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The metabolic syndrome and nonfatal ischemic heart disease; a population-based study
International Journal of Cardiology 118 (2007) 48 – 53 www.elsevier.com/locate/ijcard
The metabolic syndrome and nonfatal ischemic heart disease; a population-based study Iraj Nabipour a,⁎, Mohammad Amiri a,b , Seyed Reza Imami b , Seyed Mojtaba Jahfari b , Ebrahim Shafeiae c , Abbas Nosrati b , Dariush Iranpour c , Ali Reza Soltanian b b
a Department of Internal Medicine, School of Medicine, Bushehr University of Medical Science, Bushehr, I.R. Iran Section of Healthy Heart, The Persian Gulf Health Research Center, Bushehr University of Medical Science, Bushehr, I.R. Iran c Department of Cardiology, School of Medicine, Bushehr University of Medical Science, Bushehr, I.R. Iran
Received 4 January 2006; received in revised form 4 June 2006; accepted 18 June 2006 Available online 26 July 2006
Abstract Objectives: Metabolic syndrome comprises insulin resistance, abdominal fat distribution, dyslipidemia and hypertension. The metabolic syndrome is expected to be diagnosed in millions of subjects in the near future worldwide. There are very few data in literature clearly documenting that subjects with metabolic syndrome have an increased cardiovascular risk. Design: Cross-sectional, population-based study. Materials and methods: We used National Cholesterol Education Program (NCEP)-Adult Treatment Panel (ATP)-III criteria and Minnesota Code of a 12-lead resting electrocardiogram (EKG) to assess the association of metabolic syndrome and nonfatal ischemic heart disease in 3723 subjects, aged 25 years and over, selected by cluster random sampling in three Iranian ports in the northern Persian Gulf. Electrocardiogram with evidence of IHD (IHD EKG) was defined as myocardial infarction (codes 1.1 and 1.2) and ischemia (codes 1.3, 4.1– 4.4, 5.1–5.3 and 7.1) together. Results: An estimated 49.08% (52.04% of males and 46.34% of females) were identified as fulfilling NCEP-ATP III criteria for diagnosing the metabolic syndrome. Prevalence of EKG with evidence of ischemic heart disease (IHD EKG) was 12.7% (10.4% for men and 14.7% for women, p b 0.0001). In multiple logistic regression analysis, metabolic syndrome was found to have a significant association with IHD EKG [OR = 1.35, CI (1.09–1.66), p = 0.005] after adjusting for sex and age. Of the metabolic syndrome components, elevated blood sugar (OR = 2.69, p b 0.001), high blood pressure (OR = 1.79, p = 0.001) and low HDL-C (OR = 1.27, p = 0.02) had significant independent association with IHD EKG. Conclusion: The metabolic syndrome, which occurs very frequently in the general population, has a significant association with nonfatal ischemic heart disease by electrocardiogram criteria. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Metabolic syndrome; Ischemic heart disease; Electrocardiogram; Insulin resistance
1. Introduction The common clustering of glucose intolerance, abdominal adiposity, hypertriglyceridemia, low high-density lipoprotein cholesterol level and high blood pressure in a single individual is referred to as the metabolic syndrome [1–3]. ⁎ Corresponding author. Deputy for Research, Bushehr University of Medical Science, Moallem Street, Bushehr, P. O. Box-3631, I.R. Iran. E-mail address: [email protected] (I. Nabipour). 0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.06.017
The metabolic syndrome is expected to be diagnosed in millions of subjects in the near future worldwide by either WHO or NCEP-ATPIII criteria. The prevalence of metabolic syndrome has been reported to be 24% in the US adult population [1]. Coronary heart disease (CHD), CVD and total mortality are significantly higher in US adults with than in those without metabolic syndrome [4]. Many think that insulin resistance is the key component linking the syndrome to the development of CHD from a pathophysiologic point of view; however, a chronic inflammatory state has also been
I. Nabipour et al. / International Journal of Cardiology 118 (2007) 48–53
implicated [5]. Patients with metabolic syndrome exhibited some structural and functional alterations of systemic microvasculature; the pattern is similar to that detected in systemic inflammatory diseases and suggests a vascular lesion of inflammatory type [6]. Even, it can be suggested that metabolic syndrome is one of the significant factors affecting the development of coronary collateral vessels adversely [7]. A few prospective analyses have applied definitions from the National Cholesterol Education Program's Third Adult Treatment Panel Report (ATP III) or the World Health Organization and reported that the metabolic syndrome is associated with an approximate twofold increase in cardiovascular disease (CVD) [8–14]. Resting electrocardiogram (EKG) abnormalities suggestive of ischemic heart disease (IHD) have been shown to predict an increased risk of future CHD events in prospective population studies and in clinical trials and are utilized to define subclinical IHD [15]. A very few studies reported the association of metabolic syndrome and nonfatal IHD using EKG criteria [15–17]. The main objective of this study is to investigate the association of metabolic disease and its major components with nonfatal IHD using resting EKG criteria.
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After a primary education about CVD and its associated risk factors, they were invited to participate in the screening program in a 12–14-h fasting state in the following morning to one of local health services center belonging to Bushehr University of Medical Science. 2.2. Survey procedure
The Persian Gulf Healthy Heart Project (PGHHP) is a study to determine the risk factors for cardiovascular diseases among the northern Persian Gulf population (Bushehr and Hormozghan Provinces) and to develop community-based interventional projects to change the lifestyles of the population and to present the rising threat of CVD in the region. The design of this study encompasses two major components: phase I is a cross-sectional prevalence study of unhealthy lifestyle and ischemic heart disease (IHD) and associated risk factors, and phase II is a multiple interventional project for reduction of CVD in the region.
