O R I G I N A L A R T I C L E
The severity of coronary atherosclerosis in diabetic and
non-diabetic metabolic syndrome patients diagnosed according
to different criteria and undergoing elective angiography
S. Ertek•A. F. Cicero• M. Cesur•
M. Akcil•T. Altuner Kayhan•U. Avcioglu•
M. E. Korkmaz
Received: 30 November 2009 / Accepted: 21 July 2010 / Published online: 3 August 2010 Ó Springer-Verlag 2010
Abstract Our aim in this study was to evaluate the relationship between metabolic syndrome (MS) as defined by different criteria and the severity of coronary lesions in a sample of diabetic and non-diabetic patients undergoing elective coronary angiography. All patients had blood and urine tests, physical examinations were performed before angiography, and finally they were classified based on three criteria (World Health Organisation-WHO, Adult Treat-ment Panel-ATP III and International Diabetes Federation-IDF). Eighty-eight patients were diabetic, and 96 patients were non-diabetic. Among all patients, diabetics had sig-nificantly higher Gensini scores (P \ 0.001). According to WHO criteria (P = 0.005) and IDF criteria (P = 0.015) metabolic syndrome patients had higher Gensini scores, but
for ATP III criteria difference was not significant. When we evaluated diabetics and diabetics separately, non-diabetic patients with MS had significantly higher scores with WHO definition (P = 0.015) and mildly higher but not significant values with other MS criteria (P = 0.057 for both IDF and ATP III). Neither any one of MS components nor gender revealed significant relationship with coronary disease severity. In our study with a cohort of Turkish patients undergoing elective coronary angiography; we concluded that MS should be taken into consideration, especially in non-diabetic patients.
Keywords Metabolic syndrome Epidemiology Coronary artery disease Diabetes Coronary heart disease
Introduction
Metabolic syndrome (MS) is very common and complex disease characterized by insulin resistance with increased cardiovascular risk [1]. Currently, the most widely accep-ted criteria for diagnosis of MS are those put forward by the World Health Organization (WHO), the International Diabetes Foundation (IDF), and the updated definition of National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) [2–4].
Different studies highlighted the relationship between having diagnosis of MS and coronary mortality and mor-bidity [1, 5] and compared prognostic utility of different MS criteria [6–10]; however, the association of different MS diagnostic criteria with current vascular disease severity has been yet not been investigated in depth, and less data are available for the Mediterranean populations.
In this context, the primary aim of our study was to evaluate whether MS defined by different current S. Ertek (&)
Department of Endocrinology and Metabolic Diseases, Ufuk University, Dr. Ridvan Ege Hospital,
Mevlana Bulvari 86-88, 06520 Ankara, Turkey e-mail: sibelertek@yahoo.it
A. F. Cicero
Department of Internal Medicine, Aging and Kidney Diseases, Bologna University, Bologna, Italy
M. Cesur
Department of Endocrinology and Metabolic Diseases, Guven Hospital, Ankara, Turkey
M. Akcil
Faculty of Science and Letters, Department of Statistics and Computer Science, Baskent University, Ankara, Turkey U. Avcioglu
Department of Internal Medicine, Guven Hospital, Ankara, Turkey T. A. Kayhan M. E. Korkmaz
Department of Cardiology, Guven Hospital, Ankara, Turkey DOI 10.1007/s00592-010-0211-7
guidelines is similarly associated with coronary lesion severity in a cohort of Turkish patients who are candi-dates for elective coronary angiography. We aimed to evaluate whether there was effect of differences between three criteria predicting coronary lesions that were severe enough to require percutaneous or surgical intervention. The secondary aims were to evaluate whether single MS components could be independently associated with the coronary lesion severity and to see whether coronary lesion severity was different in MS patients with or without type 2 diabetes as diagnosed by oral glucose tolerance test.
