.028
Indication for PCI, n (%) Stable CAD Unstable angina Non-ST elevation MI Left ventricular ejection fraction, %
316 (66.2) 37 (7.8) 124 (26) 53 ± 10
107 (67.3) 15 (9.4) 37 (23.3) 54 ± 9
110 (69.6) 10 (6.3) 39 (24.5) 53 ± 11
99 (62.3) 12 (7.5) 48 (30.2) 53 ± 11
Laboratory characteristics Baseline glucose (g/l) Serum creatinine (mg/l) Total cholesterol (g/l) LDL cholesterol (g/l) HDL cholesterol (g/l) Triglycerides (g/l) BNP (pg/ml)a Hs-CRP (mg/l)a Adiponectin (μg/ml)
1.02 ± 0.30 9.9 ± 0.3 1.49 ± 0.40 0.87 ± 0.33 0.39 ± 0.11 1.15 ± 0.70 117 [25–128] 2.00 [0.74–5.88] 17.22 ± 0.29
1.07 ± 0.34 9.3 ± 0.3 1.45 ± 0.41 0.83 ± 0.34 0.36 ± 0.09 1.24 ± 0.81 85.02 [20–87] 2.16 [0.88–5.57] 9.99 ± 0.29
1.02 ± 0.28 9.7 ± 0.2 1.53 ± 0.38 0.89 ± 0.32 0.41 ± 0.12 1.15 ± 0.54 119.48 [30–128] 1.89 [0.74–6.25] 17.78 ± 0.10
0.97 ± 0.26 10.8 ± 0.9 1.50 ± 0.41 0.87 ± 0.34 0.43 ± 0.12 0.95 ± 0.44 146.03 [30–179] 1.96 [0.66–5.93] 23.90 ± 0.25
Angiographic characteristics Multivessel CAD, n (%) Target coronary vessel: Left main or Left anterior descending, n (%) ACC/AHA type C lesion, n (%)
359 (75.3) 182 (38.2) 108 (22.6)
125 (78.6) 61 (38.4) 41 (25.8)
118 (74.2) 57 (35.8) 35 (22.0)
116 (73.0) 64 (40.3) 32 (20.1)
Procedural characteristics Number of treated lesion per patient Drug eluting stent use, n (%) Number of stent per patient, n (%) Glycoprotein IIb/IIIa inhibitors, n (%) Bivaluridin, n (%)
1.24 ± 0.56 350 (73.4) 1.36 ± 0.67 134 (29.1) 133 (27.9)
1.31 ± 0.59 130 (81.8) 1.43 ± 0.68 50 (32.9) 44 (27.7)
1.26 ± 0.62 114 (71.7) 1.42 ± 0.74 38 (25.0) 51 (32.1)
1.14 ± 0.45 106 (66.7) 1.23 ± 0.56 46 (29.3) 38 (23.9)
Take home treatment prior to PCI, n (%) Aspirin Thienopyridine βBlocker Angiotensin-converting enzyme inhibitors or receptor blocker Statin
339 (71.1) 216 (45.3) 292 (61.2) 339 (71.1) 352 (73.8)
116 (73) 73 (45.9) 106 (66.7) 107 (67.3) 126 (79.2)
112 (70.4) 75 (47.2) 98 (61.6) 123 (77.4) 114 (71.7)
111 (69.8) 68 (42.8) 88 (55.3) 109 (68.6) 112 (70.4)
− 0.21
0.492
− 0.03
0.561
− 0.11 0.02 0.04 0.01 0.32 − 0.20 0.20 − 0.04
0.019 0.680 0.351 0.846 b 0.001 b 0.001 b 0.001 0.427
0.244 0.761 0.108
− 0.08 − 0.14
0.095 0.003 0.002 0.269 0.895
0.591 0.566 0.008 0.751 0.348
Data are expressed as mean ± SD or median [25–75th percentile]; r, correlation coefficient. p values are for analyses performed with adiponectin as a continuous variable. Abbreviations: ACC/AHA, American College of Cardiology/American Heart Association; BNP, brain natriuretic peptide; CAD, coronary artery disease; HDL, high-density lipoprotein; Hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; MI, myocardial infarction; PCI, percutaneous coronary intervention. a Analysis were performed using log transformed variable such as ln(BNP + 1) and ln(CRP). b Defined as any history of diabetes mellitus and/or use of hypoglycemic drugs; also included new diagnosis made during index hospitalization with fasting glucose level ≥1.26 g/L on ≥2 different occasions. c Included both patients with previously documented diagnosis of hypercholesterolemia treated with diet or medication; a new diagnosis could be made during hospitalization by elevated total cholesterol ≥160 mg/dl. d Defined as prior to MI, coronary artery bypass graft or PCI.
