Relation of Metabolic Syndrome With Long-Term Mortality in Acute and Stable Coronary Disease

Relation of Metabolic Syndrome With Long-Term Mortality in Acute and Stable Coronary Disease Yaron Arbel, MDa,*, Ofer Havakuk, MDa, Amir Halkin, MDa, Miri Revivo, MHAa, Shlomo Berliner, MDb,c, Itzhak Herz, MDa, Ahuva Weiss-Meilik, PhDd, Yael Sagy, PhDd, Gad Keren, MDa, Ariel Finkelstein, MDa, and Shmuel Banai, MDa Past studies examining the effects of the metabolic syndrome (MS) on prognosis in postangiography patients were limited in size or were controversial in results. The aim of the study was to examine the association of the MS and the risk for long-term mortality in a large cohort of patients undergoing coronary angiography for various clinical indications. Medical history, physical examination, and laboratory values were used to diagnose patients with the MS. Cox regression models were used to analyze the effect of MS on longterm all-cause mortality. We prospectively recruited 3,525 consecutive patients with a mean age of 66 – 22 years (range 24 to 97) and 72% men. Thirty percent of the cohort had MS. Patients with MS were more likely to have advanced coronary artery disease and acute coronary syndrome (p <0.001). Patients with MS had more abnormalities in their metabolic and inflammatory biomarkers regardless of their clinical presentation. A total of 495 deaths occurred during a mean follow-up period of 1,614 – 709 days (median 1,780, interquartile range 1,030 to 2,178). MS was associated with an increased risk of death in the general cohort (hazard ratio [HR] 1.27, 95% confidence interval [CI] 1.01 to 1.56, p [ 0.02). MS had a significant effect on mortality in stable patients (HR 1.55, 95% CI 1.1 to 2.18, p [ 0.01), whereas it did not have a significant effect on mortality in patients with acute coronary syndrome (HR 1.11, 95% CI 0.86 to 1.44, p [ 0.42). In conclusion, MS is associated with increased mortality in postangiography patients. Its adverse outcome is mainly seen in patients with stable angina. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;115:283e287)

In the present study, we examined whether the presence of metabolic syndrome (MS) constitutes a risk factor for long-term mortality in a large cohort of patients undergoing coronary angiography for various clinical indications. We aimed to assess the association of the MS in patients presenting with acute coronary syndrome (ACS) compared with patients presenting with stable angina. Methods The data in this study were collected from the Tel Aviv Prospective Angiographic Survey (TAPAS) database. The TAPAS is a prospective, single-center registry that enrolls all patients undergoing cardiac catheterization at the Tel Aviv Medical Center.1e6 The study cohort consisted of consecutive patients referred for coronary angiography in our institution for various clinical presentations. Excluded were patients with known diabetes mellitus (DM) because Departments of aCardiology, bInternal Medicine “D,” cInternal Medicine “E,” and dClinical Performance Research Unit, Tel Aviv Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Manuscript received September 11, 2014; revised manuscript received and accepted October 28, 2014. This study was supported by internal departmental resources. See page 286 for disclosure information. *Corresponding author: Tel: (þ972) 3-6973395; fax: (þ972) 36962334. E-mail address: [email protected] (Y. Arbel). 0002-9149/14/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.10.037

we aimed to evaluate the effect of MS on outcomes without the confounding effect of diabetic patients.7 All the enrollees signed a written informed consent for participation in the study, which was approved by the institutional ethics committee. The primary end point of the study was death from any cause. The data were obtained from the Israeli Ministry of Health mortality records. End of follow-up was defined as the first from the following events: death from any cause or November 1, 2013. MS was diagnosed according to current guidelines. Shortly, waist circumference
102 cm in men and
88 cm in women, triglycerides
150 mg/dl, high-density lipoprotein cholesterol <40 mg/dl in men and <50 mg/dl in women, elevated blood pressure (
130 mm Hg systolic pressure or
85 mm Hg diastolic pressure), and fasting glucose
100 mg/dl. The presence of
3 of the individual criteria was categorized as MS. Recently, it was shown that diagnosis of MS during hospitalization for ACS is accurate.8 Categorical variables were compared using the chisquare test and continuous variables by t test (presented as means with SD) or the Kruskal-Wallis/Mann-Whitney test (medians with interquartile range). Continuous variables were tested for normal distribution using the KolmogorovSmirnov test and Q-Q plots. All-cause mortality was evaluated using univariate and multivariate Cox proportional hazard regression. All clinical features, biochemical variables, and potential confounders that were significant in univariate analysis, as presented in Table 1, were available www.ajconline.org

