Metabolic Syndrome Affects Midterm Outcome After Coronary Artery Bypass Grafting

Transcription

1 Metabolic Syndrome Affects Midterm Outcome After Coronary Artery Bypass Grafting Emiliano Angeloni, MD, Giovanni Melina, PhD, Umberto Benedetto, PhD, Simone Refice, MD, Fabio Capuano, MD, Antonino Roscitano, MD, Cosimo Comito, MD, and Riccardo Sinatra, MD Cardiac Surgery Department, University of Rome La Sapienza, Faculty of Medicine and Psychology, Rome, Italy Background. Metabolic syndrome (MetS) is frequently associated with coronary artery disease, but data on the impact of MetS on long-term outcome of patients undergoing coronary artery bypass grafting are still lacking. The aim of the present study was to assess the effect of MetS on mortality and morbidity late after coronary artery bypass grafting. Methods. A total of 1,726 consecutive patients who had elective coronary artery bypass grafting were retrospectively reviewed and clinical follow-up was completed (mean follow-up time, 34.4 months; range, 6 to 79 months). The MetS was diagnosed using the modified Adult Treatment Panel III criteria, and to eliminate covariate differences, a propensity score adjustment was used. Major adverse cerebral and cardiovascular events were investigated, and C-reactive protein levels were assessed both preoperatively, postoperatively, and at follow-up. Results. A total of 798 of 1,726 patients (46.2%) met the diagnostic criteria for MetS. At follow-up, all-cause mortality (7% versus 4.6%; p 0.04), cardiac arrhythmias (35.3% versus 25.2%; p < ), renal failure (12% versus 8.7%; p 0.03), and major adverse cerebral and cardiovascular events (52.4% versus 39.5%; p < ) showed a significantly higher incidence in MetS patients. Variables correlated with late mortality at propensityadjusted Cox proportional-hazards regression were age (p ), preoperative left ventricular ejection fraction (p 0.001), preoperative renal failure (p 0.001), and MetS (p 0.006). Higher C-reactive protein levels were found preoperatively ( versus mg/l; p < ) and both early ( versus mg/l; p < ) and late ( versus mg/L; p < ) after surgery. Conclusions. The main finding of our study was the association between MetS and mortality both early and late after coronary artery bypass grafting. Thus, MetS should be recognized as an independent preoperative variable that can lead to the identification of high-risk patients and as a risk factor to correct with lifestyle modifications and pharmacologic therapy. (Ann Thorac Surg 2012;93:537 44) 2012 by The Society of Thoracic Surgeons Metabolic syndrome (MetS) results from the accumulation of abdominal fat and is characterized by obesity, insulin resistance, hypertriglyceridemia, low high-density lipoprotein cholesterol, and hypertension [1, 2]. The cluster of metabolic alterations constituting MetS has been estimated to affect 35% to 40% of the population in industrialized countries, and its components are frequently associated with coronary artery disease (CAD) [3]. The negative impact of isolated risk factors such as diabetes or obesity on the clinical outcome after coronary artery bypass grafting (CABG) has been previously shown [4 6], and these risk factors exert a synergistic effect when they are simultaneously present (such as occurs in MetS) in noncardiac surgery [7] or coronary percutaneous intervention populations [8]. This synergistic effect seems to be related to a proinflammatory and prothrombotic state demonstrated by Accepted for publication Oct 25, Address correspondence to Dr Angeloni, Department of Cardiac Surgery, University of Rome La Sapienza, Policlinico Sant Andrea, Via di Grottarossa 1035, Rome, Italy; emilianoangeloni@gmail.com. the higher levels of inflammatory markers found in these patients [9, 10], especially C-reactive protein (CRP) and interleukin-6. Many papers have investigated the effect exerted on CAD patients by MetS and its standalone perturbations, with special regard to diabetes, obesity, and hypertension, and there is a consensus to consider MetS much more than the sum of its components [11 13] because with respect to its singular factors, it exposes patients to a higher risk of complications. In addition, the higher levels of inflammatory markers found in MetS patients account for the low-grade inflammatory state of such patients, which expose them to subclinical atherosclerosis and the development of cardiovascular complications. Several papers have shown that MetS is an independent risk factor for both early and late mortality and morbidity in patients with CAD undergoing percutaneous coronary intervention [8, 11 13]. In these settings, MetS appears to affect the clinical history of CAD patients definitely more than diabetes and obesity alone [11 13]. Few papers focused on the early postoperative outcome of patients