Phase I of PGHHP was a cross-sectional survey in which each participant was examined only once. Examinations were conducted in 2003–2004. All subjects were asked to fast and to present to the survey center between 7.30 and 9.30 a.m. On arrival at the survey site, information on their age, sex, marital status, education, smoking, estrogen and drugs for angina, hypertension, diabetes and dyslipidemia were recorded using WHO MONICA questionnaire [18] by trained interviewers. Blood pressure was assessed twice at the right arm after a 15min rest in the sitting position, using a standard mercury sphygmomanometer. Height and weight were measured using a stadiometer. Heavy outer garments and shoes were removed before measuring height and weight. Waist circumference was defined at the midway level between the costal margins and the iliac crests. Hip circumference was measured at the level of the greater trochanters. A resting 12-lead electrocardiogram was performed. A fasting blood sample was taken, all samples were promptly centrifuged, separated and analyses were carried out at the Persian Gulf Health Research Center on the day of blood collection using a Selectra 2 autoanalyzer (Vital Scientific, Spankeren, The Netherlands). Glucose was assayed by enzymatic (glucose oxidase) colorimetric method using a commercial kit (Pars Azmun Inc., Tehran, Iran). Serum total cholesterol and HDL cholesterol were measured using a cholesterol oxidase phenol aminoantipyrine and triglycerides using a glycerol-3 phosphate oxidase phenol aminoantipyrine enzymatic method. Serum LDL cholesterol was calculated using the Friedwald formula; LDL cholesterol was not calculated when triglycerides concentration was N400 mg/dl.
2.1. Community sampling
2.3. Definitions
In phase I of the study, a multiple-stage stratified cluster random sampling technique was used to select 3000 people aged ≥ 25 years from major ports of Bushehr Province (an Iranian province with the greatest boarder with the Persian Gulf). The studied ports of the northern Persian Gulf were Bushehr Port (the center of Bushehr Province, with a population of 150,000 and coronary events of 481.05 and 156.61 per 100,000 for men and women, respectively), Genaveh and Deilam Ports. Specifications dictated that approximately two persons per selected household could be included in phase I cross-sectional survey. Publicity concerning the study appeared in the local newspapers and on the TV. The selected ≥ 25 years of households were informed about the study through a letter given door-to-door by the survey groups of the PGHHP.
The metabolic syndrome was diagnosed with the criteria indicated by the NCEP-ATP III [19]. According to these criteria, subjects with the metabolic syndrome are those with any combination of three or more of the following risk determinants: fasting plasma glucose ≥ 6.1 mmol/l, blood pressure ≥ 130/≥ 85 mm Hg or antihypertensive treatment, plasma triglycerides ≥ 1.7 mmol/l, plasma HDL cholesterol b 1.03 mmol/l in men and b 1.29 mmol/l in women, and waist circumference N102 cm in men or N 88 cm in women. EKGs were coded on the basis of the Minnesota coding criteria [20]. Codes 1.1 and 1.2 were classified as myocardial infarction, and codes 1.3, 4.1–4.4, 5.1–5.3 and 7.1 were classified as ischemia. Prevalence of EKG with evidence of IHD (IHD EKG) was defined as myocardial infarction and ischemia together [21].
2. Materials and methods
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Table 1 The prevalence of myocardial infarction, ischemia and ischemic EKG in different age groups (years) using Minnesota coding criteria among the northern Persian Gulf adults Male
Female
Myocardial infarction 25–34 35–44 45–54 55–64 Total (age-adjusted) a
7 6 7 14 34
(1.1)a (1.2) (1.9) (5.5) (1.9)
Ischemic
Ischemic EKG
Myocardial infarction
Ischemic
Ischemic EKG
35 (5.6) 28 (5.6) 41 (11.0) 44 (17.3) 148 (8.4)
42 (6.7) 34 (6.8) 48 (12.9) 58 (23.3) 182 (10.4)
2 1 11 5 19
67 (9.3) 71 (12.2) 75 (16.9) 60 (25.9) 273 (13.8)
69 (9.5) 72 (12.3) 86 (19.3) 64 (28.4) 291(14.7)
(0.3) (0.2) (2.5) (2.2) (1.0)
Data are numbers (percentages).
2.4. Statistical methods For analysis of data, the studied population was divided into four groups: 25–34, 35–44, 45–54 and 55–64 years of age. The prevalence of metabolic syndrome and EKG with evidence of ischemic heart disease (IHD EKG) was adjusted for age by a direct method using subjects residing in Bushehr Port as a standard population according to the National Census of 1996. Odds ratios (ORs) estimating the association of metabolic syndrome or its traits with subgroups of EKG alterations (myocardial infarction, ischemia and IHD EKG) were calculated. Multiple logistic regression analysis was used to ascertain the associations between metabolic syndrome and IHD EKG. Two separate models were tested. At the first, the metabolic syndrome considered as a single entity, sex and age as covariates, and IHD EKG also as the dependent variable. In another model, the metabolic syndrome traits considered as independent covariates and simultaneously included into the same equation, with IHD EKG as the dependent variable. P b 0.05 was considered statistically significant. Statistical analysis was performed with an IBM computer using the SPSS 9.05 statistical software package (SPSS Inc., Chicago, IL). 3. Results A total of 3723 (46.9% males, 53.1% females) were evaluated. The response rate of individuals was 68%. Of the studied population, 36.1% was between 25 and 34 years, 29.1% between 35 and 44 years, 22% between 45 and 54 years, and 12.7% between 55 and 64 years. Table 1 shows prevalence of ischemic heart disease end points among men and women aged 25–64 years. MyocarTable 2 The prevalence of metabolic syndrome in different age groups (years) using NCEP-ATPIII criteria among the northern Persian Gulf adults Age
Male (%)
Female (%)
Total (%)
25–34 35–44 45–54 55–64 Total (crude rate) Total (age-adjusted rate)
41.7 53.9 67.6 68.5 54.6 52.0
32.6 51.6 64.3 72.3 49.9 46.3
36.8 52.7 65.8 70.3 52.1 49.1