Materials and methods Patients and procedure
We enrolled 184 patients examined by the Cardiology Department of Ankara Guven Hospital to this study. They had clinical suspicion of coronary artery disease and electively underwent their first coronary angiography because of ECG and/or stress test findings, perfusion scintigraphy, or patients with high-risk profile with angina pectoris, on the basis of the American College of Cardi-ology/American Heart Association (ACC/AHA) guidelines [11]. In this group of 117 male (63.6%), 67 female (36.4%) patients, mean age was 57.9 ± 10.4 years. The study was initiated in March 2007 and concluded in September 2007. The patients with vasospastic angina were excluded from the study group.
Patients were evaluated on the day of their angiography, before the intervention. Blood pressure was measured on sitting position before coronary angiography at least four times for each patient, and the average value was calcu-lated [12]. The patients were grouped as hypertensive and/ or dyslipidemic according to the above-cited guidelines of seventh report of Joint Committee and ATP III [4,12]. All patients were informed about the study, and they signed informed consents. The approval of the local ethical committee was obtained.
Venous blood and urine samples were obtained early in the morning on the day of angiography for measuring fasting blood glucose, glycohemoglobin (HbA1C), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, high sensitive C-reactive protein (hsCRP), and microal-buminuria levels. All laboratory measurements were car-ried out with standardized methods in the central laboratories of Ankara Guven Hospital. All patients with-out known diabetes underwent 75 g oral glucose tolerance test (OGTT) early in the morning, before angiography.
Plasma glucose levels were measured with enzymatic colorimetric method. Microparticule enzyme immunoassay (MEIA) was used for insulin measurements, and immu-noturbidimetric method was used for hsCRP in blood and for microalbumin in urine. Insulin measurements were taken with Abbott AXSYM analyzer with an inter-assay coefficient of variation of 2.6%. Total cholesterol, LDL, and HDL levels and triglycerides were measured by enzymatic colorimetric assay. HbA1c was measured by turbidometric inhibition immunoassay with Roche Hitachi 912 analyzer with an inter-assay coefficient of variation of 2.3%.
The OGTT results of the non-diabetic patients were evaluated according to American Diabetes Association (ADA) criteria for type 2 diabetes [13]. The reciprocal index of homeostasis model assessment (HOMA-IR) was calculated as the product of fasting plasma glucose (mg/ dL) by plasma insulin (mIU/L), divided by a constant (405), as measure of insulin resistance [14].
Patients were then classified as MS in accordance with WHO, ATP III, and IDF guidelines [3, 4, 15, 16]. Fra-mingham risk scoring (FRS) was also performed [17,18]. Extent of coronary artery disease was assessed by Gensini scoring system [19], which grades narrowing of the lumens of the coronary arteries as: 1 for 1–25% nar-rowing; 2, 26–50% narnar-rowing; 4, 51–75% narrowing, 8, 76–90% narrowing; 16, 91– 99% narrowing and 32 for total occlusion. This score was then multiplied by a factor that takes into account the importance of the lesion’s position in the coronary arterial tree, for example, 5 for the left main coronary artery, 2.5 for the proximal LAD or proximal LCx, 1.5 for the mid-region of the LAD, and 1 for the distal LAD or mid-distal region of the LCx.
Statistical analyses
Kolmogorov–Smirnov test was performed to the test the distribution of all continuous variables. Since the evaluated variables did not have normal distribution, we compared them with Kruskal–Wallis non-parametric analysis of variance and by Mann–Whitney U-test. Chi-square analy-ses were used to compare three groups, and Fisher exact tests were used to compare categorical data, when neces-sary. Multivariate logistic regression models were then used to evaluate the association between coronary artery disease and different parameters described within the text, in all studied patients and in diabetic and non-diabetic subgroups.
P values of \0.05 were accepted as being statistically significant. All statistical analyses were carried out using Statistical Packages for Social Sciences (SPSS 13.0, Inc Chicago, IL, USA).
Results
Of all patients, 112 (60.9%) were reported as non-diabetic and 72 as diabetic (39.1%) before the coronary angiogra-phy and OGTT. Ninety-five of the non-diabetic patients accepted to undergo 75 g OGTT test before coronary angiography, and 16 of them were not aware of being affected by type 2 diabetes. Thus, we had 88 diabetic patients (47.8%) in total and 96 non-diabetic patients (52.2%). Among those non-diabetics; 16 had impaired fasting glucose (IFG), 17 had impaired glucose tolerance (IGT) and 17 had both.