undergoing CABG [14 16], but in by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 538 ANGELONI ET AL Ann Thorac Surg METABOLIC SYNDROME AND CORONARY SURGERY 2012;93: Abbreviations and Acronyms BMI body mass index CABG coronary artery bypass grafting CAD coronary artery disease CI confidence interval CRP C-reactive protein LVEF left ventricular ejection fraction MACCE major adverse cardiac and cerebrovascular event MetS metabolic syndrome MI myocardial infarction OR odds ratio formation on the possible late relationship between MetS and clinical events is lacking. Therefore, to better clarify the effects of MetS on mortality and morbidity after CABG and to enhance identification of high-risk patients, we sought to assess the correlation between MetS and mortality and morbidity both early and late after CABG. Patients and Methods This study was reviewed and approved by the Institutional Review Board of the University of Rome, and a waiver of consent was granted. The authors have no conflict of interest to disclose. Patients and Variables We retrospectively reviewed a consecutive series of patients who underwent elective CABG at Sant Andrea Hospital (University of Rome La Sapienza, Italy) from May 2004 to October All patients underwent a full median sternotomy, and the operation was performed on cardiopulmonary bypass. Cardiac arrest was obtained by means of antegrade cold-blood cardioplegia, repeated every 15 minutes. Conventional techniques were used for internal mammary artery and saphenous vein harvesting. Data were prospectively collected and recorded in an electronic database, and clinical follow-up was completed with routine outpatient clinics. Patients who did not present at the visit were contacted by telephone, and all symptoms, mortality, and any complications that occurred during follow-up were recorded. Metabolic syndrome was diagnosed using the modified Adult Treatment Panel III of the National Cholesterol Education Program [1, 2] criteria: three of five among body mass index (BMI) greater than 30 kg/m 2, elevated triglycerides ( 150 mg/dl or drug treatment), reduced high-density lipoprotein cholesterol ( 40 mg/dl in men, 50 mg/dl in women or drug treatment), elevated arterial blood pressure ( 130 mm Hg systolic, 85 mm Hg diastolic or drug treatment), and elevated fasting glucose ( 100 mg/dl or drug treatment). The original criterion to classify obesity in the Adult Treatment Panel III was waist circumference ( 120 cm in men, 88 cm in women) [1, 2], but this was not measured in our cohort; therefore we used BMI. Recent studies showed that most patients identified as having MetS based on the BMI would also have been diagnosed as obese according to waist circumference [17, 18]. To estimate glomerular filtration rate the four-variable Modified Diet and Renal Disease equation was used [19]; renal failure was defined as a decline of at least 50% relative to baseline in the glomerular filtration rate or need for dialysis treatment. High-sensitivity CRP was measured by an immunoturbidimetric assay (Dade Behring, Marburg, Germany). Blood samples were collected during hospitalization and at follow-up visit; the peak postoperative value was used to assess postoperative increase of CRP. The outcomes investigated were all-cause mortality, myocardial infarction (MI), stroke, cardiac arrhythmias, and renal failure. Diagnosis of MI was made on the basis of clinical findings and presence of new Q waves, new persistent ST-segment or T-wave changes (Minnesota codes to 1-2-7, 4-1, 4-2, 5-1, 5-2, and 9-2), or elevated levels of troponin I. Diagnosis of stroke was made if there was clinical evidence or evidence of focal or global defect on computed tomography or magnetic resonance imaging. Diagnosis of cardiac arrhythmia was made by means of a 12-lead electrocardiogram performed during hospitalization or the follow-up period. The composite outcome of major adverse cardiac and cerebrovascular events (MACCE) was generated from the following individual events: death, MI, cardiac arrhythmias, and stroke. To evaluate the impact of medical therapy and lifestyle behavior, we conducted a subanalysis dividing the study population into three cohorts at the time of follow-up on the basis of MetS diagnosed only because of altered parameters (eg, hyperglycemia, obesity; uncontrolled- MetS ); MetS diagnosed only because of medical therapy in patients with controlled risk factors ( controlled- MetS ); and MetS absent. Statistical Analysis Continuous data are expressed as the mean and standard deviation; categorical data are expressed as the percentage; comparisons were made using the two-sample Student s t test and the 2 or the Fisher s exact tests, respectively. To eliminate covariate differences that might lead to biased estimates of MetS effect, a propensity score