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Table 1 Clinical characteristics of the study population according to the presence or absence of the metabolic syndrome (total n ¼ 3529) Variable

Males Age(years) Hypertension Impaired fasting glucose Dyslipidemia Peripheral arterial disease Known coronary heart disease Prior myocardial infarction Prior stroke Prior coronary artery bypass surgery Current smoker Past smoker Indications for angiography Unstable angina pectoris Stable angina pectoris Non-ST elevation myocardial infarction ST elevation myocardial infarction Number of narrowed coronary arteries 0 1 2 3 Medications Aspirin Statins b-blockers Clopidogrel Angiotensin converting enzyme inhibitors Angiotensin II receptor blockers Oral Hypoglycemics

Entire cohort

Metabolic Syndrome

P value*

(N¼3525)

YES(N¼1055)

NO (N¼2470)

2555 (72.5%) 65.412.2 2347 (66.5%) 786 (22.3%) 2492 (70.6%) 581 (16.5%) 1610 (45.6%) 840 (23.8%) 337 (9.5%) 454 (12.9%) 855 (24%) 1342 (38%)

742 (70%) 65.812.5 958 (91%) 413 (39%) 838 (79%) 223 (21%) 557 (53%) 305 (29%) 115 (11%) 152 (14%) 253 (24%) 433 (41%)

1813(73%) 64.411.5 1385 (56%) 370 (15%) 1650 (67%) 356 (14%) 1052 (43%) 535 (22%) 221 (9%) 301 (12%) 600 (24%) 908 (37%)

0.06 0.01 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.07 0.07 0.017

790 1703 608 428

(22%) (48%) (17%) (12%)

277 474 195 109

(26%) (45%) (19%) (10%)

512(20%) 1226(50%) 413(17%) 319(13%)

0.055

846 776 846 1057

(24%) (22%) (24%) (30%)

211 232 274 338

(20%) (22%) (26%) (32%)

643(26%) 543(22%) 568(23%) 716(29%)

0.002

2979 2595 2242 1412 1608 388 431

(84.4%) (73.5%) (63.5%) (40%) (46%) (11%) (12.2%)

897 769 732 415 553 152 253

(85%) (73%) (69%) (39%) (52%) (14%) (24%)

2079 (84%) 1823 (74%) 1508 (61%) 996 (40%) 1053 (43%) 235 (10%) 176(7%)

0.52 0.57 <0.001 0.58 <0.001 <0.001 <0.001

b-blockers ¼ Beta blockers. * p value relates to the comparison of MetS to non-MetS patients.

considered statistically significant. All analyses were performed with the SPSS 19.0 software (SPSS Inc., Chicago, Illinois).

Results

Figure 1. Distribution of CAD severity according to the MS.

for selection in this model. The influence of MS was checked by assessing its significance by adding it in a second block in the regression models. A 2-tailed p <0.05 was

A total of 3,525 consecutive patients referred for coronary angiography at the Tel Aviv Medical Center were included in the final analysis. The mean age was 66  22 years (range 24 to 97), and 72% were men. Thirty percent of the study population was diagnosed as having MS. The baseline clinical characteristics are presented in Table 1. Patients with MS had more cardiac risk factors and more history of myocardial infarction. However, they did not receive more evidence-based medications (statins, aspirin, and so on). Patients with MS presented with more advanced coronary artery disease (CAD) (odds ratio 1.4, 95% confidence interval [CI] 1.17 to 1.76, p ¼ 0.001; Figure 1) and were more likely to present with ACS (Table 1). In addition, the rate of percutaneous coronary intervention was higher in patients with MS than in the rest of the cohort (69% vs 49%, respectively, p <0.001). Patients with MS had unfavorable laboratory tests (Table 2), regardless of the clinical presentation.

Coronary Artery Disease/Metabolic Syndrome and Coronary Angiography

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Table 2 Metabolic and inflammatory biomarkers in patients with stable and unstable coronary syndrome according to the presence of absence of the metabolic syndrome Variable

Glucose (mg/dl) Hs-CRP Fibrinogen (mg/dl) Total Cholesterol (mg/dl) Triglycerides (mg/dl) High density lipoprotein cholesterol(mg/dl) Non High density lipoprotein cholesterol (mg/dl) Low density lipoprotein cholesterol (mg/dl) HbA1c (%)

Acute Coronary Syndrome

p

Stable angina pectoris

p

Metabolic Syndrome

No Metabolic Syndrome

Metabolic Syndrome

No Metabolic Syndrome

N¼603

N¼1288

N¼452

N¼1182

12753 1222 34689 17341 191108 358

10129 1328 34297 17039 11576 4412

<0.001 <0.001 <0.001 0.09 <0.001 <0.001

11241 8.616 32683 16438 17690 378.6

9424 614 30775 16436 10955 4713

<0.001 <0.001 <0.001 0.78 <0.001 <0.001

13840

12638

<0.001

12636

11737

<0.001

10035

10333

0.07

9231

9530

0.054

6.61.4

5.80.7

<0.001

6.41.2

5.80.7

<0.001

When we evaluated the different components of the MS in univariate analysis and their effect on outcome, hypertension was the most significant factor (HR 1.97, 95% CI 1.58 to 2.45, p <0.001) and impaired glucose tolerance was the second (HR 1.53, 95% CI 1.23e1.90, p <0.001). In multivariate analysis, they were not significant unless grouped together as the MS. Discussion

Figure 2. Kaplan-Meier curves of the entire cohort and the occurrence of all-cause mortality according to the presence or absence of the MS.

A total of 495 deaths occurred during a mean follow-up period of 1,614  709 days (median 1,780, interquartile range 1,030 to 2,178). MS was associated with an increased risk of death in the general cohort (hazard ratio [HR] 1.27, 95% CI 1.01 to 1.56, p ¼ 0.02; Figure 2). The addition of MS to the regression analysis for long-term mortality was significant (chi-square ¼ 5.2, p ¼ 0.02). Death rate was 11% in the stable angina group and 17% in the ACS group (p <0.001). MS was a significant predictor of long-term mortality in patients with stable angina (HR 1.55, 95% CI 1.1 to 2.18, p ¼ 0.01), whereas it was not a significant predictor of death in the ACS group of patients (HR 1.11, 95% CI 0.86 to 1.44, p ¼ 0.42). The addition of MS to the regression was significant for predicting long-term mortality (chi-square ¼ 6.0, p ¼ 0.014) in patients presenting with the stable angina (Figure 3).

In the present study, we show that in patients referred for coronary angiography, the presence of MS is associated with an increased risk for death during a follow-up of up to 6 years. Patients with MS were more likely to present with ACS, demonstrate more advance CAD, and have more metabolic and inflammatory abnormalities. In subgroup analysis, MS was associated with increased mortality in patients presenting with stable angina but not in patients presenting with ACS. Past large-scale studies chose to evaluate the prognostic significance of a single metabolic biomarker and not the compound effect of dysmetabolism as evident by the MS.9 MS was associated with adverse outcome in some studies,10,11 whereas other studies were unable to demonstrate such an association.12,13 In addition, past studies were limited by their small size and relatively modest follow-up period.8,13 MS was shown to be related to more progressive atherosclerosis starting at an early age14 and with more plaque burden, necrotic core, and calcium content.11 Other studies have not been able to demonstrate increased CAD in patients with MS without DM.7 The importance of our findings is due to the fact that we are the largest prospective trial in patients undergoing coronary angiography evaluating the effect of MS on long-term mortality. We excluded diabetic patients from our analysis to focus only on patients with the MS without DM. Our findings should help raise awareness of physicians and patients to this important treatable risk factor.15e17 The exact mechanism that could explain the differential effect of MS on long-term mortality of patients with stable angina and