Ninety-nine patients (51.6%) were active smokers. Fifty-one (76.1%) women were menopausal (Table1).
The prevalence of diabetes among MS patients was 67% according to WHO guidelines, 70% according to ATP III guidelines and 65.5% according to IDF. For these patients, the mean HbA1c value was 8.3% (with standard error of mean 0.24).
When we consider all patients with and without MS, diabetics had significantly higher Gensini scores (P \ 0.001). Patients with MS as defined by WHO criteria (P = 0.005) and IDF criteria (P = 0.015) had higher
Gensini scores, while contrarily to those with MS defined by ATP III ones (Table2).
When we evaluated diabetics and non-diabetics sepa-rately, according to WHO criteria, non-diabetic MS patients have significantly higher Gensini scores than non-MS (P = 0.015) but in diabetic non-MS patients the difference was not significant (P = 0.551). For IDF criteria, in non-diabetic patients with MS and without MS, there was no difference regarding Gensini scores (P = 0.057), also not significant in diabetics (P = 0.421). For ATP III criteria, the differences between MS and non-MS was not statisti-cally different in either group, in diabetics (P = 0.057) and non-diabetics (P = 0.421) (Table3).
Since the Gensini scores were not normally distributed in data, we divided the patients into two atherosclerosis groups on the basis of Gensini scores, as mild (\20) and severe (C20) for logistic regression analysis [20], to ana-lyze the effects of gender, waist circumference, BMI, microalbuminuria, fasting glucose, and presence of hypertension or hyperlipidemia in diabetics and non-dia-betics. The analysis did not give any significant result for any of these parameters (P [ 0.05 for all). We also eval-uated other parameters not included in MS diagnosis Table 1 Main anagraphic and
anthropometric patient characteristics and
cardiometabolic drug used at the time of the coronary
angiography
BMI Body mass index, ACEI Angiotensin converting enzyme inhibitors, ARB angiotensin receptor blockers, B-blockers beta-blockers
a As the percent within diabetic
or non-diabetic group
b Family history of premature
coronary artery disease
c Waist circumference d Patients with Framingham
risk scores higher than 20%
e Units for fasting blood
glucose: mg/dL, total and LDL, HDL cholesterols and
triglycerides: mg/ dL.(mean ± SD)
f Other antihypertensives
(calcium channel blockers and others)
All (n = 181) Diabetics (n = 87) Non-diabetics (n = 94) Age (years) 57.9 ± 10.4 60.6 ± 9.6 55.4 ± 10.5 Malea(%) 116 (64.1) 48 (55.1) 68 (72.3) Femalea(%) 65 (35.9) 39 (44.8) 26 (27.6) Smokers (%) 98 (54.1) 53 (60.9) 45 (47.8) Family historyb(%) 76 (41.9) 36 (41.3) 40 (42.5) Previous MI storya 71 (39.2) 45 (51.7) 26 (27.6) BMI (kg/m2) 29.2 ± 4.4 29.7 ± 4.6 28.7 ± 4.2 Waist circ.c(cm) 100.2 ± 10.3 101.3 ± 11.4 99.28 ± 9.1 Waist/Hip ratio 0.93 ± 0.1 0.93 ± 0.1 0.94 ± 0.1
High risk patientsd 30 22 8
Fasting glucosee 133.46 ± 60.77 170.05 ± 69.72 99.23 ± 13.78 Total cholesterol 192.28 ± 43.44 192.16 ± 47.44 192.39 ± 39.63 LDL-C 115.14 ± 35.7 114.39 ± 39.34 115.84 ± 32.23 HDL-C 46.71 ± 14.03 44.23 ± 12.25 49.01 ± 15.20 Triglycerides 158.72 ± 97.51 169.18 ± 95.26 149.05 ± 99.08 hs-CRP 8.31 ± 3.23 10.07 ± 5.41 6.54 ± 2.52 HbA1C (%) 6.99 ± 2.04 8.29 ± 2.23 5.77 ± 0.56 Microalbuminuria 16.67 ± 6.41 21.29 ± 7.59 12.51 ± 4.98 Medications ACEI (%) 53 (29.2) 32 (36.7) 21 (22.3) ARB (%) 41 (22.9) 26 (29.9) 15 (16.3) B-blockers (%) 64 (35.6) 32 (36.4) 32 (34.8) Other antiHTf 76 (41.9) 44 (50.5) 32 (34.0) Statins (%) 56 (30.9) 30 (34.5) 26 (27.6) Fibrates (%) 6 (3.4) 4 (4.5) 2 (2.2) Insulin (%) 20 (10.9) 20 (22.7) 0 (0)
criteria, postprandial (120th min) glucose and insulin lev-els, HbA1c, hsCRP, and Gensini scores by another analy-sis, and it also revealed no significant relationship with any of them.