adjustment was also used [20]. Propensity score was computed with logistic regression, with the dependent variable being MetS and the independent variables (covariates) being sex, peripheral vascular disease, chronic obstructive pulmonary disease, diabetes, smoking, preoperative left ventricular ejection fraction (LVEF), preoperative glomerular filtration rate, preoperative CRP levels, preoperative MI, and preoperative stroke; continuous and binary variables were mixed to obtain a semisaturated model. The propensity score showed acceptable goodness of fit (c statistic, 0.72; p ). We estimated the adjusted odds ratios (OR) of selected outcomes associated with MetS by using the propensity score as a covariate into the model. Early postoperatively, age-adjusted univariate logistic

3 Ann Thorac Surg ANGELONI ET AL 2012;93: METABOLIC SYNDROME AND CORONARY SURGERY 539 analysis was performed to identify variables correlated with mortality (p 0.1). Variables independently correlated with the end points were further analyzed in a propensity score adjusted multivariate logistic regression (stepwise fashion, significance level p 0.05). Actuarial estimates of survival and freedom from MACCE at follow-up were analyzed by means of both Kaplan-Meyer method and Cox proportional-hazards regression (stepwise fashion, significance level p 0.05), always using the propensity score adjustment in the multivariate model. The survival time of a patient started at the time of surgery and ended at death (event) or at last follow-up (censoring). Statistical analysis was performed using Statistical Package for the Social Sciences, version 11 (SPSS, Chicago, IL). Results A total of 1,726 patients (mean age, years; male, 81.1%) undergoing elective on-pump CABG were reviewed, and 798 of 1,726 patients (46.2%) met the diagnostic criteria of MetS. Baseline characteristics stratified for MetS occurrence are shown in Table 1. Patients with MetS showed several significant differences in baseline characteristics such as peripheral vascular disease, renal function, and history of stroke. In addition, operative mortality predicted by logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) was found to be increased in patients with MetS (5.2% 4.6% versus 2.7% 3.9%; p ). Early Outcome Analysis The overall 30-day mortality rate was 2.7 (49 of 1,726 patients); postoperative morbidity and mortality are reported in Table 2. There was a statistically significant difference between cohorts in the rate of 30-day mortality (3.6% versus 1.9% in patients with and without MetS, respectively; 95% confidence interval [CI], 0.16 to 3.38; p 0.04), renal failure (9.9% versus 6.5% for MetS and no-mets patients, respectively; 95% CI, 0.81 to 6.07; p 0.01), and cardiac arrhythmias (25.4% versus 21.4% for MetS and no-mets patients, respectively; 95% CI, 0.15 to 8.21; p 0.05). A trend toward higher rates of stroke and MI in MetS patients was noted, but it did not reach statistical significance; however, cumulative incidence of MACCE was significantly higher in MetS patients (292 of 798 patients; 36.6%) than in patients without MetS (276 of 928 patients; 29.7%; 95% CI, 2.45 to 11.34; p for difference between groups). Univariate analysis showed age (OR, 3.27; 95% CI, 2.34 to 7.51; p ), female sex (OR, 1.91; 95% CI, 1.28 to 2.47; p 0.01), hypertension (OR, 2.19; 95% CI, 1.52 to 2.72; p 0.002), diabetes mellitus (OR, 1.61; 95% CI, 1.21 to 2.74; p 0.05), peripheral vascular disease (OR, 2.02; 95% CI, 1.41 to 2.27; p 0.04), chronic pulmonary disease (OR, 2.29; 95% CI, 1.85 to 5.36; p 0.003), renal failure (OR, 3.61; 95% CI, 2.05 to 6.89; p ), left ventricular dysfunction (OR, 2.47; 95% CI, 1.55 to 3.72; p 0.02), Table 1. Baseline and Operative Characteristics Characteristic a MetS Present (n 798) MetS Absent (n 928) p Value Age (y) Sex female, n (%) 224 (28.1) 143 (15.4) Body mass index (kg/m 2 ) Active smoking, n (%) 148 (18.5) 197 (21.2) 0.18 Hypertension, n (%) 804 (86.6) 410 (51.4) Diabetes mellitus, n (%) 409 (51.3) 160 (17.2) Glycemia (mmol/l) Triglycerides (mmol/l) HDL cholesterol (mmol/l) Peripheral vascular disease, n (%) 142 (17.8) 116 (12.5) COPD, n (%) 86 (10.8) 103 (11.1) 0.90 Preoperative GFR (ml min m 2 ) LVEF Previous MI, n (%) 408 (51.1) 469 (50.5) 0.87 Previous coronary interventions, n (%) 105 (13.2) 118 (12.7) 0.81 Previous stroke, n (%) 50 (6.3) 38 (4.1) 0.05 Logistic EuroSCORE, % CPB time (min) Aortic cross-clamp time (min) Distal anastomosis, n a Mean standard deviation for continuous variables are shown. COPD chronic obstructive pulmonary disease; CPB cardiopulmonary bypass; EuroSCORE European System for Cardiac Operative Risk Evaluation; GFR glomerular filtration rate; HDL high-density lipoprotein; LVEF left ventricular ejection fraction; MetS metabolic syndrome; MI myocardial infarction.