cause mortality or MI or stroke. MI was defined as proposed by the guidelines [7]. Stroke was defined as the occurrence of a new neurological deficit and was confirmed by a neurologist and on imaging. Target vessel revascularization (TVR) was an examined secondary end point and characterized by ischemia-driven percutaneous or surgical revascularization of the treated vessel. We categorized adiponectin into tertiles for the purposes of presentation. The relationships between adiponectin as continuous variable and other parameters were analysed by Spearman's correlation for continuous variable and by Student's t test for categorical variables. To study the relation between adiponectin level and multiple determinants, a multiple linear regression
analysis with stepwise forward model was performed including potential explanatory variables having an association after univariate analysis (p b 0.1). For that, all variables in Table 1 were considered apart from procedural characteristics. Survival curves were constructed using the Kaplan–Meier method and differences between adiponectin tertiles tested by a log-rank test. Hazard ratios (HR) were calculated using univariate and multivariate Cox models. A stepwise forward procedure was used to determine independent predictors of events. Candidate covariates for multiple Cox regression analysis for death/MI/Stroke were chosen based on both the p value b0.10 in Cox univariate analysis (age, diabetes, left ventricular ejection fraction, baseline serum creatinine level, LDL,
Letters to the Editor
4923
Fig. 1. Kaplan–Meier MI/stroke-free survival curves in subgroups of patients divided according to tertiles of adiponectin levels. The HR of death/MI/stroke was 2.11 (95% CI, 1.23–3.62, p = 0.007) in the highest (N 20.12 μg/ml) compared with the lowest tertile (b15.25 μg/ml) of adiponectin.
BNP, hs-CRP, and total adiponectin level) and clinically relevant variables known to be associated with outcomes in the literature (gender, body mass index (BMI), prior CAD, MI as clinical presentation, HDL, and multivessel CAD). All statistical analysis was performed using SPSS (SPSS Inc., Chicago, Illinois). Statistical significance was assumed at p b 0.05. The baseline characteristics, stratified according to the adiponectin tertiles, are detailed in Table 1. By multiple regression analysis, the factors independently associated with high levels of adiponectin were age (p = 0.030), female gender (p = 0.013), low triglyceride levels (p = 0.005), high levels of HDL cholesterol (p b 0.001), high levels of BNP (p = 0.021), and lack of β blocker therapy prior to PCI (p =0.046). During a median follow-up period of 3.7 years, there were 55 (11.5%) deaths, 20 (4.2%) MIs, and 7 (1.4%) strokes. The composite of death/MI/stroke occurred in 76 (15.9%) patients. In univariate analysis, adiponectin as a continuous variable had a significant positive relationship (HR = 1.05, 95% confidence interval [CI] = 1.01–1.09, p = 0.006) with the primary end point. Fig. 1 shows Kaplan–Meier survival curves by tertiles of adiponectin levels. In multivariate analysis, diabetes mellitus, high levels of BNP, hs-CRP, and adiponectin (HR = 1.06, 95% CI = 1.02–1.10, p = 0.006) were associated with the primary end point (Table 2). When adiponectin
Table 2 Multivariable correlates of death/MI/Stroke by Cox model analysis.