Discussion
Numerous studies have shown that MS is able to predict cardiovascular events and diabetes [9,21–25], but there is still an open debate about whether MS or any of its com-ponents are independently associated with cardiovascular risk [26] and role of MS in cardiovascular risk related to diabetic patients, since the latter could have increased risk irrespective of an MS diagnosis. It was shown that car-diovascular incidents were significantly associated with HDL levels, systolic blood pressure, sex and total choles-terol, but not with the presence of MS defined by the ATP III criteria in diabetics [27]. In another study, MS defined by IDF criteria failed to predict coronary heart disease in Chinese diabetics [28].
Although in the medical literature several authors evaluated the association between MS, diabetes and severity of coronary atherosclerosis in cross-sectional and longitudinal studies, they either considered one sex [29] or studied in ethnicities different than Caucasian [30], or they did not compare diabetics and non-diabetics [31,32].
In our study, the primary aim was to evaluate the rela-tionship between the presence of MS based on different diagnostic criteria and the staging of coronary artery lesions in a Turkish patient population. We also aimed at testing whether the coexistence of MS diagnosis and DM could influence the possibility to detect worse coronary lesions.
When we evaluated the patient sample as a whole, patients with MS has higher coronary artery Gensini scores with WHO and IDF criteria, while the diabetics and non-diabetics were separated, only non-diabetic MS patients with WHO criteria had significantly higher scores of arte-rial lesions. IDF and ATP III criteria also showed mild relationship in non-diabetic groups, with statistically insignificant levels (P = 0.057). Although the regression analysis did not revealed significant relationship between the presence of hypertension and arterial lesion severity, probably because of low number of cases, the higher diagnostic cut-off point for blood pressure in WHO-MS could delay the MS diagnosis. It is known that the presence of MS in non-diabetic patients is strongly related to vas-cular events and stroke [33]. But diabetic patients consti-tute a heterogeneous group; there are some other powerful prospective risk determinants like LDL cholesterol, HbA1C levels, and albuminuria [34] and probable other Table 2 Gensini scores in patients with MS according to different criteria and median values for diabetics and non-diabetics
MS diagnostic criteria
Number (and percent) of patients
P values for higher Gensini scores in patients with MS vs. without MS
Median of Gensini scores
Minimum and maximum values of Gensini scores
WHO MS (?) 104 (57.5%) Higher (P = 0.005) D: 8,5 ND: 6 D: 0–124 ND: 0–86 WHO MS (-) 77 (42.5%) D: 16 ND: 0 D: 0–96 ND: 0–94 IDF MS (?) 111 (61.3%) Higher (P = 0.015) D:9 ND: 6 D: 0–124 ND: 0–84 IDF MS (-) 70 (38.7%) D: 30 ND: 0 D: 0–96 ND: 0–94 ATP III MS (?) 98 (54.1%) NS (P = 0.063) D: 8 ND: 5 D: 0–124 ND: 0–84 ATP III MS (-) 83 (45.9%) D: 24 ND: 0 D: 0–96 ND: 0–94 D diabetic patients, ND non-diabetic patients, NS difference was not statistically significant
Since the Gensini scores were not normally distributed, statistical evaluation was done using Mann–Whitney U-tests, and the median, minimum and maximum values are indicated in the table instead of mean and standard deviations
Table 3 Pvalues of statistical analyses for evaluation of difference regarding Gensini scores in patients with metabolic syndrome, when grouped according to the presence of diabetes
MS criteria P values for non-diabetics
P values for diabetics MS patients WHO 0.015* 0.551
MS patients IDF 0.057 0.421
MS patients ATP III 0.057 0.421 * Statistically significant. (Mann–Whitney U-test)
risks due to complications related to the duration of dia-betes. Also the presence of diabetes itself may be the cause of cardiomyopathy, even in the absence of coronary, hypertensive or valvular disease [35]. The drugs used in the treatment of diabetes itself may increase cardiovascular risk [36], and the use of antiaggregants in this group for primary prevention and dosage are still under debate [37,38] Probably in non-diabetic group, the effects of MS and its components are more direct and determinant factors for vascular risks in the absence of diabetes related con-ditions. This is also important for the prevention of MS in non-diabetics, to prevent severe cardiovascular pathologies in non-MS patients, and also for prediction of severity of coronary lesions in MS patients during clinical practice.
First limitation of our study is the enrolment of limited number of patients who already had indication for angi-ography by our Cardiology Department. Then, the trans-versal design of the study is not amenable to stratify patients on the basis of the evolution of the coronary lesions. Thus, we do not know whether the assumed pre-ventive drug could have influenced the lesion evolution. Meanwhile, on the basis of ACC/AHA guidelines, we included patients with both stable and unstable angina evaluated together with their cardiac risk status, and we only included the patients who had their first angiograph-ies, thus we omitted the patients with post-revasculariza-tion ischemia and patients with acute coronary diseases.
Secondly, our evaluation is cross-sectional, but the coronary artery disease is time-processing disease, and the duration of MS components also affects the end point.
Also the measurement of microalbuminuria in 24-h urine samples would have yielded more reliable results than that of spot measurements. Meanwhile, in the medical literature, there is no common agreement about the cut-off point for Gensini scoring of coronary arterial lesions. While subdividing patients on the basis of the Gensini score cut-off, we had decreased number of patients, and this may be reason for insignificant results. We also per-formed the categorical evaluation of dyslipidemia, and hypertension as the heterogeneity of drug use did not allow for the evaluation of the effects of their respective levels.
In the prospective Turkish Adult Risk Factor Study (TEKHARF study), presence of MS (defined by the ATP III guidelines) was already found as independent predictor of subsequent overall coronary heart disease in subjects with low cholesterol levels [39]. Besides the relevant results of this study, no comparative evaluation was per-formed between diabetic and non-diabetic MS patients, nor among MS patients as defined by other guidelines. Last interim statement paper of international cardiology, dia-betes, atherosclerosis, and obesity associations, written by Alberti et al. declared, the need for harmonization of all MS criteria and the need for different cut-off points for
each population, about ethnical differences of waist cir-cumference [40], pointing out the disagreement of different MS criteria, besides general agreement on its results like coronary heart disease, thrombotic state and diabetes. Our study emphasizes the importance of the MS diagnosis especially in non-diabetic Turkish population, regarding coronary diseases.
It was also interesting to diagnose 16 new diabetes cases that were unaware of their disease among that group, and even high number of IFG and IGT among non-diabetics. That shows the importance and higher frequency of glu-cose metabolism abnormalities among patients going to elective coronary angiography with suspected coronary disease, similar to results of other studies in patients with coronary lesions [41,42].
In conclusion, based on our data, the detection of MS in Turkish patients is of strong relevance to early detection of subjects with severe coronary lesions, especially in non-diabetics. In diabetics, the presence of MS does not seem to be associated with more frequent severe coronary lesions, probably because of some other factors contributing to coronary risks.
Acknowledgments This study has been performed with the finan-cial support from Ankara Guven Hospital.
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