4 540 ANGELONI ET AL Ann Thorac Surg METABOLIC SYNDROME AND CORONARY SURGERY 2012;93: Table 2. Incidence of Postoperative Complications Stratified for Metabolic Syndrome Occurrence Complication MetS Present (n 798) MetS Absent (n 928) p Value Early postoperative 30-day mortality, n (%) 29 (3.6) 18 (1.9) 0.04 Myocardial infarction, n (%) 45 (5.6) 44 (4.7) 0.46 Stroke, n (%) 15 (1.9) 15 (1.6) 0.77 Cardiac arrhythmias, n (%) 203 (25.4) 199 (21.4) 0.05 MACCE, n (%) 292 (36.6) 276 (29.7) Renal failure, n (%) 79 (9.9) 60 (6.5) 0.01 At follow-up All-cause mortality, n (%) 56 (7) 43 (4.6) 0.04 Myocardial infarction, n (%) 61 (7.6) 59 (6.4) 0.37 Stroke, n (%) 23 (2.9) 25 (2.7) 0.91 Cardiac arrhythmias, n (%) 282 (35.3) 234 (25.2) MACCE, n (%) 418 (52.4) 367 (39.5) Renal failure, n (%) 96 (12) 81 (8.7) 0.03 MACCE major adverse cardiac and cerebrovascular events; MetS metabolic syndrome. history of stroke (OR, 2.55; 95% CI, 1.51 to 3.64; p 0.002), longer cardiopulmonary bypass time (OR, 4.17; 95% CI, 2.6 to 9.3; p ), and MetS (OR, 2.62; 95% CI, 1.71 to 4.9; p ) to be correlated with 30-day mortality. Multivariate propensity-adjusted logistic regression (Table 3) found as independent predictors of 30-day mortality older age (OR, 2.86; 95% CI, 1.77 to 4.83; p ), preoperative renal failure (OR, 2.33; 95% CI, 1.46 to 3.72; p 0.05), preoperative LVEF (OR, 2.26; 95% CI, 1.93 to 4.16; p 0.03), longer cardiopulmonary bypass time (OR, 2.25; 95% CI, 2.4 to 10.9; p ), and preoperative presence of metabolic syndrome (OR, 2.54; 95% CI, 1.51 to 5.26; p ). Follow-Up Analysis At a mean follow-up time of months (median, 38 months; range, 6 to 79 months), 1,679 of 1,726 hospital survivors (97.3%) were alive, and of the 769 hospital survivors having MetS at the time of surgery, despite medical recommendations and postoperative therapies, 668 of 769 of them (86.8%) still had MetS at the time of follow-up. Morbidity and mortality rates at follow-up are reported in Table 2: all-cause mortality (7% versus 4.6%; Table 3. Multivariable Propensity-Adjusted Hazards Ratios for Operative Mortality From Cox-Proportional Hazard Regression Variable Hazard Ratio 95% CI p Value Older age Metabolic syndrome Preoperative renal failure Preoperative LV dysfunction Longer CPB time CI confidence interval; CPB cardiopulmonary bypass; LV left ventricular. 95% CI, 0.2 to 4.7; p 0.04), cardiac arrhythmias (35.3% versus 25.2%; 95% CI, 5.76 to 14.42; p ), and renal failure (12% versus 8.7%; 95% CI, 0.43 to 6.24; p 0.03) still showed a significantly higher incidence in MetS patients. Similar to early postoperatively, at follow-up a higher incidence of stroke and MI was found among MetS patients, but it was not statistically significant, although the composite outcome of MACCE showed a significantly higher rate in MetS patients (52.4% versus 39.5%; 95% CI, 8.19 to 17.53; p ). At Kaplan-Meyer analysis, survival at 79 months after surgery (Fig 1) significantly differed between patients with and without MetS: 87.4% and 91.3%, respectively ( 2, 7.35; p 0.03). Variables correlated with late mortality at univariate analysis (age, male