dial infarction was determined for 53 cases [1.4%, 95% CI (1.2–1.7%)]; ischemia was determined for 421 cases [11.3%, 95% CI (10.3–11.0%)]. The age-adjusted prevalence of EKG with evidence of ischemic heart disease (IHD EKG) was 12.7% [10.4%, 95% CI (9.0–11.7%) for men and 14.7%, 95% CI (13.3–16.07%) for women]. The age-adjusted prevalence of metabolic syndrome as defined by ATP III criteria, was 49.0%, 95% CI (47.5–50.6%) [52.0%, 95% CI (50.0–54.0%) of males and 46.3%, 95% CI (44.3–48.3%) of females] (Table 2). A total of 151 (4.0%), 565 (15.1%), 1073 (28.7), 1150 (30.8%), 661 (17.7%), 135 (3.6%), had just none, just one, just two, just three, just four and just five metabolic syndrome traits, respectively. Unadjusted odds ratio (95% CI) between metabolic syndrome and IHD EKG was 1.64 (1.34–2.00), p b 0.001 [OR = 1.89 (1.36–2.63), p b 0.001 for men and OR = 1.56 (1.21–2.00), p b 0.001 for women]. The same association of metabolic syndrome and IHD EKG in the study population increased when the subjects with four [unadjusted OR = 1.88, CI (1.27–2.79), p = 0.002] or five [unadjusted OR = 2.31, CI (1.14–4.60), p = 0.02] components of metabolic syndrome entered into the equation. Unadjusted odds ratios (95% CI) relating metabolic syndrome and subgroups of IHD EKG also revealed significant associations [OR = 1.96 (1.19–3.50), p = 0.02 for myocardial infarction and OR = 1.57 (1.28–1.94), p b 0.001 for ischemia]. In multiple logistic regression analysis, metabolic syndrome showed a significant association with IHD EKG [OR = 1.35, CI (1.09–1.66), p = 0.005] after adjusting for sex and age (Table 3). Table 3 Multivariately adjusted (age and sex) odds ratios (OR) and 95% CI relating metabolic syndrome and IHD EKG among the northern Persian Gulf adultsa IHD EKG
Metabolic syndrome Sex (female) Age Groups (years)b
35–44 45–54 55–64
OR
CI
p value
1.35 1.58 1.15 2.00 3.54
(1.09–1.66) (1.30–1.93) (0.87–1.52) (1.52–2.64) (2.64–4.74)
0.005 0.001 0.34 0.001 0.001
a The metabolic syndrome considered as a single entity, sex and age as covariates, and IHD EKG also as the dependent variable. b The risks are relative to age group 25–34 years.
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Of the metabolic syndrome components, elevated blood sugar (OR = 2.69, p b 0.001), high blood pressure (OR = 1.79, p = 0.001) and low HDL-C (OR = 1.27, p = 0.02) had significant independent association with IHD EKG. 4. Discussion In the current study, we found that among the northern Persian Gulf adults, there was a highly significant association between metabolic syndrome and resting EKG evidence of IHD. This association remained after controlling of sex and age. To the best of our knowledge, the present study provides the fourth population-based information on IHD and metabolic syndrome using resting EKG abnormalities suggestive of IHD [15–17]. Association between metabolic syndrome components and prevalent IHD were investigated in a cross-sectional, community-based study of elderly men and women in Rancho Bernardo, California, in 1984–1987; in this study, there was also a significant association between resting ischemic EKG and all common components of the metabolic syndrome [15]. In prospective data from the Bruneck Study/Italy which also used a 12-lead EKG at the baseline and at the follow-up, subjects with metabolic syndrome had an increased incidence of CHD during follow-up: 8% vs. 3% in control subjects [16]. Comparing prevalence of metabolic syndrome among persons with IHD and without IHD in middle-aged Kaunas population/ Lithuania, metabolic syndrome was associated with IHD in men aged 45–64 years [17]. A two-fold increase risk of mortality from CHD and CVD in men and women with metabolic syndrome was demonstrated in a prospective cohort study in US; in persons with metabolic syndrome but without diabetes, risks of CHD and CVD mortality remained elevated [4]. The observations in the US adult population are consistent with previous reports of the prognostic importance of metabolic syndrome among men in the West of Scotland study, in Finnish adults, and more recently from Framingham Heart Study and San Antonio Heart Study cohorts [10,11,13,22]. According to the Atherosclerosis Risk in Communities (ARIC) Study, individuals without diabetes or CVD, but with the metabolic syndrome, are at increased risk for long-term cardiovascular outcomes [14]. In this study, metabolic syndrome was present in 23% of individuals without diabetes or prevalent CVD at baseline. Over an average of 11 years of follow-up, 879 incident CHD and 216 ischemic stroke events occurred [14]. One of the limitations of this cross-sectional, populationbased investigation was study design that lacked CVD mortality and morbidity data; we focused only on EKG criteria for prevalent IHD without regard to known (clinical) IHD. However, it is well known that the ST-T segment of EKG carries prognostic value in the univariate sense [23]. De Bacquer et al. showed that both men and women with major ischemic findings in the baseline EKG using Minnesota codes had an increased risk of CVD death [24]. They concluded that abnormalities in the baseline EKG are strongly associated with
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subsequent all cause, CVD and CHD mortality [24]. ECG with evidence of ischemic hear disease (IHD EKG) is not equivalent to ischemic cardiomyopathy, despite it has been associated with a bad prognosis, and thus results should not be interpreted as if both terms were interchangeable. We found a high prevalence of IHD EKG in 10.4% and 14.7% of the studied men and women, respectively (Table 1). Similar high prevalence of EKG-based possible ischemia (12.3% for women and 7.5% for men) was reported from an urban population in central part of Iran/Isfahan [25]. A crosssectional study in a Japanese population showed that the prevalence of IHD EKGs was 10% and 11.3% in men and women, respectively [21]. Similar difference in prevalence of ischemic EKG in women (10.6%) and men (8.4%) was reported from the Belgian study [26]. Overall, women have significantly more ST changes and T wave abnormalities on their resting EKG compared to men when adjustment is made for age [27]. This sex difference in ischemic EKG is surprising because men have a higher prevalence of myocardial infarction using Minnesota codes. However, 10-year followup data from a subset of the Belgian cohort support the hypothesis that women with ischemic EKG have the same increased risk of death due to CVD as men [26]. Although a definition of the metabolic syndrome may be difficult to agree upon, it is important that such a definition exists and is applied so that comparisons between populations of the prevalence of the syndrome and its relationship with various health outcomes can be made. We identified an estimated 49.0% of our population (25–64 years) had metabolic syndrome using the ATP III definition which is more amenable to measurement in clinical practice. The differences in the prevalence of the syndrome between populations may be due to lifestyle influences, genetic factors, the age and sex structures of the populations under study, and the era in which each of the studies was conducted, due to temporal changes in prevalence. Looking at those studies that indicate a population sample aged from 20 to 25 and upward, the prevalence varies from 8% (India) to 24% (United States) in men and from 7% (France) to 46% (India) in women [28]. A consistent finding is the observation that the prevalence of the metabolic syndrome is highly age-dependent. This is demonstrated in the Iranian population (Tehran Lipid and Glucose Study), in which the prevalence is less than 10% for both men and women in the 20- to 29-year age group, rising to 38% and 67% in the 60- to 69-year age group for men and women, respectively [29]. Because the metabolic syndrome is extremely common and likely increasing among the northern Persian Gulf population, health care professionals are likely to encounter these patients in their daily practice. This large number of people with the metabolic syndrome has serious implications for public health and clinical practice. The associated costs, which have not been defined so far, are likely to be substantial. Future increases in the incidence of cardiovascular disease and diabetes could occur in the region. The relationship of metabolic syndrome to cardiovascular risk can be approached in two ways: (a) by considering the