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Figure 3. Kaplan-Meier curves of patients with and without the MS according to clinical presentation. (A) Patients with stable angina. (B) Patients with ACS.

ACS is not clear. It can be hypothesized that because patients with ACS are regarded as very high-risk patients, MS is a weaker risk factor compared with lower ejection fraction, residual ischemia, and so on. In addition, patients with ACS receive more evidencebased therapies and, therefore, are less influenced by MS compared with patients with stable angina. MS is a cluster of risk factors and can be treated effectively by evidence-based therapies.18 Weight reduction strategies were shown not to be limited to weight loss, but also to an improvement in inflammatory and metabolic biomarkers.19,20 Other strategies that were found to be effective in risk reduction are lipid-lowering therapies using statins18e21 and exercise training. Yet, despite this accumulating data, it was shown that health care providers fail to recognize the magnitude of the problem and to address its implications.21 Limitations of the study include the fact that it is observational and not randomized. In addition, referral bias could lead to differential referral of patients with MS to coronary angiogram compared with patients without MS. Furthermore, we do not have data on the changes of waist circumference or laboratory results over time and the incidence of new DM. In conclusion, MS was found to be significantly associated with adverse outcome in stable patients and not in patients with ACS.

4.

5.

6.

7.

8.

9.

10.

Disclosures The authors have no conflicts of interest to disclose. 1. Arbel Y, Zlotnik M, Halkin A, Havakuk O, Berliner S, Herz I, Rabinovich I, Keren G, Bazan S, Finkelstein A, Banai S. Admission glucose, fasting glucose, HbA1c levels and the SYNTAX score in nondiabetic patients undergoing coronary angiography. Clin Res Cardiol 2014;103:223e227. 2. Arbel Y, Szekely Y, Berliner S, Hallevi H, Halkin A, Herz I, Keren G, Bazan S, Bornstein N, Banai S, Finkelstein A. Lack of correlation between coronary blood flow and carotid intima media thickness. Clin Hemorheol Microcirc 2014;56:371e381. 3. Arbel Y, Sternfeld A, Barak A, Burgansky-Eliash Z, Halkin A, Berliner S, Herz I, Keren G, Rubinstein A, Banai S, Finkelstein A. Inverse correlation between coronary and retinal blood flows in patients with

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Coronary Artery Disease/Metabolic Syndrome and Coronary Angiography in young people with a clinical diagnosis of familial hypercholesterolaemia. Kardiol Pol 2013;71:566e572. 15. Zhao XQ, Krasuski RA, Baer J, Whitney EJ, Neradilek B, Chait A, Marcovina S, Albers JJ, Brown BG. Effects of combination lipid therapy on coronary stenosis progression and clinical cardiovascular events in coronary disease patients with metabolic syndrome: a combined analysis of the Familial Atherosclerosis Treatment Study (FATS), the HDLAtherosclerosis Treatment Study (HATS), and the Armed Forces Regression Study (AFREGS). Am J Cardiol 2009;104:1457e1464. 16. Tang L, Patao C, Chuang J, Wong ND. Cardiovascular risk factor control and adherence to recommended lifestyle and medical therapies in persons with coronary heart disease (from the National Health and Nutrition Examination Survey 2007-2010). Am J Cardiol 2013;112: 1126e1132. 17. Prasad SB, Fahrtash F, Malaiapan Y, Meredith IT, Cameron J. Obesity and the metabolic syndrome in patients with acute myocardial infarction. Int J Cardiol 2010;144:450e451.

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