sex, MetS, chronic pulmonary disease, previous MI, preoperative LVEF, number of diseased vessels, and preoperative renal failure) were forced into a propensity adjusted Cox proportional hazards regression that showed only age (p ), preoperative LVEF (p 0.001), preoperative renal failure (p 0.001), and MetS (p 0.006) to be independent predictors of mortality late after surgery. The model was well fitted and calibrated ( 2, 28.2; p ). Interestingly, when substituting MetS with its individual components (waist circumference, diabetes mellitus, hypertension, hypertriglyceridemia, and low high-density lipoprotein cholesterol), only diabetes (p 0.04) correlated with mortality. The estimates of freedom from MACCE (Fig 2) also showed a statistically significant difference between cohorts at Kaplan-Meyer analysis: 47.6% versus 60.5% for patients with and without MetS, respectively ( 2, 9.63; p 0.001). Propensity adjusted Cox proportional hazards regression was performed using variables that showed a correlation with late occurrence of MACCE at univariate analysis (age, male sex, MetS, chronic pulmonary disease, previous MI, previous stroke, preoperative LVEF, number of diseased vessels, and preoperative renal failure) and showed age (p ), preoperative LVEF

5 Ann Thorac Surg ANGELONI ET AL 2012;93: METABOLIC SYNDROME AND CORONARY SURGERY 541 Fig 1. Survival after coronary artery bypass grafting stratified for metabolic syndrome (MS) occurrence at Kaplan-Meyer analysis. Dashed line indicates patients with metabolic syndrome, solid line patients without metabolic syndrome. (FU follow-up.) (p 0.03), preoperative renal failure (p ), and MetS (p ) as independent predictors of MACCE occurrence at follow-up. Also in these settings, when separately analyzing MetS components, only diabetes shows a statistically significant correlation with MACCE (p 0.05). The model was well fitted and calibrated (c index, 0.71). Levels of C-Reactive Protein At baseline, CRP was mg/l and mg/l in patients with and without MetS, respectively (p ). Postoperatively a minimum fivefold increase was found in every patient between days 5 and 7 after the operation, and the difference between MetS and no MetS patients was statistically significant ( mg/l versus mg/l, respectively; p ). At follow-up a significant difference in CRP levels was still noted: mg/l in patients with MetS and mg/l in patients without MetS (p ). Subanalysis of Diabetic Patients Diabetes was present in a consistently different proportion of patients among MetS and not MetS cohorts; 409 of 798 (51.3%) and 160 of 928 (17.2%), respectively. Although this statistically significant difference (p ) should have been corrected with the introduction of propensity score in the multivariate model, it would be of interest to look deeper into this result. Fig 2. Freedom from major adverse cardiac and cerebrovascular events (MACCE) after coronary artery bypass grafting stratified for metabolic syndrome (MS) occurrence at Kaplan-Meyer analysis. Dashed line indicates patients with metabolic syndrome, solid line patients without metabolic syndrome. (FU follow-up.)