Diabetes mellitus BNP Hs-CRP Adiponectin
Multivariate analysis model using adiponectin as continuous variable
Multivariate analysis model using adiponectin as tertile (tertile 3 vs. tertiles 1 + 2 [ref])
HR [95% CI]
p value
HR [95% CI]
p value
1.95 [1.22–3.10] 1.33 [1.08–1.64]a 1.24 [1.06–1.46]a 1.06 [1.02–1.10]b
0.009 0.007 0.009 0.005
1.93 [1.21–3.07] 1.34 [1.09–1.65]a 1.24 [1.06–1.46]a 2.16 [1.35–3.46]c
0.005 0.005 0.008 0.001
Abbreviations as in Table 1; CI, confidence interval; HR, hazard ratio; ref, reference. a HR is provided for one log increase of the variable unit [ln(BNP + 1) and ln(CRP)]. b HR is provided for one unit (μg/ml) increase of adiponectin. c HR is provided for tertile 3 vs. tertile 1 + 2 (ref) of adiponectin.
Fig. 2. Kaplan–Meier MI/stroke-free survival curves in subgroups of patients divided according to adiponectin levels (tertiles 1 + 2 vs. 3) and (A) diabetic status, (B) median of BNP levels (54.5 pg/ml), and (C) median of CRP levels (2.01 mg/l).
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was entered into the multivariate model as tertile, patients in the upper tertile (tertile 3; N20.12 μg/ml) had twice more risk of death, MI, or stroke as compared to patients in the lowest tertiles (tertiles 1 + 2, b20.12 μg/ml, HR = 2.16 [1.35–3.46], p = 0.001). Fig. 2 shows the MI/stroke-free survival curves of subgroups divided according to adiponectin levels and diabetic status (Fig. 2A), BNP levels (Fig. 2B), and hs-CRP levels (Fig. 2C). TVR was performed in 53 (11.1%) patients, and no association was found between preprocedural adiponectin levels and TVR (p = 0.72). In patients with symptomatic stable CAD and non-ST-elevation ACS undergoing contemporary PCI, an elevation of preprocedural total adiponectin level is an independent predictor of adverse events including death, MI, or stroke at long-term follow-up. Such a positive correlation could be counterintuitive given the anti-inflammatory and antiatherogenic properties attributed to adiponectin [1], but it is possible that the increase in adiponectin in the context of CAD represents a compensatory mechanism against persistent inflammation and atherogenesis [8]. However, we cannot exclude the possibility that adiponectin serve as a marker for a more detrimental cascade that ultimately contributes to adverse outcomes in the longer term. Given the role of adiponectin in the inhibition of both proliferation and migration of smooth muscular cell [1], a potential relationship between the preprocedural level of adiponectin and the risk of restenosis or the need of TVR has been investigated. Conflicting scarce results have been produced regarding this association [9,10]. The present study shows in a patient population that predominantly
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.07.092
received DES that no relationship exists between the preprocedural adiponectin level and the rate of TVR during more than 3-years follow-up. References [1] Vaiopoulos AG, Marinou K, Christodoulides C, Koutsilieris M. The role of adiponectin in human vascular physiology. Int J Cardiol 2011;155:188–93. [2] Barseghian A, Gawande D, Bajaj M. Adiponectin and vulnerable atherosclerotic plaques. J Am Coll Cardiol 2011;57:761–70. [3] Schnabel R, Messow CM, Lubos E, et al. Association of adiponectin with adverse outcome in coronary artery disease patients: results from the AtheroGene study. Eur Heart J 2008;29:649–57. [4] Pilz S, Mangge H, Wellnitz B, et al. Adiponectin and mortality in patients undergoing coronary angiography. J Clin Endocrinol Metab 2006;91:4277–86. [5] Lindberg S, Pedersen SH, Mogelvang R, et al. Usefulness of adiponectin as a predictor of all cause mortality in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Am J Cardiol 2012;109:492–6. [6] Cavusoglu E, Ruwende C, Chopra V, et al. Adiponectin is an independent predictor of all-cause mortality, cardiac mortality, and myocardial infarction in patients presenting with chest pain. Eur Heart J 2006;27:2300–9. [7] Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. J Am Coll Cardiol 2007;50:2173–95. [8] Rathmann W, Herder C. Adiponectin and cardiovascular mortality: evidence for “reverse epidemiology”. Horm Metab Res 2007;39:1–2. [9] Shimada K, Miyauchi K, Mokuno H, et al. Predictive value of the adipocytederived plasma protein adiponectin for restenosis after elective coronary stenting. Jpn Heart J 2002;43:85–91. [10] Kitta Y, Takano H, Nakamura T, et al. Low adiponectin levels predict late in-stent restenosis after bare metal stenting in native coronary arteries. Int J Cardiol 2008;131:78–82.
cannot be confirmed as a higher frequency of conduction abnormalities in arrhythmogenic cardiomyopathy can be definitely excluded. These findings correspond to fibrofatty lesions in Tabib's work possibly representing true conduction abnormalities within arrhythmogenic cardiomyopathy usually sparing the conduction system. References [1] Tabib A, Loire R, Chalabreysse L, et al. Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia. Circulation 2003;108:3000–5. [2] Quarta G, Syrris P, Ashworth M, et al. Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy. Eur Heart J 2012;33:1128–36. [3] Taylor M, Graw S, Sinagra G, et al. Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Circulation 2011;124:876–85. [4] Marshall W, Furey M, Larsen B, et al. Correspondence to: right ventricular cardiomyopathy and sudden death in young people. N Eng J Med 1988;319:174–5.
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[5] Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 2010;31:806–14. [6] Peters S, Trümmel M, Koehler B. Special features of right bundle branch block in patients with arrhythmogenic right ventricular cardfiomyopathy/dysplasia. Int J Cardiol 2012;157:102–3. [7] Peters S, Trümmel M, Koehler B. QRS fragmentation in standard ECG as a diagnostic marker of arrhythmogenic right ventricular dysplasia–cardiomyopathy. Heart Rhythm 2008;5:1417–21. [8] Vasawala SC, Finn C, Delpriore J, et al. Prospective study of cardiac sarcoid mimicking arrhythmogenic right ventricular dysplasia. J Cardiovasc Electrophysiol 2009;20:473–6. [9] Martini B, Nava A, Thiene G, et al. Ventricular fibrillation without apparent heart disease: description of six cases. Am Heart J 1989;118:1203–9. [10] Hodgkinson KA, Parfrey PS, Bassett AS, et al. The impact of implantable cardioverterdefibrillator therapy on survival in autosomal-dominant arrhythmogenic right ventricular cardiomyopathy (ARVD5). J Am Coll Cardiol 2005;45:400–8. [11] Von Tintelen JP, Van Gelder IC, Asimaki A, et al. Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missence mutation in the DES gene. Heart Rhythm 2009;6:1574–83.
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.07.093
Long-term prognostic value of preprocedural adiponectin levels in patients undergoing percutaneous coronary intervention☆ Cédric Delhaye a,⁎, Natalia Kpogbemabou a,b, Thomas Modine a, Gilles Lemesle a, Bart Staels c, Michael Mahmoudi d, Anne Tailleux c, Gérald Luc e, Christophe Bauters a,b, Jean-Marc Lablanche a,b, Arnaud Sudre a a
Hôpital Cardiologique, CHRU de Lille, boulevard Pr Leclercq, 59037 Lille cedex, France Faculté de médecine, Université de Lille 2, 59045 Lille, France c Inserm, U1011, F-59000, Lille, France; Université Lille 2, F-59000, Lille, France; Institut Pasteur de Lille, F-59019, Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France d University of Surrey, Guilford, Surrey, GU2-7XH, UK e EA 2694, Laboratoire de Santé Publique, 59045 Lille cedex; Faculté des Sciences Pharmaceutiques et Biologiques, Université de Lille 2, 59006 Lille, France b
a r t i c l e
i n f o
Article history: Received 4 July 2013 Accepted 8 July 2013 Available online 15 August 2013 Keywords: Adiponectin Percutaneous coronary intervention Outcome
Adiponectin, an adipocyte-derived protein, is considered to possess cardioprotective properties mainly through antiinflammatory and anti-atherogenic mechanisms [1]. Low levels of adiponectin have thus been suspected to be associated with an increased risk of coronary artery disease (CAD) and acute coronary syndrome (ACS) in several though not all studies [2]. In patients presenting with manifest CAD, an inverse association has been suggested; high rather than low adiponectin levels may be associated with adverse outcomes and death [3–6]. In those presenting with
☆ Funding: INTERREG III, FEDER project EEC. ⁎ Corresponding author. Tel.: +33 320445301; fax: +33 320444898. E-mail address: [email protected] (C. Delhaye).
acute ST elevation myocardial infarction (STEMI), adiponectin has been shown to be a predictor of all cause mortality or cardiovascular death at long follow-up [5]. However, there is currently limited data regarding the long-term prognostic value of adiponectin in patients undergoing percutaneous coronary intervention (PCI) outside the setting of STEMI. Furthermore, the relationship between adiponectin and stent-related complication such as restenosis has not been explored. This study was design to examine these issues. Between March 2006 and September 2007, we constructed a prospective cardiovascular registry of 477 patients who underwent PCI for stable angina and non-ST-elevation ACS and for whom total plasma adiponectin were systematically assessed at the time of the procedure. Patients presenting with a STEMI were not included. Each patient gave informed consent. This study has received authorization from the local Patient Protection Committee. The authors of this manuscript certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. Circulating levels of plasma total adiponectin were determined with a multiplex bioassay using commercially available kit from Linco Research Inc. (Billerica, MA, USA; Human cardiovascular disease panel 1 multiplex immunoassay). PCI with bare metal or drug-eluting stent (DES) implantation was performed using conventional techniques. Aspirin and clopidogrel were systematically used before the procedure and thereafter. The median follow-up was 3.7 years [interquartile range = 3.4–4.2years]. The primary end point was defined as either all-
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Table 1 Baseline characteristics stratified by adiponectin tertile. Total (N = 477)
Tertile1 (n = 159), Adipo b 15.25 μg/ml
Tertile2 (n = 159), 15.25 b Adipo b 20.12
Tertile3 (n = 159), Adipo N 20.12 μg/ml
r
P
Age (year) Male gender, n (%) Diabetes mellitus, n (%)b Systemic hypertension, n (%) Current smoker, n (%) Hypercholesterolemia, n (%)c Body mass index (kg/m2) Previous CAD, n (%)d
62.5 ± 11 399 (83.6) 148 (31.0) 280 (58.7) 137 (28.7) 395 (82.8) 27.6 ± 4.4 266 (55.8)
59.6 ± 10 139 (87.4) 53 (33.3) 93 (58.5) 50 (31.4) 138 (86.8) 28.4 ± 4.1 98 (61.6)
63.1 ± 11 140 (88.1) 49 (30.8) 92 (57.9) 48 (30.2) 131 (82.4) 27.8 ± 4.4 95 (59.7)
64.7 ± 11 120 (75.5) 46 (28.9) 95 (59.7) 39 (24.5) 126 (79.2) 26.4 ± 4.5 73 (45.9)
0.20
b 0.001 b 0.001 0.607 0.696 0.080 0.010 b 0.001 0.028
Indication for PCI, n (%) Stable CAD Unstable angina Non-ST elevation MI Left ventricular ejection fraction, %
316 (66.2) 37 (7.8) 124 (26) 53 ± 10
107 (67.3) 15 (9.4) 37 (23.3) 54 ± 9
110 (69.6) 10 (6.3) 39 (24.5) 53 ± 11
99 (62.3) 12 (7.5) 48 (30.2) 53 ± 11
Laboratory characteristics Baseline glucose (g/l) Serum creatinine (mg/l) Total cholesterol (g/l) LDL cholesterol (g/l) HDL cholesterol (g/l) Triglycerides (g/l) BNP (pg/ml)a Hs-CRP (mg/l)a Adiponectin (μg/ml)
1.02 ± 0.30 9.9 ± 0.3 1.49 ± 0.40 0.87 ± 0.33 0.39 ± 0.11 1.15 ± 0.70 117 [25–128] 2.00 [0.74–5.88] 17.22 ± 0.29
1.07 ± 0.34 9.3 ± 0.3 1.45 ± 0.41 0.83 ± 0.34 0.36 ± 0.09 1.24 ± 0.81 85.02 [20–87] 2.16 [0.88–5.57] 9.99 ± 0.29
1.02 ± 0.28 9.7 ± 0.2 1.53 ± 0.38 0.89 ± 0.32 0.41 ± 0.12 1.15 ± 0.54 119.48 [30–128] 1.89 [0.74–6.25] 17.78 ± 0.10
0.97 ± 0.26 10.8 ± 0.9 1.50 ± 0.41 0.87 ± 0.34 0.43 ± 0.12 0.95 ± 0.44 146.03 [30–179] 1.96 [0.66–5.93] 23.90 ± 0.25
Angiographic characteristics Multivessel CAD, n (%) Target coronary vessel: Left main or Left anterior descending, n (%) ACC/AHA type C lesion, n (%)
359 (75.3) 182 (38.2) 108 (22.6)
125 (78.6) 61 (38.4) 41 (25.8)
118 (74.2) 57 (35.8) 35 (22.0)
116 (73.0) 64 (40.3) 32 (20.1)
Procedural characteristics Number of treated lesion per patient Drug eluting stent use, n (%) Number of stent per patient, n (%) Glycoprotein IIb/IIIa inhibitors, n (%) Bivaluridin, n (%)
1.24 ± 0.56 350 (73.4) 1.36 ± 0.67 134 (29.1) 133 (27.9)
1.31 ± 0.59 130 (81.8) 1.43 ± 0.68 50 (32.9) 44 (27.7)
1.26 ± 0.62 114 (71.7) 1.42 ± 0.74 38 (25.0) 51 (32.1)
1.14 ± 0.45 106 (66.7) 1.23 ± 0.56 46 (29.3) 38 (23.9)
Take home treatment prior to PCI, n (%) Aspirin Thienopyridine βBlocker Angiotensin-converting enzyme inhibitors or receptor blocker Statin
339 (71.1) 216 (45.3) 292 (61.2) 339 (71.1) 352 (73.8)
116 (73) 73 (45.9) 106 (66.7) 107 (67.3) 126 (79.2)
112 (70.4) 75 (47.2) 98 (61.6) 123 (77.4) 114 (71.7)
111 (69.8) 68 (42.8) 88 (55.3) 109 (68.6) 112 (70.4)
− 0.21
0.492
− 0.03
0.561
− 0.11 0.02 0.04 0.01 0.32 − 0.20 0.20 − 0.04
0.019 0.680 0.351 0.846 b 0.001 b 0.001 b 0.001 0.427
0.244 0.761 0.108
− 0.08 − 0.14
0.095 0.003 0.002 0.269 0.895
0.591 0.566 0.008 0.751 0.348
Data are expressed as mean ± SD or median [25–75th percentile]; r, correlation coefficient. p values are for analyses performed with adiponectin as a continuous variable. Abbreviations: ACC/AHA, American College of Cardiology/American Heart Association; BNP, brain natriuretic peptide; CAD, coronary artery disease; HDL, high-density lipoprotein; Hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; MI, myocardial infarction; PCI, percutaneous coronary intervention. a Analysis were performed using log transformed variable such as ln(BNP + 1) and ln(CRP). b Defined as any history of diabetes mellitus and/or use of hypoglycemic drugs; also included new diagnosis made during index hospitalization with fasting glucose level ≥1.26 g/L on ≥2 different occasions. c Included both patients with previously documented diagnosis of hypercholesterolemia treated with diet or medication; a new diagnosis could be made during hospitalization by elevated total cholesterol ≥160 mg/dl. d Defined as prior to MI, coronary artery bypass graft or PCI.
cause mortality or MI or stroke. MI was defined as proposed by the guidelines [7]. Stroke was defined as the occurrence of a new neurological deficit and was confirmed by a neurologist and on imaging. Target vessel revascularization (TVR) was an examined secondary end point and characterized by ischemia-driven percutaneous or surgical revascularization of the treated vessel. We categorized adiponectin into tertiles for the purposes of presentation. The relationships between adiponectin as continuous variable and other parameters were analysed by Spearman's correlation for continuous variable and by Student's t test for categorical variables. To study the relation between adiponectin level and multiple determinants, a multiple linear regression
analysis with stepwise forward model was performed including potential explanatory variables having an association after univariate analysis (p b 0.1). For that, all variables in Table 1 were considered apart from procedural characteristics. Survival curves were constructed using the Kaplan–Meier method and differences between adiponectin tertiles tested by a log-rank test. Hazard ratios (HR) were calculated using univariate and multivariate Cox models. A stepwise forward procedure was used to determine independent predictors of events. Candidate covariates for multiple Cox regression analysis for death/MI/Stroke were chosen based on both the p value b0.10 in Cox univariate analysis (age, diabetes, left ventricular ejection fraction, baseline serum creatinine level, LDL,
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Fig. 1. Kaplan–Meier MI/stroke-free survival curves in subgroups of patients divided according to tertiles of adiponectin levels. The HR of death/MI/stroke was 2.11 (95% CI, 1.23–3.62, p = 0.007) in the highest (N 20.12 μg/ml) compared with the lowest tertile (b15.25 μg/ml) of adiponectin.
BNP, hs-CRP, and total adiponectin level) and clinically relevant variables known to be associated with outcomes in the literature (gender, body mass index (BMI), prior CAD, MI as clinical presentation, HDL, and multivessel CAD). All statistical analysis was performed using SPSS (SPSS Inc., Chicago, Illinois). Statistical significance was assumed at p b 0.05. The baseline characteristics, stratified according to the adiponectin tertiles, are detailed in Table 1. By multiple regression analysis, the factors independently associated with high levels of adiponectin were age (p = 0.030), female gender (p = 0.013), low triglyceride levels (p = 0.005), high levels of HDL cholesterol (p b 0.001), high levels of BNP (p = 0.021), and lack of β blocker therapy prior to PCI (p =0.046). During a median follow-up period of 3.7 years, there were 55 (11.5%) deaths, 20 (4.2%) MIs, and 7 (1.4%) strokes. The composite of death/MI/stroke occurred in 76 (15.9%) patients. In univariate analysis, adiponectin as a continuous variable had a significant positive relationship (HR = 1.05, 95% confidence interval [CI] = 1.01–1.09, p = 0.006) with the primary end point. Fig. 1 shows Kaplan–Meier survival curves by tertiles of adiponectin levels. In multivariate analysis, diabetes mellitus, high levels of BNP, hs-CRP, and adiponectin (HR = 1.06, 95% CI = 1.02–1.10, p = 0.006) were associated with the primary end point (Table 2). When adiponectin
Table 2 Multivariable correlates of death/MI/Stroke by Cox model analysis.
Diabetes mellitus BNP Hs-CRP Adiponectin
Multivariate analysis model using adiponectin as continuous variable
Multivariate analysis model using adiponectin as tertile (tertile 3 vs. tertiles 1 + 2 [ref])
HR [95% CI]
p value
HR [95% CI]
p value
1.95 [1.22–3.10] 1.33 [1.08–1.64]a 1.24 [1.06–1.46]a 1.06 [1.02–1.10]b
0.009 0.007 0.009 0.005
1.93 [1.21–3.07] 1.34 [1.09–1.65]a 1.24 [1.06–1.46]a 2.16 [1.35–3.46]c
0.005 0.005 0.008 0.001
Abbreviations as in Table 1; CI, confidence interval; HR, hazard ratio; ref, reference. a HR is provided for one log increase of the variable unit [ln(BNP + 1) and ln(CRP)]. b HR is provided for one unit (μg/ml) increase of adiponectin. c HR is provided for tertile 3 vs. tertile 1 + 2 (ref) of adiponectin.
Fig. 2. Kaplan–Meier MI/stroke-free survival curves in subgroups of patients divided according to adiponectin levels (tertiles 1 + 2 vs. 3) and (A) diabetic status, (B) median of BNP levels (54.5 pg/ml), and (C) median of CRP levels (2.01 mg/l).
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was entered into the multivariate model as tertile, patients in the upper tertile (tertile 3; N20.12 μg/ml) had twice more risk of death, MI, or stroke as compared to patients in the lowest tertiles (tertiles 1 + 2, b20.12 μg/ml, HR = 2.16 [1.35–3.46], p = 0.001). Fig. 2 shows the MI/stroke-free survival curves of subgroups divided according to adiponectin levels and diabetic status (Fig. 2A), BNP levels (Fig. 2B), and hs-CRP levels (Fig. 2C). TVR was performed in 53 (11.1%) patients, and no association was found between preprocedural adiponectin levels and TVR (p = 0.72). In patients with symptomatic stable CAD and non-ST-elevation ACS undergoing contemporary PCI, an elevation of preprocedural total adiponectin level is an independent predictor of adverse events including death, MI, or stroke at long-term follow-up. Such a positive correlation could be counterintuitive given the anti-inflammatory and antiatherogenic properties attributed to adiponectin [1], but it is possible that the increase in adiponectin in the context of CAD represents a compensatory mechanism against persistent inflammation and atherogenesis [8]. However, we cannot exclude the possibility that adiponectin serve as a marker for a more detrimental cascade that ultimately contributes to adverse outcomes in the longer term. Given the role of adiponectin in the inhibition of both proliferation and migration of smooth muscular cell [1], a potential relationship between the preprocedural level of adiponectin and the risk of restenosis or the need of TVR has been investigated. Conflicting scarce results have been produced regarding this association [9,10]. The present study shows in a patient population that predominantly
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received DES that no relationship exists between the preprocedural adiponectin level and the rate of TVR during more than 3-years follow-up. References [1] Vaiopoulos AG, Marinou K, Christodoulides C, Koutsilieris M. The role of adiponectin in human vascular physiology. Int J Cardiol 2011;155:188–93. [2] Barseghian A, Gawande D, Bajaj M. Adiponectin and vulnerable atherosclerotic plaques. J Am Coll Cardiol 2011;57:761–70. [3] Schnabel R, Messow CM, Lubos E, et al. Association of adiponectin with adverse outcome in coronary artery disease patients: results from the AtheroGene study. Eur Heart J 2008;29:649–57. [4] Pilz S, Mangge H, Wellnitz B, et al. Adiponectin and mortality in patients undergoing coronary angiography. J Clin Endocrinol Metab 2006;91:4277–86. [5] Lindberg S, Pedersen SH, Mogelvang R, et al. Usefulness of adiponectin as a predictor of all cause mortality in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Am J Cardiol 2012;109:492–6. [6] Cavusoglu E, Ruwende C, Chopra V, et al. Adiponectin is an independent predictor of all-cause mortality, cardiac mortality, and myocardial infarction in patients presenting with chest pain. Eur Heart J 2006;27:2300–9. [7] Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. J Am Coll Cardiol 2007;50:2173–95. [8] Rathmann W, Herder C. Adiponectin and cardiovascular mortality: evidence for “reverse epidemiology”. Horm Metab Res 2007;39:1–2. [9] Shimada K, Miyauchi K, Mokuno H, et al. Predictive value of the adipocytederived plasma protein adiponectin for restenosis after elective coronary stenting. Jpn Heart J 2002;43:85–91. [10] Kitta Y, Takano H, Nakamura T, et al. Low adiponectin levels predict late in-stent restenosis after bare metal stenting in native coronary arteries. Int J Cardiol 2008;131:78–82.