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individual risks posed by the components and (b) by considering the components together as a syndrome. Insulin resistance is thought by many to be the common pathology linking the components, so a lot of attention has focused on glucose homeostasis and its role in the development of CVD [30]. We found a positive association between increasing number of ATP III metabolic syndrome components and nonfatal IHD by EKG, results from our analysis indicate that the individual components of elevated fasting glucose, elevated blood pressure and low HDL cholesterol have significant association with IHD EKG. These findings suggest the need for intensified treatment recommendations in persons with metabolic syndrome risk factors. In persons with metabolic syndrome, up to 80% of CHD events may be preventable from control of LDL-C, HDL-C and blood pressure [31]. In addition, the presence of the metabolic syndrome is highly predictive of the development of diabetes mellitus. A treatment strategy focusing on aerobic exercise and weight loss can help delay or prevent the development of diabetes and can help reduce cardiovascular risk [32]. The current risk reduction recommendations, focusing on single risk factor identification and correction, should be replaced by targeting individuals with the cluster and tailoring treatment possibly on the underlying mechanisms, like insulin resistance, responsible for or contributing to the complex of coexisting abnormalities. 5. Conclusion In conclusion, the metabolic syndrome, which occurs very frequently in the general population, is burden by more frequent prevalent IHD EKG, treatment strategies must focus on therapy for all risk factors, including dyslipidemia, hypertension and insulin resistance. Acknowledgement This study was supported in part by a grant from Joint Ministry of Health and World Health Organization Regional Office (JPRM) fund (A/C: 02.01.01.01.ACS 2002-03) and Bushehr Province Research Committee. References [1] Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among U.S. adults. Diabetes Care 2004;27: 2444–9. [2] Liese AD, Mayer-Davis EJ, Haffner SM. Development of the multiple metabolic syndrome: an epidemiologic perspective. Epidemiol Rev 1998;20:157–72. [3] Grundy S. Obesity, metabolic syndrome, and coronary atherosclerosis. Circulation 2002;105:2696–8. [4] Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation 2004;110: 1245–50. [5] Vitarius JA. The metabolic syndrome and cardiovascular disease. Mt Sinai J med 2005;72:257–62.
[6] Pasqui AL, Puccetti L, Di Renzo M, et al. Structural and functional abnormality of systemic microvessels in cardiac syndrome X. Nutr Metab Cardiovasc Dis 2005;15:56–64. [7] Turhan H, Yasar AS, Erbay AR, Yetkin E, Sasmaz H, Sabah I. Impaired coronary collateral vessel development in patients with metabolic syndrome. Coron Artery Dis 2005;16:281–5. [8] Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709–16. [9] Ford ES. The metabolic syndrome and mortality from cardiovascular disease and all-causes: findings from the National Health and Nutrition Examination Survey II Mortality Study. Atherosclerosis 2004;173: 309–14. [10] Hunt KJ, Resendez RG, Williams K, Haffner SM, Stern MP. San Antonio Heart Study. National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular mortality in the San Antonio Heart Study. Circulation 2004;110:1251–7. [11] Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683–9. [12] Resnick HE, Jones K, Ruotolo G, et al. Insulin resistance, the metabolic syndrome, and risk of incident cardiovascular disease in nondiabetic American Indians: the Strong Heart Study. Diabetes Care 2003;26:861–7. [13] Rutter MK, Meigs JB, Sullivan LM, D'Agostino Sr RB, Wilson PW. C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation 2004;110:380–5. [14] Mc Neili AM, Rosamond W, Girman CJ, et al. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the Atherosclerosis Risk in Communities Study. Diabetes Care 2005;28:385–90. [15] Lindblad U, Langer RD, Wingard DL, Thomas RG, Barrett-Connor EL. Metabolic syndrome and ischemic heart disease in elderly men and women. Am J Epidemiol 2001;153:481–9. [16] Bonora E, Kiechl S, Willeit J, et al. Carotid atherosclerosis and coronary heart disease in the metabolic syndrome. Diabetes Care 2003;26:1251–7. [17] Cerniauskiene LR, Reklaitiene R, Luksiene DI, Domarkiene S, Tamosiunas A, Margeviciene L. Association of metabolic syndrome with ischemic heart disease among middle-aged Kaunas population. Medicina 2005;41:435–41. [18] WHO MONICA Project. MONICA manual, 1999 (http://www.ktl.fi/ publications/monica/manual/index.htm). [19] 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;285:2486–97. [20] Prineas RJ, Crowe RS, Blackburn H. The Minnesota Code manual of electrocardiographic findings. Bristol: John Wright; 1982. [21] Choudhury SR, Yoshida Y, Kita Y, Nozaki A. Association between electrocardiographic ischemic abnormalities and ischemic heart disease risk factors in a Japanese population. J Hum Hypertens 1996;10: 225–34. [22] Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome with and without C-reactive protein as a predictor of heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 2003;108: 414–9. [23] Macfarlane PW, Norrie J. Looking for prognostic information in the ST-T segment. Is it really worth it? J Electrocardiol 2004;37: 209–13. [24] De Bacquer D, De Backer G, Kornitzer M, Blackburn H. Prognostic value of ECK findings for total, cardiovascular disease, and heart disease death in men and women. Heart 1998;80:570–7. [25] Sarrf-Zadegan N, Sayed-Tabatabaei FA, Bashardoost N, et al. The prevalence of coronary artery disease in an urban population in Isfahan, Iran. Acta Cardiol 1999;54:257–63.
I. Nabipour et al. / International Journal of Cardiology 118 (2007) 48–53 [26] De Bacquer D, De Backer G, Kornitzer M, et al. Prognostic value of ischemic electrocardiographic findings for cardiovascular mortality in men and women. J Am Coll Cardiol 1998;32:680–5. [27] Macfarlane PW. Minnesota coding and the prevalence of ECG abnormalities. Heart 2000;84:582–4. [28] Cameron AJ, Shaw JE, Zimmet PZ. The metabolic syndrome: prevalence in worldwide population. Endocrinol Metab Clin N Am 2004;33:351–75. [29] Azizi F, Salehi P, Etemadi A, Zahedi-Asl S. Prevalence of metabolic syndrome in an urban population: Tehran Lipid and Glucose Study. Diabetes Res Clin Pract 2003;61:29–37.
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[30] Natali A, Ferrannini E. Hypertension, insulin resistance, and the metabolic syndrome. Endocrinol Metab Clin N Am 2004;33: 417–29. [31] Wong ND, Pio JR, Franklin SS, L'Italien GJ, Pio JR, Williams GR. Preventing coronary events by optimal control of blood pressure and lipids in patients with the metabolic syndrome. Am J Cardiol 2003;91: 1421–6. [32] Sorrentino MJ. Implications of the metabolic syndrome: the new epidemic. Am J Cardiol 2005;96(4A):3E–7E.
The metabolic syndrome and nonfatal ischemic heart disease; a population-based study Iraj Nabipour a,⁎, Mohammad Amiri a,b , Seyed Reza Imami b , Seyed Mojtaba Jahfari b , Ebrahim Shafeiae c , Abbas Nosrati b , Dariush Iranpour c , Ali Reza Soltanian b b
a Department of Internal Medicine, School of Medicine, Bushehr University of Medical Science, Bushehr, I.R. Iran Section of Healthy Heart, The Persian Gulf Health Research Center, Bushehr University of Medical Science, Bushehr, I.R. Iran c Department of Cardiology, School of Medicine, Bushehr University of Medical Science, Bushehr, I.R. Iran
Received 4 January 2006; received in revised form 4 June 2006; accepted 18 June 2006 Available online 26 July 2006
Abstract Objectives: Metabolic syndrome comprises insulin resistance, abdominal fat distribution, dyslipidemia and hypertension. The metabolic syndrome is expected to be diagnosed in millions of subjects in the near future worldwide. There are very few data in literature clearly documenting that subjects with metabolic syndrome have an increased cardiovascular risk. Design: Cross-sectional, population-based study. Materials and methods: We used National Cholesterol Education Program (NCEP)-Adult Treatment Panel (ATP)-III criteria and Minnesota Code of a 12-lead resting electrocardiogram (EKG) to assess the association of metabolic syndrome and nonfatal ischemic heart disease in 3723 subjects, aged 25 years and over, selected by cluster random sampling in three Iranian ports in the northern Persian Gulf. Electrocardiogram with evidence of IHD (IHD EKG) was defined as myocardial infarction (codes 1.1 and 1.2) and ischemia (codes 1.3, 4.1– 4.4, 5.1–5.3 and 7.1) together. Results: An estimated 49.08% (52.04% of males and 46.34% of females) were identified as fulfilling NCEP-ATP III criteria for diagnosing the metabolic syndrome. Prevalence of EKG with evidence of ischemic heart disease (IHD EKG) was 12.7% (10.4% for men and 14.7% for women, p b 0.0001). In multiple logistic regression analysis, metabolic syndrome was found to have a significant association with IHD EKG [OR = 1.35, CI (1.09–1.66), p = 0.005] after adjusting for sex and age. Of the metabolic syndrome components, elevated blood sugar (OR = 2.69, p b 0.001), high blood pressure (OR = 1.79, p = 0.001) and low HDL-C (OR = 1.27, p = 0.02) had significant independent association with IHD EKG. Conclusion: The metabolic syndrome, which occurs very frequently in the general population, has a significant association with nonfatal ischemic heart disease by electrocardiogram criteria. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Metabolic syndrome; Ischemic heart disease; Electrocardiogram; Insulin resistance
1. Introduction The common clustering of glucose intolerance, abdominal adiposity, hypertriglyceridemia, low high-density lipoprotein cholesterol level and high blood pressure in a single individual is referred to as the metabolic syndrome [1–3]. ⁎ Corresponding author. Deputy for Research, Bushehr University of Medical Science, Moallem Street, Bushehr, P. O. Box-3631, I.R. Iran. E-mail address: [email protected] (I. Nabipour). 0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.06.017
The metabolic syndrome is expected to be diagnosed in millions of subjects in the near future worldwide by either WHO or NCEP-ATPIII criteria. The prevalence of metabolic syndrome has been reported to be 24% in the US adult population [1]. Coronary heart disease (CHD), CVD and total mortality are significantly higher in US adults with than in those without metabolic syndrome [4]. Many think that insulin resistance is the key component linking the syndrome to the development of CHD from a pathophysiologic point of view; however, a chronic inflammatory state has also been
I. Nabipour et al. / International Journal of Cardiology 118 (2007) 48–53
implicated [5]. Patients with metabolic syndrome exhibited some structural and functional alterations of systemic microvasculature; the pattern is similar to that detected in systemic inflammatory diseases and suggests a vascular lesion of inflammatory type [6]. Even, it can be suggested that metabolic syndrome is one of the significant factors affecting the development of coronary collateral vessels adversely [7]. A few prospective analyses have applied definitions from the National Cholesterol Education Program's Third Adult Treatment Panel Report (ATP III) or the World Health Organization and reported that the metabolic syndrome is associated with an approximate twofold increase in cardiovascular disease (CVD) [8–14]. Resting electrocardiogram (EKG) abnormalities suggestive of ischemic heart disease (IHD) have been shown to predict an increased risk of future CHD events in prospective population studies and in clinical trials and are utilized to define subclinical IHD [15]. A very few studies reported the association of metabolic syndrome and nonfatal IHD using EKG criteria [15–17]. The main objective of this study is to investigate the association of metabolic disease and its major components with nonfatal IHD using resting EKG criteria.
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After a primary education about CVD and its associated risk factors, they were invited to participate in the screening program in a 12–14-h fasting state in the following morning to one of local health services center belonging to Bushehr University of Medical Science. 2.2. Survey procedure
The Persian Gulf Healthy Heart Project (PGHHP) is a study to determine the risk factors for cardiovascular diseases among the northern Persian Gulf population (Bushehr and Hormozghan Provinces) and to develop community-based interventional projects to change the lifestyles of the population and to present the rising threat of CVD in the region. The design of this study encompasses two major components: phase I is a cross-sectional prevalence study of unhealthy lifestyle and ischemic heart disease (IHD) and associated risk factors, and phase II is a multiple interventional project for reduction of CVD in the region.
Phase I of PGHHP was a cross-sectional survey in which each participant was examined only once. Examinations were conducted in 2003–2004. All subjects were asked to fast and to present to the survey center between 7.30 and 9.30 a.m. On arrival at the survey site, information on their age, sex, marital status, education, smoking, estrogen and drugs for angina, hypertension, diabetes and dyslipidemia were recorded using WHO MONICA questionnaire [18] by trained interviewers. Blood pressure was assessed twice at the right arm after a 15min rest in the sitting position, using a standard mercury sphygmomanometer. Height and weight were measured using a stadiometer. Heavy outer garments and shoes were removed before measuring height and weight. Waist circumference was defined at the midway level between the costal margins and the iliac crests. Hip circumference was measured at the level of the greater trochanters. A resting 12-lead electrocardiogram was performed. A fasting blood sample was taken, all samples were promptly centrifuged, separated and analyses were carried out at the Persian Gulf Health Research Center on the day of blood collection using a Selectra 2 autoanalyzer (Vital Scientific, Spankeren, The Netherlands). Glucose was assayed by enzymatic (glucose oxidase) colorimetric method using a commercial kit (Pars Azmun Inc., Tehran, Iran). Serum total cholesterol and HDL cholesterol were measured using a cholesterol oxidase phenol aminoantipyrine and triglycerides using a glycerol-3 phosphate oxidase phenol aminoantipyrine enzymatic method. Serum LDL cholesterol was calculated using the Friedwald formula; LDL cholesterol was not calculated when triglycerides concentration was N400 mg/dl.
2.1. Community sampling
2.3. Definitions
In phase I of the study, a multiple-stage stratified cluster random sampling technique was used to select 3000 people aged ≥ 25 years from major ports of Bushehr Province (an Iranian province with the greatest boarder with the Persian Gulf). The studied ports of the northern Persian Gulf were Bushehr Port (the center of Bushehr Province, with a population of 150,000 and coronary events of 481.05 and 156.61 per 100,000 for men and women, respectively), Genaveh and Deilam Ports. Specifications dictated that approximately two persons per selected household could be included in phase I cross-sectional survey. Publicity concerning the study appeared in the local newspapers and on the TV. The selected ≥ 25 years of households were informed about the study through a letter given door-to-door by the survey groups of the PGHHP.
The metabolic syndrome was diagnosed with the criteria indicated by the NCEP-ATP III [19]. According to these criteria, subjects with the metabolic syndrome are those with any combination of three or more of the following risk determinants: fasting plasma glucose ≥ 6.1 mmol/l, blood pressure ≥ 130/≥ 85 mm Hg or antihypertensive treatment, plasma triglycerides ≥ 1.7 mmol/l, plasma HDL cholesterol b 1.03 mmol/l in men and b 1.29 mmol/l in women, and waist circumference N102 cm in men or N 88 cm in women. EKGs were coded on the basis of the Minnesota coding criteria [20]. Codes 1.1 and 1.2 were classified as myocardial infarction, and codes 1.3, 4.1–4.4, 5.1–5.3 and 7.1 were classified as ischemia. Prevalence of EKG with evidence of IHD (IHD EKG) was defined as myocardial infarction and ischemia together [21].
2. Materials and methods
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Table 1 The prevalence of myocardial infarction, ischemia and ischemic EKG in different age groups (years) using Minnesota coding criteria among the northern Persian Gulf adults Male
Female
Myocardial infarction 25–34 35–44 45–54 55–64 Total (age-adjusted) a
7 6 7 14 34
(1.1)a (1.2) (1.9) (5.5) (1.9)
Ischemic
Ischemic EKG
Myocardial infarction
Ischemic
Ischemic EKG
35 (5.6) 28 (5.6) 41 (11.0) 44 (17.3) 148 (8.4)
42 (6.7) 34 (6.8) 48 (12.9) 58 (23.3) 182 (10.4)
2 1 11 5 19
67 (9.3) 71 (12.2) 75 (16.9) 60 (25.9) 273 (13.8)
69 (9.5) 72 (12.3) 86 (19.3) 64 (28.4) 291(14.7)
(0.3) (0.2) (2.5) (2.2) (1.0)
Data are numbers (percentages).
2.4. Statistical methods For analysis of data, the studied population was divided into four groups: 25–34, 35–44, 45–54 and 55–64 years of age. The prevalence of metabolic syndrome and EKG with evidence of ischemic heart disease (IHD EKG) was adjusted for age by a direct method using subjects residing in Bushehr Port as a standard population according to the National Census of 1996. Odds ratios (ORs) estimating the association of metabolic syndrome or its traits with subgroups of EKG alterations (myocardial infarction, ischemia and IHD EKG) were calculated. Multiple logistic regression analysis was used to ascertain the associations between metabolic syndrome and IHD EKG. Two separate models were tested. At the first, the metabolic syndrome considered as a single entity, sex and age as covariates, and IHD EKG also as the dependent variable. In another model, the metabolic syndrome traits considered as independent covariates and simultaneously included into the same equation, with IHD EKG as the dependent variable. P b 0.05 was considered statistically significant. Statistical analysis was performed with an IBM computer using the SPSS 9.05 statistical software package (SPSS Inc., Chicago, IL). 3. Results A total of 3723 (46.9% males, 53.1% females) were evaluated. The response rate of individuals was 68%. Of the studied population, 36.1% was between 25 and 34 years, 29.1% between 35 and 44 years, 22% between 45 and 54 years, and 12.7% between 55 and 64 years. Table 1 shows prevalence of ischemic heart disease end points among men and women aged 25–64 years. MyocarTable 2 The prevalence of metabolic syndrome in different age groups (years) using NCEP-ATPIII criteria among the northern Persian Gulf adults Age
Male (%)
Female (%)
Total (%)
25–34 35–44 45–54 55–64 Total (crude rate) Total (age-adjusted rate)
41.7 53.9 67.6 68.5 54.6 52.0
32.6 51.6 64.3 72.3 49.9 46.3
36.8 52.7 65.8 70.3 52.1 49.1
dial infarction was determined for 53 cases [1.4%, 95% CI (1.2–1.7%)]; ischemia was determined for 421 cases [11.3%, 95% CI (10.3–11.0%)]. The age-adjusted prevalence of EKG with evidence of ischemic heart disease (IHD EKG) was 12.7% [10.4%, 95% CI (9.0–11.7%) for men and 14.7%, 95% CI (13.3–16.07%) for women]. The age-adjusted prevalence of metabolic syndrome as defined by ATP III criteria, was 49.0%, 95% CI (47.5–50.6%) [52.0%, 95% CI (50.0–54.0%) of males and 46.3%, 95% CI (44.3–48.3%) of females] (Table 2). A total of 151 (4.0%), 565 (15.1%), 1073 (28.7), 1150 (30.8%), 661 (17.7%), 135 (3.6%), had just none, just one, just two, just three, just four and just five metabolic syndrome traits, respectively. Unadjusted odds ratio (95% CI) between metabolic syndrome and IHD EKG was 1.64 (1.34–2.00), p b 0.001 [OR = 1.89 (1.36–2.63), p b 0.001 for men and OR = 1.56 (1.21–2.00), p b 0.001 for women]. The same association of metabolic syndrome and IHD EKG in the study population increased when the subjects with four [unadjusted OR = 1.88, CI (1.27–2.79), p = 0.002] or five [unadjusted OR = 2.31, CI (1.14–4.60), p = 0.02] components of metabolic syndrome entered into the equation. Unadjusted odds ratios (95% CI) relating metabolic syndrome and subgroups of IHD EKG also revealed significant associations [OR = 1.96 (1.19–3.50), p = 0.02 for myocardial infarction and OR = 1.57 (1.28–1.94), p b 0.001 for ischemia]. In multiple logistic regression analysis, metabolic syndrome showed a significant association with IHD EKG [OR = 1.35, CI (1.09–1.66), p = 0.005] after adjusting for sex and age (Table 3). Table 3 Multivariately adjusted (age and sex) odds ratios (OR) and 95% CI relating metabolic syndrome and IHD EKG among the northern Persian Gulf adultsa IHD EKG
Metabolic syndrome Sex (female) Age Groups (years)b
35–44 45–54 55–64
OR
CI
p value
1.35 1.58 1.15 2.00 3.54
(1.09–1.66) (1.30–1.93) (0.87–1.52) (1.52–2.64) (2.64–4.74)
0.005 0.001 0.34 0.001 0.001
a The metabolic syndrome considered as a single entity, sex and age as covariates, and IHD EKG also as the dependent variable. b The risks are relative to age group 25–34 years.
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Of the metabolic syndrome components, elevated blood sugar (OR = 2.69, p b 0.001), high blood pressure (OR = 1.79, p = 0.001) and low HDL-C (OR = 1.27, p = 0.02) had significant independent association with IHD EKG. 4. Discussion In the current study, we found that among the northern Persian Gulf adults, there was a highly significant association between metabolic syndrome and resting EKG evidence of IHD. This association remained after controlling of sex and age. To the best of our knowledge, the present study provides the fourth population-based information on IHD and metabolic syndrome using resting EKG abnormalities suggestive of IHD [15–17]. Association between metabolic syndrome components and prevalent IHD were investigated in a cross-sectional, community-based study of elderly men and women in Rancho Bernardo, California, in 1984–1987; in this study, there was also a significant association between resting ischemic EKG and all common components of the metabolic syndrome [15]. In prospective data from the Bruneck Study/Italy which also used a 12-lead EKG at the baseline and at the follow-up, subjects with metabolic syndrome had an increased incidence of CHD during follow-up: 8% vs. 3% in control subjects [16]. Comparing prevalence of metabolic syndrome among persons with IHD and without IHD in middle-aged Kaunas population/ Lithuania, metabolic syndrome was associated with IHD in men aged 45–64 years [17]. A two-fold increase risk of mortality from CHD and CVD in men and women with metabolic syndrome was demonstrated in a prospective cohort study in US; in persons with metabolic syndrome but without diabetes, risks of CHD and CVD mortality remained elevated [4]. The observations in the US adult population are consistent with previous reports of the prognostic importance of metabolic syndrome among men in the West of Scotland study, in Finnish adults, and more recently from Framingham Heart Study and San Antonio Heart Study cohorts [10,11,13,22]. According to the Atherosclerosis Risk in Communities (ARIC) Study, individuals without diabetes or CVD, but with the metabolic syndrome, are at increased risk for long-term cardiovascular outcomes [14]. In this study, metabolic syndrome was present in 23% of individuals without diabetes or prevalent CVD at baseline. Over an average of 11 years of follow-up, 879 incident CHD and 216 ischemic stroke events occurred [14]. One of the limitations of this cross-sectional, populationbased investigation was study design that lacked CVD mortality and morbidity data; we focused only on EKG criteria for prevalent IHD without regard to known (clinical) IHD. However, it is well known that the ST-T segment of EKG carries prognostic value in the univariate sense [23]. De Bacquer et al. showed that both men and women with major ischemic findings in the baseline EKG using Minnesota codes had an increased risk of CVD death [24]. They concluded that abnormalities in the baseline EKG are strongly associated with
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subsequent all cause, CVD and CHD mortality [24]. ECG with evidence of ischemic hear disease (IHD EKG) is not equivalent to ischemic cardiomyopathy, despite it has been associated with a bad prognosis, and thus results should not be interpreted as if both terms were interchangeable. We found a high prevalence of IHD EKG in 10.4% and 14.7% of the studied men and women, respectively (Table 1). Similar high prevalence of EKG-based possible ischemia (12.3% for women and 7.5% for men) was reported from an urban population in central part of Iran/Isfahan [25]. A crosssectional study in a Japanese population showed that the prevalence of IHD EKGs was 10% and 11.3% in men and women, respectively [21]. Similar difference in prevalence of ischemic EKG in women (10.6%) and men (8.4%) was reported from the Belgian study [26]. Overall, women have significantly more ST changes and T wave abnormalities on their resting EKG compared to men when adjustment is made for age [27]. This sex difference in ischemic EKG is surprising because men have a higher prevalence of myocardial infarction using Minnesota codes. However, 10-year followup data from a subset of the Belgian cohort support the hypothesis that women with ischemic EKG have the same increased risk of death due to CVD as men [26]. Although a definition of the metabolic syndrome may be difficult to agree upon, it is important that such a definition exists and is applied so that comparisons between populations of the prevalence of the syndrome and its relationship with various health outcomes can be made. We identified an estimated 49.0% of our population (25–64 years) had metabolic syndrome using the ATP III definition which is more amenable to measurement in clinical practice. The differences in the prevalence of the syndrome between populations may be due to lifestyle influences, genetic factors, the age and sex structures of the populations under study, and the era in which each of the studies was conducted, due to temporal changes in prevalence. Looking at those studies that indicate a population sample aged from 20 to 25 and upward, the prevalence varies from 8% (India) to 24% (United States) in men and from 7% (France) to 46% (India) in women [28]. A consistent finding is the observation that the prevalence of the metabolic syndrome is highly age-dependent. This is demonstrated in the Iranian population (Tehran Lipid and Glucose Study), in which the prevalence is less than 10% for both men and women in the 20- to 29-year age group, rising to 38% and 67% in the 60- to 69-year age group for men and women, respectively [29]. Because the metabolic syndrome is extremely common and likely increasing among the northern Persian Gulf population, health care professionals are likely to encounter these patients in their daily practice. This large number of people with the metabolic syndrome has serious implications for public health and clinical practice. The associated costs, which have not been defined so far, are likely to be substantial. Future increases in the incidence of cardiovascular disease and diabetes could occur in the region. The relationship of metabolic syndrome to cardiovascular risk can be approached in two ways: (a) by considering the
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individual risks posed by the components and (b) by considering the components together as a syndrome. Insulin resistance is thought by many to be the common pathology linking the components, so a lot of attention has focused on glucose homeostasis and its role in the development of CVD [30]. We found a positive association between increasing number of ATP III metabolic syndrome components and nonfatal IHD by EKG, results from our analysis indicate that the individual components of elevated fasting glucose, elevated blood pressure and low HDL cholesterol have significant association with IHD EKG. These findings suggest the need for intensified treatment recommendations in persons with metabolic syndrome risk factors. In persons with metabolic syndrome, up to 80% of CHD events may be preventable from control of LDL-C, HDL-C and blood pressure [31]. In addition, the presence of the metabolic syndrome is highly predictive of the development of diabetes mellitus. A treatment strategy focusing on aerobic exercise and weight loss can help delay or prevent the development of diabetes and can help reduce cardiovascular risk [32]. The current risk reduction recommendations, focusing on single risk factor identification and correction, should be replaced by targeting individuals with the cluster and tailoring treatment possibly on the underlying mechanisms, like insulin resistance, responsible for or contributing to the complex of coexisting abnormalities. 5. Conclusion In conclusion, the metabolic syndrome, which occurs very frequently in the general population, is burden by more frequent prevalent IHD EKG, treatment strategies must focus on therapy for all risk factors, including dyslipidemia, hypertension and insulin resistance. Acknowledgement This study was supported in part by a grant from Joint Ministry of Health and World Health Organization Regional Office (JPRM) fund (A/C: 02.01.01.01.ACS 2002-03) and Bushehr Province Research Committee. References [1] Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among U.S. adults. Diabetes Care 2004;27: 2444–9. [2] Liese AD, Mayer-Davis EJ, Haffner SM. Development of the multiple metabolic syndrome: an epidemiologic perspective. Epidemiol Rev 1998;20:157–72. [3] Grundy S. Obesity, metabolic syndrome, and coronary atherosclerosis. Circulation 2002;105:2696–8. [4] Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation 2004;110: 1245–50. [5] Vitarius JA. The metabolic syndrome and cardiovascular disease. Mt Sinai J med 2005;72:257–62.
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