6 542 ANGELONI ET AL Ann Thorac Surg METABOLIC SYNDROME AND CORONARY SURGERY 2012;93: Overall, diabetic patients (n 569) showed a higher incidence of mortality both early (2.5%) and late after surgery (4.8%) when compared with mortality rates of nondiabetic patients (n 1,175; early mortality, 2%; mortality at follow-up, 3.6%); in fact, as stated above, isolated diabetes was found to predict mortality when used instead of MetS in the multivariate analysis (p 0.04). On the other hand, MetS patients with (n 409) and without diabetes (n 389) did not show different rates of mortality both early (3.9% versus 3.6%; not significant) and late (7.1% versus 6.9%; not significant) after CABG. Subanalysis of Controlled Metabolic Syndrome Patients Of the 668 hospital survivors still meeting MetS diagnostic criteria at follow-up, 491 patients (73.5%), despite medical therapy and lifestyle recommendations, did not show a good control of one or more of the risk factors ( uncontrolled-mets group). The remaining 177 of 668 patients (26.5%), thanks to optimal medical therapy and appropriate lifestyle, instead reached a good control of their risk factors ( controlled-mets group). Compared with the uncontrolled-mets cohort, the subgroup of controlled-mets patients showed significantly lower rates of all-cause mortality (2.8% versus 4.5%; p 0.03), MI (1.7% versus 2.6%; p 0.04), cardiac arrhythmias (9.6% versus 12.6%; p 0.005), and cumulative MACCE (14.7% versus 21.2%; p 0.001; Table 4). In addition, compared with those patients not having MetS, the controlled-mets subgroup showed similar rates of mortality (2.8% versus 2.5%; p 0.11), MI (1.7% versus 1.5%; p 0.52), and renal failure (2.3% versus 2.1%; p 0.27). Levels of CRP were significantly higher in the uncontrolled-mets group ( mg/l) versus the controlled-mets group ( mg/l; p ), which was similar to the mean value found in the group of patients not having MetS ( mg/l; p 0.57). Comment The main finding of our study was the association between MetS and mortality both early and late after CABG. In addition to this major finding, both early and at midterm follow-up we also found that MetS correlated with renal failure, cardiac arrhythmias, and cumulative incidence of MACCE. Of note, the rates of stroke and MI were not significantly different, although definitely higher in the cohort of patients with MetS. Whereas several risk factors included in MetS, such as diabetes and obesity, have been reported to increase mortality and morbidity after CABG [4, 5, 21], results are discordant and only a few papers investigated the role of MetS in these patients [14 16], although none of them focused attention on the late outcome after CABG. In particular, a study by Alexander and colleagues [22] showed a lower prevalence of CAD in patients with diabetes but without MetS and a significantly higher incidence of CAD in those patients who, instead, had MetS including diabetes, thus suggesting that the metabolic alterations associated with MetS should play an important role in the genesis of CAD. Furthermore, consistent with previous reports [23], our population of CAD patients showed an increased prevalence of MetS with respect to the general population, underlying the strong association between these two diseases. In addition other studies investigated the effects of MetS in CABG patients [24 27], reporting controversial results, but two of those [24, 25] were statistically underpowered because of the small sample size (respectively n 50 and n 74 patients having MetS), the paper by Brackbill and associates [26] investigated a little larger sample (n 333 patients with MetS) but performed a sex-based analysis, and finally, the paper by Kajimoto and coworkers [27] refers to patients operated on back in the 1980s, with different surgical techniques and medical management. Early Outcome Results In MetS patients a low-grade proinflammatory state is described, confirmed by elevated levels of circulating Table 4. Subanalysis of the Impact on the Outcomes at Follow-Up of Optimal Medical Therapy and Appropriate Lifestyle Behaviors Variable Uncontrolled MetS (n 491) p Value Controlled MetS (n 177) p Value MetS Absent (n 1,011) Mortality, n (%) 22 (4.5) (2.8) (2.5) MI, n (%) 13 (2.6) (1.7) (1.5) Stroke, n (%) 6 (1.2) (1.1) (1.0) Cardiac arrhythmias, n (%) 62 (12.6) (9.6) (3.5) MACCE, n (%) 104 (21.2) (14.7) (9.0) Renal failure, n (%) 13 (2.6) (2.3) (2.1) CRP (mg/l) a a Values are mean standard deviation. CRP C-reactive protein; MACCE major adverse cardiac and cerebrovascular events; MetS metabolic syndrome; MI myocardial infarction.

7 Ann Thorac Surg ANGELONI ET AL 2012;93: METABOLIC SYNDROME AND CORONARY SURGERY 543 cytokines [9, 10, 28]; specifically, an elevated level of CRP and a decrease in adipocytokines levels has been demonstrated [29, 30]. Adipose tissue acts as an endocrine organ, secreting adipocytokines that are related to systemic inflammation and being responsible for glucose and lipid metabolism, which play a substantial role in the pathogenesis and complications of obesity [9]. Adiponectin, the most abundant adipocytokine, has been shown to be related to CRP in various populations [9, 10] and has been demonstrated to inhibit the inflammatory activation of the vascular wall [30]. The elevation of CRP levels correlates with the liver stimulation induced by interleukin-6 secreted by visceral adipocytes [31]. All these factors could exacerbate the inflammatory response as a result of extracorporeal circulation and surgical trauma, which seems to be the best explanation of the impact of MetS on the early outcome after CABG. Furthermore, the logistic euroscore identified those with MetS as high-risk patients, showing a significantly higher predicted operative mortality in that cohort. As expected, other factors, such as older age, preoperative left ventricular dysfunction, preoperative renal failure, and prolonged cardiopulmonary bypass time, were found to be correlated with mortality early after surgery. Late Outcome Results Patients with MetS appear as a selected high-risk population because of all the important comorbidities (obesity, diabetes, dyslipidemia, hypertension), and the poor outcomes observed at long-term follow-up appear to be correlated with that patient profile. Given that, the different (higher) levels of CRP found at follow-up in patients with MetS may contribute to the low-grade inflammatory state that predisposes those patients to the occurrence of related complications and confirm the key role played by MetS in the clinical outcome late after CABG. Indeed, CRP has already been correlated to atherosclerosis and cardiovascular events after CABG [32]. Moreover, the subanalysis of single components of MetS did not identify any of them as a risk factor for mortality and morbidity after CABG, except for the weak correlation (p 0.05) found with diabetes. This indicates that MetS should be considered as an independent, unique risk factor affecting outcomes late after CABG. Furthermore, given that the other independent predictors of long-term mortality (age, preoperative LVEF, and preoperative renal failure) are not modifiable variables, postoperative therapy of MetS should be of paramount importance to reduce the risk of mortality late after surgery. From this point of view, optimal medical therapy and lifestyle behavior play a key role to achieve good control of the risk factors clustered into MetS. In a subanalysis of such patients, the controlled MetS subgroup showed rates of mortality, MI, and stroke similar to those found in patients not having MetS; on the other hand, patients with controlled MetS showed significantly lower rates of mortality and MI with respect to those patients with uncontrolled MetS. In these settings, the finding of lower CRP levels in such controlled MetS patients may indicate a regression of the low-grade proinflammatory state normally present in MetS patients, and may partially account for the improved outcome of those patients. Thus, optimal medical therapy and appropriate lifestyle behavior can lead to a controlled form of MetS, showing better long-term outcomes after CABG. Limitations Although all the data, including complications and CRP measurements, were prospectively collected, this is a retrospective study. The numerous differences in baseline characteristics between MetS and no MetS cohorts used to perform a propensity score adjustment were found to reduce the effect of confounding factors. Metabolic syndrome was assessed using BMI because waist circumferences were not available. Although international guidelines suggest the use of waist circumference to classify obesity, there are several studies demonstrating there is no significant difference between the two classification methods and MetS using BMI instead of waist circumference. Conclusions Given that only MetS and none of its individual components showed a significant predictive power for mortality and morbidity early and late after CABG, MetS should be recognized as a novel, independent preoperative variable that can lead to identification of high-risk patients and, moreover, as a risk factor to correct with lifestyle modifications and pharmacologic therapy [33] to improve the results of surgery. Finally, the modifiable nature of MetS should lead to a careful, patient-fitted postoperative management of medications and lifestyle issues to reverse the metabolic alterations responsible for MetS [12, 13, 16]. References 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285: Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112: Ford ES. Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the U.S. Diabetes Care 2005;28: Carson JL, Scholz PM, Chen AY, Peterson ED, Gold J, Schneider SH. Diabetes mellitus increases short-term mortality and morbidity in patients undergoing coronary artery bypass graft surgery. J Am Coll Cardiol 2002;40: Nalysnyk L, Fahrbach K, Reynolds MW, Zhao SZ, Ross S. Adverse events in coronary artery bypass graft (CABG) trials: a systematic review and analysis. Heart 2003;89: Wigfield CH, Lindsey JD, Muñoz A, Chopra PS, Edwards NM, Love RB. Is extreme obesity a risk factor for cardiac surgery? An analysis of patients with a BMI 40. Eur J Cardiothorac Surg 2006;29:

8 544 ANGELONI ET AL Ann Thorac Surg METABOLIC SYNDROME AND CORONARY SURGERY 2012;93: Glance LG, Wissler R, Mukamel DB, et al. Perioperative outcomes among patients with the modified metabolic syndrome who are undergoing noncardiac surgery. Anesthesiology 2010;113: Yatskar L, Holper E, Bansilal S, et al; BARI Investigators. Long-term outcomes in non-diabetic patients with metabolic syndrome undergoing revascularization for multi-vessel coronary artery disease. Atherosclerosis 2008;198: von Eynatten M, Hamann A, Twardella D, Nawroth PP, Brenner H, Rothenbacher D. Relationship of adiponectin with markers of systemic inflammation, atherogenic dyslipidemia, and heart failure in patients with coronary heart disease. Clin Chem 2006;52: Kistorp C, Faber J, Galatius S, et al. Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure. Circulation 2005;112: Nigam A, Bourassa MG, Fortier A, Guertin MC, Tardif JC. The metabolic syndrome and its components and the longterm risk of death in patients with coronary heart disease. Am Heart J 2006;151: Kasai T, Miyauchi K, Kurata T, et al. Impact of metabolic syndrome among patients with and without diabetes mellitus on long-term outcomes after percutaneous coronary intervention. Hypertens Res 2008;31: Kasai T, Miyauchi K, Kajimoto K, et al. The adverse prognostic significance of the metabolic syndrome with and without hypertension in patients who underwent complete coronary revascularization. J Hypertens 2009;27: Echaidi N, Pibarot P, Després JP, et al. Metabolic syndrome increases operative mortality in patients undergoing coronary artery bypass grafting surgery. J Am Coll Cardiol 2007;50: Echaidi N, Mohty D, Pibarot P, et al. Obesity and metabolic syndrome are independent risk factors for atrial fibrillation after coronary artery bypass graft surgery. Circulation 2007; 116(11 Suppl):I Kajimoto K, Miyauchi K, Kasai T, et al. Metabolic syndrome is an independent risk factor for stroke and acute renal failure after coronary artery bypass grafting. J Thorac Cardiovasc Surg 2009;137: Wong ND, Sciammarella MG, Polk D, et al. The metabolic syndrome, diabetes and subclinical atherosclerosis assessed by coronary calcium. J Am Coll Cardiol 2003;41: Janssen I, Katzmarzyk PT, Ross R. Body mass index, waist circumference and health risk. Arch Inten Med 2002;162: Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function measured and estimated glomerular filtration rate. N Engl J Med 2006;354: Blackstone EH. Comparing apples and oranges. J Thorac Cardiovasc Surg 2002;123: Hakala T, Pitkänen O, Halonen P, Mustonen J, Turpeinen A, Hippelainen M. Early and late outcome after coronary artery bypass surgery in diabetic patients. Scand Cardiovasc J 2005;39: Alexander CM, Landsman PB, Teutsch SM, Haffner SM; Third National Health and Nutrition Examination Survey (NHANES III); National Cholesterol Education Program (NCEP). NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 2003;52: Solymoss BC, Bourassa MG, Lespérance J, et al. Incidence and clinical characteristics of the metabolic syndrome in patients with coronary artery disease. Coron Artery Dis 2003;14: Ozyazicioglu A, Yalcinkaya S, Vural AH, Yumun G, Bozhurt O. Effects of metabolic syndrome on early mortality and morbidity in coronary artery bypass graft patients. J Int Med Res 2010;38: Pimenta E, Passarelli O Jr, Borelli F, et al. Metabolic syndrome in patients undergoing coronary artery bypass graft: prevalence and a marker of morbidity/mortality during hospitalization and 30 days after hospital discharge. Arq Bras Cardiol 2007;88: Brackbill ML, Sytsma CS, Sykes K. Perioperative outcomes of coronary artery bypass grafting: effects of metabolic syndrome and patient s sex. Am J Crit Care 2009;18: Kajimoto K, Kasai T, Miyauchi K, et al. Metabolic syndrome predicts 10-year mortality in non-diabetic patients following coronary artery bypass surgery. Circ J 2008;72; Després JP. Inflammation and cardiovascular disease: is abdominal obesity the missing link? Int J Obes Metab Disord 2003;27(Suppl 3):S Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 1998;83: Côté M, Mauriège P, Bergeron J, et al. Adiponectinemia in visceral obesity: impact on glucose tolerance and plasma lipoprotein and lipid levels in men. J Clin Endocrinol Metab 2005;90: Ouchi N, Kihara S, Arita Y, et al. Adiponectin, an adipocytederived plasma protein, inhibits endothelial NF-kappaB signaling through a camp-dependent pathway. Circulation 2000;102: Sung SH, Wu TC, Huang CH, Lin SJ, Chen JW. Prognostic impact of body mass index in patients undergoing coronary artery bypass surgery. Heart 2011;97: Després JP, Golay A, Sjostrom L; Rimonabant in Obesity- Lipids Study Group. Effects of rimonabant on the metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353: