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Impact of metabolic syndrome on ischemic heart disease – A prospective cohort study in an Iranian adult population: Isfahan cohort study
Nutrition, Metabolism & Cardiovascular Diseases (2012) 22, 434e441 available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/nmcd
Impact of metabolic syndrome on ischemic heart disease e A prospective cohort study in an Iranian adult population: Isfahan cohort study M. Talaei a,*, M. Sadeghi a, T. Marshall b, G.N. Thomas b, P. Kabiri c, S. Hoseini a, N. Sarrafzadegan a a
Isfahan Cardiovascular Research Center, Isfahan University of Medical Sciences, Isfahan, Iran Public Health, Epidemiology & Biostatistics, University of Birmingham, UK c Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran b
Received 16 May 2010; received in revised form 5 August 2010; accepted 9 August 2010
KEYWORDS Ischemic heart disease; Metabolic syndrome; Iran; Longitudinal study
Abstract Background: The impact of the metabolic syndrome among populations in the Middle East region is unknown; we therefore examined the association between the syndrome and the risk of ischemic heart disease (IHD) in an Iranian population. Methods and results: The Isfahan Cohort Study (ICS) prospectively followed 6146 Iranian people (51.8% women, aged 35e75 years) from three cities and their rural districts who were initially free of ischemic heart disease. During the 5 year follow-up, 209 (56% men) cases of ischemic heart disease were detected. The metabolic syndrome was defined by the modified criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATPIII). End points were defined as fatal and nonfatal myocardial infarction, sudden cardiac death and unstable angina. A clear dose-response relationship was found between the number of metabolic risk factors and the incidence of IHD, with the hazard ratios increasing dose-dependently from 1.72 (95% CI 0.863.46) for only one to 1.97 (1.00e3.90), 2.85 (1.45e5.58) and 4.44 (2.25e8.76) for 2, 3 and 4 metabolic syndrome component respectively, relative to those with no component. The adjusted hazard ratio (95% CI) associated with the metabolic syndrome was 1.58 (1.06e2.35) in men and 1.72 (1.08e2.74) in women for IHD. The contribution of metabolic syndrome to the IHD risk was particularly strong among smokers although there was no significant interaction. Conclusions: The metabolic syndrome by NCEP/ATPIII definition is a major determinant of ischemic heart disease in this middle-aged Iranian population, especially among smokers. ª 2010 Elsevier B.V. All rights reserved.
* Corresponding author. Tel.: þ44 7731662894. E-mail address: [email protected] (M. Talaei). 0939-4753/$ - see front matter ª 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2010.08.003
Metabolic syndrome and ischemic heart disease in Iran
Introduction During past decades, Iran has experienced rapid economic growth and the aging of its population. The resultant change in lifestyle and longer life expectancy have led to increasing levels of risk factors for cardiovascular diseases (CVD) and a concomitant rise in the burden of cardiovascular disease [1,2]. The metabolic syndrome (MetS) is a constellation of physiological cardiovascular risk factors [3]. While the prevalence of MetS was relatively low in South and East Asia, it was comparable to that of the US for areas like India, Turkey and Iran but with a large excess in females, resulting in a significant public health problem [4]. Although there are several studies describing the association of the MetS and CVD in USA and European countries, the impact of the MetS has not been thoroughly examined among Asian populations [3], particularly in the Middle East, where there are very limited data. Many reviews and meta-analyses have called for additional information from developing countries to confirm the importance of the association between the MetS entity and the CVD [5e7]. We therefore assessed the association between NCEP-ATPIII defined MetS and ischemic heart disease during the 5-years of follow-up in the Isfahan Cohort Study (ICS) which includes Iranian participants aged 35e75 who did not have CVD at baseline.
Methods The ICS is a community-based, ongoing longitudinal study of 6504 adults aged 35 and older at baseline. Participants lived in both urban and rural (27.5%) areas of three cities and their associated district villages in the central Iran (Isfahan, Arak and Najafabad) who had participated in IHHP (Isfahan Healthy Heart Program) baseline survey [8]. Informed consent was obtained from each subject. They were recruited from January to September 2001 using multistage random sampling and have been followed since then. The response rate for house interviews was 98%, with 95% of the total attending the examination clinic. Details of the IHHP including its baseline survey have previously reported elsewhere [8] and quality of data collection and management was confirmed through external evaluation [9]. The updated Adult Treatment Panel III guideline of the National Cholesterol Education Program definition [10] was used to categorize the subjects according to the number of components of the MetS. It was defined as the presence of 3 or more of the following components: 1) serum triglycerides 150 mg/dL; 2) HDL-cholesterol <40 mg/dL for men and <50 mg/dL for women; 3) glucose 100 mg/dL fasting or on treatment; 4) blood pressure (BP) 130/85 mmHg or antihypertensive medication use, and 5) waist circumference 102 cm in men and 88 cm in women.
Follow-up The follow-up of the participants was carried out in two episodes using structured telephone call interviews or home visits (15%) in 2003 and 2005e2006. The subjects are
435 being followed-up biannually until they complete 10 years follow-up. Of the whole sample, 978 (15.0%) and 464 (7.1%) participants were lost in 2003 and 2005e2006 follow-ups respectively. The high amount of loss to follow-up was partly owing to changes in telephone numbers that were made by government in some areas. A physician reviewed all 1032 (20%) participants’ or relatives’ reports of hospitalization or death and identified a total of 528 (10.4%) IHD related reports containing 132 (2.6%) deaths and 396 (7.8%) hospitalizations. For these reports, further investigations were done to provide patients record (hospital documents). Verbal autopsies were carried out by a trained nurse as a secondary interview with surviving family members using a defined questionnaire to elicit medical history, signs and symptoms prior to out-of-hospital deaths. This method has been used in other studies and has been shown to be useful in distinguishing broad causes of death [11,12]. Additional secondary interviews by expert nurses were carried out for hospitalized cases whenever incompatible or incomplete information had meant that researchers were unable to obtain their records. Unrelated reports included 82 (1.6%) other internal diseases, 235 (4.6%) elective surgery, 43 (0.8%) trauma and 144 (2.8%) other diseases.
Confirmation of end points Ischemic heart disease was the primary outcome events considered for the analysis. These included definite or probable acute myocardial infarction (AMI), unstable angina (UA), and sudden cardiac death. To confirm them a specialists panel of three cardiologists reviewed all relevant documents including death certificates to make a final decision. They were unaware of the information regarding risk factors. The criteria for ischemic heart disease were modified from those of the World Health Organization (WHO) Expert Committee. The diagnosis of AMI was based on the presence of at least two of the following criteria: 1) typical chest pain lasting more than 30 min, 2) ST elevation >0.1 mV in at least 2 adjacent electrocardiograph leads and 3) an increase in serum levels of cardiac biomarkers including cardiac troponins, and creatine kinase (CK) and CK-MB [13]. The definition of UA required typical chest discomfort lasting more than 20 min within the 24 h preceding hospitalization and representing a change in the usual pattern of angina or pain: occurring with a crescendo pattern, being severe and described as a frank pain [14]. The diagnosis of UA might be new or based on dynamic ST-interval or T-wave changes in at least two contiguous ECG leads. Sudden cardiac death was defined as death within 1 h of onset, a witnessed cardiac arrest, or abrupt collapse not preceded by >1 h of symptoms. Although the in-hospital diagnoses of clinicians were considered, the final decisions of the panel were made independently.
Statistical analysis Data entry was carried out using EPI info (windows version). All data were analyzed by SPSS (SPSS Inc., Chicago, IL, USA; Version 15). Student’s t-test and the c2 test
436 were used for bivariate analysis. Person-years were calculated as the sum of individual follow-up times until the last telephone call interview, incident IHD, non-cardiovascular death, emigration or any other loss to follow-up (i.e. when they censored). The hazard ratios for ischemic heart disease were calculated using a Cox proportional hazards model. The models were adjusted for age (years), sex and for other potential confounding variables including hypercholesterolemia, smoking status, and menopausal status for women. A variable represented the number of MetS components (0, 1, 2, 3 and 4) was examined in the models indicating trends across the categories of the number of metabolic risk factors. The multivariable-adjusted associations of ischemic heart disease were examined overall and stratified by serum total cholesterol levels, (<200 mg/dL and 200 mg/dL) and current smoking status. The models including LDL-C instead of total cholesterol did not result in significant differences in the study findings. The significance of the interaction of MetS with serum total cholesterol levels and smoking status was tested using cross-product terms of these variables in multivariable models. KaplaneMeier analysis was used to evaluate time to outcome as a function of dichotomous independent variables with log-rank test for determining statistically significant differences. For all analyses, 2-tail statistical significance was assessed at a level of 0.05 and P-value lower than 0.1 was considered as borderline significance.
Results There were 6504 subjects recruited to the Isfahan Cohort Study, of these 5441 (83.7%) completed the first follow-up; after 5 years, 5062 (77.8%) of the participants were successfully followed during 2nd follow-up. There was no significant difference between available participants and loss-to-follow up group in terms of sex, age, MetS and its component except for WC (51% vs. 48%, P Z 0.023) and BP (36% vs. 33%, P Z 0.018) components. As the IHHP did not have any inclusion criteria that were related to individual’s cardiovascular health, 108 participants who had a history of myocardial infarction, stroke or heart failure at baseline, as well as 250 individual aged more than 75 years were
M. Talaei et al. excluded from analysis. Finally, 5224 (80.3%) eligible participants who had at least two years of follow-up were included in the analysis. With respect to the whole sample, participants with and without the MetS, the most prevalent component was high triglycerides in all 3 groups (58.9%, 89.5% and 41.9% respectively) with abdominal obesity being the second most common (49.6%, 86.1% and 29.5% respectively), except in participants without MetS for which HDL-C component was slightly more prevalent (30.2%). The least prevalent component was FBS with 14.6%, 32.2% and 4.9% respectively. The differences between the cumulative survival of participants with and without the MetS by gender are depicted in Fig. 1 (P < 0.001, the log-rank test). Women with the MetS had a significantly lower 5-year survival rate than women with a normal metabolic status (94.5% versus 98.1%, P < 0.001), as was the case for men (89.0% versus 95.4%, P < 0.001). After 23,734 person-years of follow-up (with median follow-up of 4.8 years; 4.6 and 5 years for the 25th and the 75th quartiles, respectively), we documented 209 incident cases of ischemic heart disease (117 in men). Ischemic heart disease included 12 (7 in men) fatal and 42 (28 in men) nonfatal myocardial infarctions, 111 (52 in men) unstable angina pectoris, and 44 (30 in men) sudden cardiac deaths. Absolute risk of ischemic heart disease was 8.8 (7.6e10.0) per 1000 person-years for total subjects, it was 10.2 (8.5e12.2) and 7.4 (6.0e9.1) per 1000 person-years for men and women respectively (95% CI). The MetS was detected in 2191 (35.6%) of the people aged 35e75 years. In men and women, there were 610 (20.6%) and 1581 (49.6%) individuals, respectively, who met the MetS definition. Table 1 compares values and proportions of the MetS components and other cardiovascular risk factors between subjects who developed ischemic heart disease and those who did not. Subjects who developed ischemic heart disease were older, more hypertensive, smoked more, and had higher total cholesterol serum levels, serum triglycerides, and fasting blood sugar. In addition they had more central adiposity with a higher waist circumference and waist to hip ratio. The associations of individual metabolic risk factors as continuous variable with IHD are depicted in appendix. Risk of ischemic heart disease was 2.5-fold higher in the presence of the increased blood pressure and blood sugar
Figure 1 Five-year KaplaneMeier plots of survival for ischemic heart disease (MI, Sudden Cardiac Death, and Unstable Angina) by metabolic status at study entry.
Metabolic syndrome and ischemic heart disease in Iran Table 1
437
Baseline characteristics in subjects who subsequently developed or did not develop ischemic heart disease.
Characteristics Demographics: Age (years) Sex n (%) Male Female Region Urban n (%) Rural n (%) Risk Factors: DM n (%) IGT n (%)b FBS (mg/dl) 2 h Postprandial (mg/dl) Antidiabetic drugs treatment (%) Smoking n (%) HTN (140/90) n (%) Systolic BP (mmHg) Diastolic BP (mmHg) Antihypertensive drugs treatment (%) T. chol (mg/dl) TG (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) Hypolipidaemic drugs treatment BMI n(%) <25 25e29.9 30 BMI, kg/m2 High Waist Circumference n (%)c WC (cm) High Waist Hip Ratio n (%)c WHR
IHDa (n Z 209)
No Events (n Z 5015)
P-Value
58.1 10.7
49.5 10.6
<0.001
117 (56.0) 92 (44.0)
2408 (48.0) 2607 (52.0)
0.024
161 (77.0) 48 (23.0)
3634 (72.5) 1381 (27.5)
0.146
39 (19.0) 24 (12.6) 97.3 40.7 125.5 5.2 19 (9.1) 57 (27.3) 115 (55.0) 136 24 83.8 12.7 61 (29.2) 231 53 221 116 143 47 46.3 10.3 21 (10)
463 (9.3) 420 (8.8) 88.1 32.3 110.3 56.5 247 (4.9) 1031 (20.6) 1355 (27.1) 120 20 78.0 11.4 497 (9.9) 211 49 190 103 127 42 46.8 10.4 465 (9.3)
64 (31.5) 94 (46.3) 45 (22.2) 27.2 4.2 156 (75.7) 97.36 11.59 147 (71.4) 0.95 0.06
1813 (37.0) 2002 (40.9) 1084 (22.1) 26.7 4.5 3505 (70.2) 94.67 12.29 3273 (65.6) 0.92 0.07
<0.001 0.072 0.002 0.002 0.007 0.019 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.483 0.705 0.224
0.111 0.086 0.002 0.085 <0.001
Data are presented as means standard deviation or percentages. a Ischemic Heart Disease (MI, Sudden Cardiac Death and Unstable Angina). b Impaired glucose tolerance (IGT) was identified as 2-h postprandial (2 h PP) 140 but less than 200 mg/dl. c Waist Circumference 80 and 94, Waist Hip Ratio 0.80 and 0.95 for women and men respectively (IDF definition).
components of the MetS among men and more than 1.5-fold higher for the triglyceride component. There was no association with waist circumference or HDL-cholesterol (Table 2). For women, similar associations were found but the association with high blood sugar was weaker; on the other hand, it was stronger regarding blood pressure component. The strength of associations were somewhat attenuated after mutual adjustment for the other metabolic factors and other confounding variables, but the associations with blood pressure remained statistically significant in both sexes and blood sugar in men. Risk of ischemic heart disease was positively associated with the number of MetS components for both men and women with no interaction with sex (P for interaction >0.05; Table 3). With 0 MetS components as the reference group, the multivariate hazard ratio (95% CI) for ischemic heart disease for 3 or more components was 2.57 (1.31e5.03) and 3.10 (1.52e6.32) for 4 or more components. With fewer than 3 components as the reference group, the multivariate hazard ratio (95% CI) associated with 3
components was 1.61 (1.19e2.17). The associations were similar for men and women. The association between the MetS and risk of ischemic heart disease was examined for the total group, stratified by serum total cholesterol levels and smoking status (Table 4). The excess risk of ischemic heart disease associated with the MetS was slightly larger for persons with serum cholesterol levels 200 mg/dL than for those with lower cholesterol levels. The excess risk for IHD associated with the MetS was more evident among smokers than among never smokers. However, significant interaction was found for neither of smoking or hypercholesterolemia with MetS.
Discussion Various studies have been published on the relationship between the MetS and the incidence of IHD, many of which were included in the meta-analysis carried out by Gami
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Table 2 Hazard Ratio of metabolic syndrome’s components for ischemic heart disease (MI, Sudden Cardiac Death, and Unstable Angina) in men and women. Crude HR (95% CI)
P-Value
Adjusted HR(95% CI)a
P-Value
(49.6) (58.9) (44.3) (35.9) (14.6)
1.08 1.70 1.04 2.92 2.03
(0.82e1.41) (1.26e2.30) (0.79e1.37) (2.20e3.88) (1.48e2.79)
0.581 <0.001 0.766 <0.001 <0.001
1.02 1.19 1.25 1.70 1.40
(0.71e1.40) (0.75e1.48) (0.93e1.68) (1.25e2.33) (1.01e1.94)
0.979 0.742 0.125 0.001 0.041
636 1751 920 977 388
(21.5) (59.1) (31.1) (33.0) (13.1)
1.45 1.56 1.21 2.81 2.50
(0.96e2.17) (1.05e2.31) (0.82e1.78) (1.93e4.08) (1.65e3.79)
0.078 0.025 0.323 <0.001 <0.001
0.95 1.28 1.25 1.74 1.71
(0.61e1.47) (0.82e1.99) (0.83e1.88) (1.15e2.64) (1.10e2.65)
0.835 0.261 0.271 0.009 0.016
2415 1870 1805 1229 510
(75.8) (58.7) (56.7) (38.6) (16.0)
1.84 1.99 1.08 3.61 1.70
(1.07e3.18) (1.25e3.15) (0.71e1.64) (2.31e5.65) (1.05e2.75)
0.027 0.003 0.699 <0.001 0.029
1.49 1.20 1.25 1.96 1.13
(0.83e2.65) (0.73e1.97) (0.82e1.92) (1.21e3.17) (0.69e1.85)
0.174 0.453 0.295 0.006 0.612
Metabolic Syndrome Components
n (%)
Total Waist circumference Triglyceride HDL-cholesterol Blood pressure Blood sugar
3051 3621 2725 2206 898
Men Waist circumference Triglyceride HDL-cholesterol Blood pressure Blood sugar Women Waist circumference Triglyceride HDL-cholesterol Blood pressure Blood sugar a
Adjusted Model includes age, sex, smoking status and hypercholesterolemia, in addition to the MetS components.
et al., consisting of 43 cohorts and 17,2573 participants. The meta-analysis concluded that MetS itself, apart from its components, increases the risk of cardiovascular events 1.78 times; and 1.54 times after adjustment. They even suggested that in addition to targeting individual cardiovascular risk factors, primary prevention trials should study interventions that address the MetS as a single entity. However, all the longitudinal studies evaluated in this meta-analysis, except for the two conducted in Turkey and Japan, were carried out in Western countries [5]. Another meta-analysis performed by Galassi et al. evaluated 21 cohort studies reached similar conclusions [15]. The findings of the current study in an Iranian population identified a slightly higher crude risk, but the adjusted risk was similar to those previously reported and contrasted with study from Pakistan which showed no association using NCEPATPIII criteria [16]. The magnitude of risk was similar to those observed in other Asian populations (except for Turkey, mostly from East Asia), ranged from 1.7 to 3 [2,17e20]. In addition, the ICS considered serious IHD events. The strength of the association of the MetS with cardiovascular events in East Asian populations were considerably higher than from our study, which was more similar to those from Western populations. On the other hand, the positive effect of adding risk factors one by one to the predictive models of CVD and IHD (dose response effect) which was observed in various studies [2,18,19,21,22], and to some extent is evident in the present study, indicate partly the non-dominance of MetS and suggest the use of a continuous metabolic score [23e25]. Furthermore, the prediction power of the MetS in the ICS was very close to that of blood pressure and serum glucose level, which shows that MetS might not be more effective than these two components independently.
Moreover, whether the adverse impact on health by MetS is greater than the sum of its parts remains unclear [6,7,26]. In spite of the recommendations by WHO and others to define the criterion for abdominal obesity locally [15,27], the two Iranian published studies presented inconsistent results [28,29] and there remains no agreement on the cut point for waist circumference in Iran. It is strongly believed that abdominal obesity plays a pivotal role in MetS [15,30,31], but in ICS although the WC was significantly higher in the group later affected by IHD, abdominal obesity as defined according to both ATPIII or IDF was not associated with risk of IHD. This finding is in line with those studies which indicate Asian data favors the ATPIII definition for Asian populations [4]. However, further study on central obesity index is required in Iran. On balance, until sufficient data from developing countries become available and the definition of the MetS components in these countries, including Iran, are agreed upon, the impact of the MetS can not be adequately assessed. This study tried to fulfill partly this need. In their extensive review, Kahn et al. recommended that until much needed research is completed, clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the MetS [31]. The present study determined the MetS risk for women to be slightly higher than in men. The meta-analysis carried out by Gami et al. similarly suggested the risk of incident CVD events to be higher in women (RR Z 2.63 vs. 1.98) [5], which is in agreement with data from a meta-analysis by Galassi et al. [7]. In contrast, the relation between the MetS and the prevalence of CHD was significant only in men in a Turkish population [17]. The Tehran Lipid and Glucose Study (TLGS), which is among the few Iranian studies analyzing the relationship between the MetS and CVD, also reported higher risk for men [32], but this may be the result
Metabolic syndrome and ischemic heart disease in Iran Table 3
439
Hazard Ratio of ischemic heart disease according to the number of Metabolic syndrome’s components.
n (%) Total subjects No. of metabolic 0 1 2 3 4þ 3þ P for trend
Person-years
No. of Events
Crude HR (95% CI)
Multivariable HR (95% CI)
factors 729 (11.9) 1476 (24.0) 1750 (28.5) 1380 (22.5) 811 (13.2) 2191 (36)
2740 5769 6717 5333 3171 8505
10 38 51 58 52 110
1 1.72 (0.86e3.46) 1.97 (1.00e3.90)* 2.85 (1.45e5.58)y 4.44 (2.25e8.76)z 3.43 (1.79e6.55)z P < 0.001
1 1.56 (0.77e3.16) 1.80 (0.90e3.59)x 2.29 (1.15e4.59)* 3.10 (1.52e6.32)y 2.57 (1.31e5.03)y 0.005
Metabolic syndrome No 3955 (64.4) Yes 2191 (35.6)
15228 8505
99 110
1 2.00 (1.52e2.63)z
1 1.61 (1.19e2.17)y
factors 564 (19.0) 939 (31.7) 848 (28.6) 432 (14.6) 178 (6.0) 610 (20.6)
2128 3630 3225 1742 682 2425
10 28 33 30 16 46
1 1.66 (0.80e3.43) 2.09 (1.02e4.25)* 3.44 (1.66e6.99)y 5.17 (2.34e11.40)z 3.88 (1.95e7.70)z P < 0.001
1 1.30 (0.62e2.70) 1.46 (0.71e3.02) 1.93 (0.92e4.06)x 2.47 (1.09e4.06)* 2.09 (1.03e4.25)* 0.143
Metabolic syndrome No 2351 (79.4) Yes 610 (20.6)
8983 2425
71 46
1 2.33 (1.60e3.38)z
1 1.58 (1.06e2.35)*
factors 165 (5.2) 537 (16.9) 702 (22.0) 902 (28.3) 948 (29.8) 633 (19.9) 1581 (49.6)
612 2139 2751 3492 3591 2489 6080
0 10 10 18 28 36 64
1 1.48 (0.68e3.23) 2.33 (1.13e4.82)* 4.30 (2.12e8.72)z 3.13 (1.60e6.13)y P < 0.001
e e 1 1.35 (0.60e3.06) 1.80 (0.83e3.88) 2.43 (1.14e5.19)* 2.09 (1.01e4.30)* 0.066
Metabolic syndrome No 1604 (50.4) Yes 1581 (49.6)
6244 6080
28 64
1 2.49 (1.58e3.86)z
1 1.72(1.08e2.74)*
Men No. of metabolic 0 1 2 3 4þ 3þ P for trend
Women No. of metabolic 0 1 1a 2 3 4þ 3þ P for trend
HR indicates hazard ratios, Ischemic Heart Disease include: MI, SCD, USA. Test for significance: xP < 0.1, *P < 0.05, yP < 0.01, zP < 0.001. Multivariable HR adjusted for age, sex, serum total cholesterol, cigarette smoking and for women, menopausal status. a There was no event in women who did not have any of the metabolic syndrome components; so, this stratum merged with women with only one component.
of the cross-sectional nature of that study. Similarly, the Framingham Offspring Study reported the relative risk of CVD events in men was two times higher than that for women which was attributed to the premenopausal and perimenopausal status of most of the female participants [3]. However, the Hoorn Cohort Study which was carried out on individuals older than 50 demonstrated similar pattern [33]. A Japanese study also reported almost similar risks (HR 2.4 vs. 2.3 in men and women respectively) [18]. According to the ICS findings, both smoking and hypercholesterolemia strengthened the relationship between MetS and incident IHD, although no significant interaction was observed, suggesting the relationship is additive and
not multiplicative. A recent report from China reported a dose response relationship between the severity of smoking and exacerbation of MetS effect on IHD. As in the current study, an interaction was also not observed [34]. However, data from Japan identified similar results in terms of smoking, but in this case there was a significant interaction between the MetS and hypercholesterolemia on incident IHD [18]. In a recent report of 34 cohort studies in the Asia-Pacific region, smoking exacerbated the association between total cholesterol and the risk of IHD and mitigated the protective effects of HDL-C on coronary risk, interacting with both [35]. There is therefore a clear need to study the relations among MetS and other risk factors and
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Table 4 Multivariable Hazard Ratio of ischemic heart disease associated with metabolic syndrome, stratified by serum total cholesterol Levels and smoking status. Crude HR (95% CI)
Multivariable HR (95% CI)
1.75 (1.04e2.93)*
1.60 (0.93e2.57)x
Serum total cholesterol 200 mg/dL Metabolic syndrome P for interaction
1.86 (1.33e259)z
1.77 (1.24e2.53)y 0.092
Never smokers Metabolic syndrome
1.86 (1.35e2.57)z
1.52 (1.07e2.16)*
Smokers Metabolic syndrome P for interaction
3.29 (1.94e5.56)z
1.98 (1.13e3.48)* 0.244
Serum total cholesterol <200 mg/dL Metabolic syndrome
HR indicates hazard ratios. Test for significance: xP < 0.1, *P < 0.05, yP < 0.01, zP < 0.001. Multivariable HR adjusted for the same variables shown in Table 2 except for the stratified variables.
the incidence of IHD, as has been emphasized in other studies [31].
Limitation Although the loss-to-follow up rate was remarkable, characteristics of subjects lost to follow-up did not differed except for WC and BP components that the differences were just around 3%. Hence it seems unlikely that losses to follow up could have introduced serious bias, however, it is still a limitation for this study. The role of treatment of metabolic syndrome and its components as well as successfulness of such treatments was not investigated during follow up. This shortcoming might have changed strength of associations and could be a subject for further research. In addition, no data were collected on subclinical coronary artery disease because of resource limitations.
Conclusion MetS based on NECP-ATPIII definition is a major determinant of ischemic heart disease among Iranian men and women but current international cut-off points for waist circumference failed to define central obesity as a predictor of IHD. Furthermore, the number of the constituent factors provides informative graded assessment of risk. High blood pressure is the most individual important component. The excess risk associated with the MetS was slightly larger among smokers and hypercholesterolemics.
Acknowledgement The baseline survey as a part of Isfahan Healthy Heart Program (IHHP) was supported by a grant (No. 31309304) from the Iranian Budget and Planning Organization and the Ministry of Health in Iran. Isfahan Cardiovascular Research Centre, affiliated to Isfahan University of Medical Sciences, supported the biannual follow-ups. We thank the personnel of Isfahan Cardiovascular Research Centre, especially those in the Surveillance Department and IHHP Evaluation
Committee for their close cooperation. Moreover, we owe a debt of gratitude to Dr. Majid Ahsan regarding his technical assistance for converting dates in Persian calendar (Solar Hejri) to Gregorian.
References [1] Sarrafzadegan N, Kelishadi R, Esmaillzadeh A, Mohammadifard N, Rabiei K, Roohafza H, et al. Do lifestyle interventions work in developing countries? Findings from the Isfahan healthy heart program in the Islamic Republic of Iran. Bull World Health Organ 2009;87:39e50. [2] Park HS, Cho SI, Song YM, Sung J. Multiple metabolic risk factors and total and cardiovascular mortality in men with low prevalence of obesity. Atherosclerosis 2006 Jul;187(1): 123e30. [3] Wilson PWF, D’Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005;112(20): 3066e72. [4] Pan WH, Yeh WT, Weng LC. Epidemiology of metabolic syndrome in Asia. Asia Pac J Clin Nutr 2008;17(Suppl. 1):37e42. [5] Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK, et al. Metabolic sydrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007;49(4):403e14. [6] Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care 2005;28(7): 1769e78. [7] Galassi A, Reynolds K, He J. Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. Am J Med 2006; 119(10):812e9. [8] Sarraf-Zadegan N, Sadri G, Malek AH, Baghaei M, Mohammadi FN, Shahrokhi S, et al. Isfahan Healthy Heart Programme: a comprehensive integrated community-based programme for cardiovascular disease prevention and control. Design, methods and initial experience. Acta Cardiol 2003; 58(4):309e20. [9] Vartiainen E, Laatikainen T. Isfahan Healthy heart Program (IHHP): external evaluation 12.5.-18.5.2009 [Internet] [cited 2009 Jun 25]. Isfahan: Isfahan Cardiovascular Research Center. Available from: http://ihhp.mui.ac.ir/ihhp/sounds/ 1656/1656_0.pdf; 2009.
Metabolic syndrome and ischemic heart disease in Iran [10] Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome. An American heart Association/National heart, Lung, and blood Institute Scientific statement. Executive summary. Cardiol Rev 2005;13(6):322e7. [11] Yang G, Rao C, Ma J, Wang L, Wan X, Dubrovsky G, et al. Validation of verbal autopsy procedures for adult deaths in China. Int J Epidemiol 2006;35(3):741e8. [12] Kumar R, Thakur JS, Rao BT, Singh MM, Bhatia SP. Validity of verbal autopsy in determining causes of adult deaths. Indian J Public Health 2006;50(2):90e4. [13] Luepker RV, Apple FS, Christenson RH, Crow RS, Fortmann SP, Goff D, et al. Case definitions for acute coronary heart disease in epidemiology and clinical research studies: a statement from the AHA Council on Epidemiology and prevention; AHA Statistics Committee; World heart Federation Council on Epidemiology and prevention; the European Society of Cardiology Working group on Epidemiology and prevention; Centers for disease control and prevention; and the national heart, Lung, and blood Institute. Circulation 2003;108(20): 2543e9. [14] Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-STsegment elevation myocardial infarctione2002: summary article: a report of the American College of Cardiology/American heart association Task Force on Practice guidelines (Committee on the management of patients with unstable angina). Circulation 2002;106(14):1893e900. [15] Alberti KGM, Zimmet P, Shaw J. The metabolic syndromeea new worldwide definition. Lancet 2005;366(9491):1059e62. [16] Wierzbicki AS, Nishtar S, Lumb PJ, Lambert-Hammill M, Crook MA, Marber MS, et al. Waist circumference, metabolic syndrome and coronary artery disease in a Pakistani cohort. Int J Cardiol 2008;128(1):77e82. [17] Onat A, Ceyhan Kk, Basar O, Erer B, Toprak S, Sansoy V. Metabolic syndrome: major impact on coronary risk in a population with low cholesterol levelsea prospective and crosssectional evaluation. Atherosclerosis 2002;165(2):285e92. [18] Iso H, Sato S, Kitamura A, Imano H, Kiyama M, Yamagishi K, et al. Metabolic syndrome and the risk of ischemic heart disease and stroke among Japanese men and women. Stroke 2007;38(6):1744e51. [19] Chien KL, Hsu HC, Sung FC, Su TC, Chen MF, Lee YT. Metabolic syndrome as a risk factor for coronary heart disease and stroke: an 11-year prospective cohort in Taiwan community. Atherosclerosis 2007;194(1):214e21. [20] Thomas GN, Schooling CM, McGhee SM, Ho SY, Cheung BM, Wat NM, et al. Metabolic syndrome increases all-cause and vascular mortality: the Hong Kong cardiovascular risk factor study. Clin Endocrinol (Oxf) 2007;66(5):666e71. [21] Eberly LE, Prineas R, Cohen JD, Vazquez G, Zhi X, Neaton JD, et al. Metabolic syndrome: risk factor distribution and 18-year mortality in the multiple risk factor intervention trial. Diabetes Care 2006 1;29(1):123e30.
441 [22] McNeill AM, Rosamond WD, Girman CJ, Golden SH, Schmidt MI, East HE, et al. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study. Diabetes Care 2005;28(2):385e90. [23] Hillier TA, Rousseau A, Lange C, Lepinay P, Cailleau M, Novak M, et al. Practical way to assess metabolic syndrome using a continuous score obtained from principal components analysis. Diabetologia 2006;49(7):1528e35. [24] Does diagnosis of the metabolic syndrome detect further men at high risk of cardiovascular death beyond those identified by a conventional cardiovascular risk score? The DECODE Study. Eur J Cardiovasc Prev Rehabil 2007;14(2):192e9. [25] Woodward M, Tunstall-Pedoe H. The metabolic syndrome is not a sensible tool for predicting the risk of coronary heart disease. Eur J Cardiovasc Prev Rehabil 2009;16(2):210e4. [26] Nilsson PM. Cardiovascular risk in the metabolic syndrome: fact or fiction? Curr Cardiol Rep 2007;9(6):479e85. [27] World Health Organization (WHO). Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 2000;894. i-253. [28] Delavari A, Forouzanfar MH, Alikhani S, Sharifian A, Kelishadi R. The First nationwide study of the prevalence of the metabolic syndrome and optimal cut-off points of waist circumference in the middle east: the national survey of risk factors for non-communicable diseases of Iran. Diabetes Care; 2009:dc08e1800. [29] Esteghamati A, Ashraf H, Rashidi A, Meysamie A. Waist circumference cut-off points for the diagnosis of metabolic syndrome in Iranian adults. Diabetes Res Clin Pract 2008; 82(1):104e7. [30] Zimmet P, Alberti KG, Serrano Rios M. A New International Diabetes Federation (IDF) worldwide definition of the metabolic syndrome: the rationale and the results. Revista Espanola de Cardiologia 2005;58(12):1371e5. [31] Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005;28(9): 2289e304. [32] Zabetian A, Hadaegh F, Azizi F. Relationship between metabolic syndrome and its components with coronary heart disease in Iranian men and women. Exp Clin Endocrinol Diabetes 2008;116(9):525e31. [33] Dekker JM, Girman C, Rhodes T, Nijpels G, Stehouwer CDA, Bouter LM, et al. Metabolic syndrome and 10-year cardiovascular disease risk in the Hoorn study. Circulation 2005;112(5): 666e73. [34] He Y, Lam TH, Jiang B, Wang J, Sai X, Fan L, et al. Combined effects of tobacco smoke exposure and metabolic syndrome on cardiovascular risk in older residents of China. J Am Coll Cardiol 2009;53(4):363e71. [35] Nakamura K, Barzi F, Huxley R, Lam TH, Suh I, Woo J, et al. Does cigarette smoking exacerbate the effect of total cholesterol and high-density lipoprotein cholesterol on the risk of cardiovascular diseases? Heart 2009;95(11):909e16.
journal homepage: www.elsevier.com/locate/nmcd
Impact of metabolic syndrome on ischemic heart disease e A prospective cohort study in an Iranian adult population: Isfahan cohort study M. Talaei a,*, M. Sadeghi a, T. Marshall b, G.N. Thomas b, P. Kabiri c, S. Hoseini a, N. Sarrafzadegan a a
Isfahan Cardiovascular Research Center, Isfahan University of Medical Sciences, Isfahan, Iran Public Health, Epidemiology & Biostatistics, University of Birmingham, UK c Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran b
Received 16 May 2010; received in revised form 5 August 2010; accepted 9 August 2010
KEYWORDS Ischemic heart disease; Metabolic syndrome; Iran; Longitudinal study
Abstract Background: The impact of the metabolic syndrome among populations in the Middle East region is unknown; we therefore examined the association between the syndrome and the risk of ischemic heart disease (IHD) in an Iranian population. Methods and results: The Isfahan Cohort Study (ICS) prospectively followed 6146 Iranian people (51.8% women, aged 35e75 years) from three cities and their rural districts who were initially free of ischemic heart disease. During the 5 year follow-up, 209 (56% men) cases of ischemic heart disease were detected. The metabolic syndrome was defined by the modified criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATPIII). End points were defined as fatal and nonfatal myocardial infarction, sudden cardiac death and unstable angina. A clear dose-response relationship was found between the number of metabolic risk factors and the incidence of IHD, with the hazard ratios increasing dose-dependently from 1.72 (95% CI 0.863.46) for only one to 1.97 (1.00e3.90), 2.85 (1.45e5.58) and 4.44 (2.25e8.76) for 2, 3 and 4 metabolic syndrome component respectively, relative to those with no component. The adjusted hazard ratio (95% CI) associated with the metabolic syndrome was 1.58 (1.06e2.35) in men and 1.72 (1.08e2.74) in women for IHD. The contribution of metabolic syndrome to the IHD risk was particularly strong among smokers although there was no significant interaction. Conclusions: The metabolic syndrome by NCEP/ATPIII definition is a major determinant of ischemic heart disease in this middle-aged Iranian population, especially among smokers. ª 2010 Elsevier B.V. All rights reserved.
* Corresponding author. Tel.: þ44 7731662894. E-mail address: [email protected] (M. Talaei). 0939-4753/$ - see front matter ª 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2010.08.003
Metabolic syndrome and ischemic heart disease in Iran
Introduction During past decades, Iran has experienced rapid economic growth and the aging of its population. The resultant change in lifestyle and longer life expectancy have led to increasing levels of risk factors for cardiovascular diseases (CVD) and a concomitant rise in the burden of cardiovascular disease [1,2]. The metabolic syndrome (MetS) is a constellation of physiological cardiovascular risk factors [3]. While the prevalence of MetS was relatively low in South and East Asia, it was comparable to that of the US for areas like India, Turkey and Iran but with a large excess in females, resulting in a significant public health problem [4]. Although there are several studies describing the association of the MetS and CVD in USA and European countries, the impact of the MetS has not been thoroughly examined among Asian populations [3], particularly in the Middle East, where there are very limited data. Many reviews and meta-analyses have called for additional information from developing countries to confirm the importance of the association between the MetS entity and the CVD [5e7]. We therefore assessed the association between NCEP-ATPIII defined MetS and ischemic heart disease during the 5-years of follow-up in the Isfahan Cohort Study (ICS) which includes Iranian participants aged 35e75 who did not have CVD at baseline.
Methods The ICS is a community-based, ongoing longitudinal study of 6504 adults aged 35 and older at baseline. Participants lived in both urban and rural (27.5%) areas of three cities and their associated district villages in the central Iran (Isfahan, Arak and Najafabad) who had participated in IHHP (Isfahan Healthy Heart Program) baseline survey [8]. Informed consent was obtained from each subject. They were recruited from January to September 2001 using multistage random sampling and have been followed since then. The response rate for house interviews was 98%, with 95% of the total attending the examination clinic. Details of the IHHP including its baseline survey have previously reported elsewhere [8] and quality of data collection and management was confirmed through external evaluation [9]. The updated Adult Treatment Panel III guideline of the National Cholesterol Education Program definition [10] was used to categorize the subjects according to the number of components of the MetS. It was defined as the presence of 3 or more of the following components: 1) serum triglycerides 150 mg/dL; 2) HDL-cholesterol <40 mg/dL for men and <50 mg/dL for women; 3) glucose 100 mg/dL fasting or on treatment; 4) blood pressure (BP) 130/85 mmHg or antihypertensive medication use, and 5) waist circumference 102 cm in men and 88 cm in women.
Follow-up The follow-up of the participants was carried out in two episodes using structured telephone call interviews or home visits (15%) in 2003 and 2005e2006. The subjects are
435 being followed-up biannually until they complete 10 years follow-up. Of the whole sample, 978 (15.0%) and 464 (7.1%) participants were lost in 2003 and 2005e2006 follow-ups respectively. The high amount of loss to follow-up was partly owing to changes in telephone numbers that were made by government in some areas. A physician reviewed all 1032 (20%) participants’ or relatives’ reports of hospitalization or death and identified a total of 528 (10.4%) IHD related reports containing 132 (2.6%) deaths and 396 (7.8%) hospitalizations. For these reports, further investigations were done to provide patients record (hospital documents). Verbal autopsies were carried out by a trained nurse as a secondary interview with surviving family members using a defined questionnaire to elicit medical history, signs and symptoms prior to out-of-hospital deaths. This method has been used in other studies and has been shown to be useful in distinguishing broad causes of death [11,12]. Additional secondary interviews by expert nurses were carried out for hospitalized cases whenever incompatible or incomplete information had meant that researchers were unable to obtain their records. Unrelated reports included 82 (1.6%) other internal diseases, 235 (4.6%) elective surgery, 43 (0.8%) trauma and 144 (2.8%) other diseases.
Confirmation of end points Ischemic heart disease was the primary outcome events considered for the analysis. These included definite or probable acute myocardial infarction (AMI), unstable angina (UA), and sudden cardiac death. To confirm them a specialists panel of three cardiologists reviewed all relevant documents including death certificates to make a final decision. They were unaware of the information regarding risk factors. The criteria for ischemic heart disease were modified from those of the World Health Organization (WHO) Expert Committee. The diagnosis of AMI was based on the presence of at least two of the following criteria: 1) typical chest pain lasting more than 30 min, 2) ST elevation >0.1 mV in at least 2 adjacent electrocardiograph leads and 3) an increase in serum levels of cardiac biomarkers including cardiac troponins, and creatine kinase (CK) and CK-MB [13]. The definition of UA required typical chest discomfort lasting more than 20 min within the 24 h preceding hospitalization and representing a change in the usual pattern of angina or pain: occurring with a crescendo pattern, being severe and described as a frank pain [14]. The diagnosis of UA might be new or based on dynamic ST-interval or T-wave changes in at least two contiguous ECG leads. Sudden cardiac death was defined as death within 1 h of onset, a witnessed cardiac arrest, or abrupt collapse not preceded by >1 h of symptoms. Although the in-hospital diagnoses of clinicians were considered, the final decisions of the panel were made independently.
Statistical analysis Data entry was carried out using EPI info (windows version). All data were analyzed by SPSS (SPSS Inc., Chicago, IL, USA; Version 15). Student’s t-test and the c2 test
436 were used for bivariate analysis. Person-years were calculated as the sum of individual follow-up times until the last telephone call interview, incident IHD, non-cardiovascular death, emigration or any other loss to follow-up (i.e. when they censored). The hazard ratios for ischemic heart disease were calculated using a Cox proportional hazards model. The models were adjusted for age (years), sex and for other potential confounding variables including hypercholesterolemia, smoking status, and menopausal status for women. A variable represented the number of MetS components (0, 1, 2, 3 and 4) was examined in the models indicating trends across the categories of the number of metabolic risk factors. The multivariable-adjusted associations of ischemic heart disease were examined overall and stratified by serum total cholesterol levels, (<200 mg/dL and 200 mg/dL) and current smoking status. The models including LDL-C instead of total cholesterol did not result in significant differences in the study findings. The significance of the interaction of MetS with serum total cholesterol levels and smoking status was tested using cross-product terms of these variables in multivariable models. KaplaneMeier analysis was used to evaluate time to outcome as a function of dichotomous independent variables with log-rank test for determining statistically significant differences. For all analyses, 2-tail statistical significance was assessed at a level of 0.05 and P-value lower than 0.1 was considered as borderline significance.
Results There were 6504 subjects recruited to the Isfahan Cohort Study, of these 5441 (83.7%) completed the first follow-up; after 5 years, 5062 (77.8%) of the participants were successfully followed during 2nd follow-up. There was no significant difference between available participants and loss-to-follow up group in terms of sex, age, MetS and its component except for WC (51% vs. 48%, P Z 0.023) and BP (36% vs. 33%, P Z 0.018) components. As the IHHP did not have any inclusion criteria that were related to individual’s cardiovascular health, 108 participants who had a history of myocardial infarction, stroke or heart failure at baseline, as well as 250 individual aged more than 75 years were
M. Talaei et al. excluded from analysis. Finally, 5224 (80.3%) eligible participants who had at least two years of follow-up were included in the analysis. With respect to the whole sample, participants with and without the MetS, the most prevalent component was high triglycerides in all 3 groups (58.9%, 89.5% and 41.9% respectively) with abdominal obesity being the second most common (49.6%, 86.1% and 29.5% respectively), except in participants without MetS for which HDL-C component was slightly more prevalent (30.2%). The least prevalent component was FBS with 14.6%, 32.2% and 4.9% respectively. The differences between the cumulative survival of participants with and without the MetS by gender are depicted in Fig. 1 (P < 0.001, the log-rank test). Women with the MetS had a significantly lower 5-year survival rate than women with a normal metabolic status (94.5% versus 98.1%, P < 0.001), as was the case for men (89.0% versus 95.4%, P < 0.001). After 23,734 person-years of follow-up (with median follow-up of 4.8 years; 4.6 and 5 years for the 25th and the 75th quartiles, respectively), we documented 209 incident cases of ischemic heart disease (117 in men). Ischemic heart disease included 12 (7 in men) fatal and 42 (28 in men) nonfatal myocardial infarctions, 111 (52 in men) unstable angina pectoris, and 44 (30 in men) sudden cardiac deaths. Absolute risk of ischemic heart disease was 8.8 (7.6e10.0) per 1000 person-years for total subjects, it was 10.2 (8.5e12.2) and 7.4 (6.0e9.1) per 1000 person-years for men and women respectively (95% CI). The MetS was detected in 2191 (35.6%) of the people aged 35e75 years. In men and women, there were 610 (20.6%) and 1581 (49.6%) individuals, respectively, who met the MetS definition. Table 1 compares values and proportions of the MetS components and other cardiovascular risk factors between subjects who developed ischemic heart disease and those who did not. Subjects who developed ischemic heart disease were older, more hypertensive, smoked more, and had higher total cholesterol serum levels, serum triglycerides, and fasting blood sugar. In addition they had more central adiposity with a higher waist circumference and waist to hip ratio. The associations of individual metabolic risk factors as continuous variable with IHD are depicted in appendix. Risk of ischemic heart disease was 2.5-fold higher in the presence of the increased blood pressure and blood sugar
Figure 1 Five-year KaplaneMeier plots of survival for ischemic heart disease (MI, Sudden Cardiac Death, and Unstable Angina) by metabolic status at study entry.
Metabolic syndrome and ischemic heart disease in Iran Table 1
437
Baseline characteristics in subjects who subsequently developed or did not develop ischemic heart disease.
Characteristics Demographics: Age (years) Sex n (%) Male Female Region Urban n (%) Rural n (%) Risk Factors: DM n (%) IGT n (%)b FBS (mg/dl) 2 h Postprandial (mg/dl) Antidiabetic drugs treatment (%) Smoking n (%) HTN (140/90) n (%) Systolic BP (mmHg) Diastolic BP (mmHg) Antihypertensive drugs treatment (%) T. chol (mg/dl) TG (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) Hypolipidaemic drugs treatment BMI n(%) <25 25e29.9 30 BMI, kg/m2 High Waist Circumference n (%)c WC (cm) High Waist Hip Ratio n (%)c WHR
IHDa (n Z 209)
No Events (n Z 5015)
P-Value
58.1 10.7
49.5 10.6
<0.001
117 (56.0) 92 (44.0)
2408 (48.0) 2607 (52.0)
0.024
161 (77.0) 48 (23.0)
3634 (72.5) 1381 (27.5)
0.146
39 (19.0) 24 (12.6) 97.3 40.7 125.5 5.2 19 (9.1) 57 (27.3) 115 (55.0) 136 24 83.8 12.7 61 (29.2) 231 53 221 116 143 47 46.3 10.3 21 (10)
463 (9.3) 420 (8.8) 88.1 32.3 110.3 56.5 247 (4.9) 1031 (20.6) 1355 (27.1) 120 20 78.0 11.4 497 (9.9) 211 49 190 103 127 42 46.8 10.4 465 (9.3)
64 (31.5) 94 (46.3) 45 (22.2) 27.2 4.2 156 (75.7) 97.36 11.59 147 (71.4) 0.95 0.06
1813 (37.0) 2002 (40.9) 1084 (22.1) 26.7 4.5 3505 (70.2) 94.67 12.29 3273 (65.6) 0.92 0.07
<0.001 0.072 0.002 0.002 0.007 0.019 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.483 0.705 0.224
0.111 0.086 0.002 0.085 <0.001
Data are presented as means standard deviation or percentages. a Ischemic Heart Disease (MI, Sudden Cardiac Death and Unstable Angina). b Impaired glucose tolerance (IGT) was identified as 2-h postprandial (2 h PP) 140 but less than 200 mg/dl. c Waist Circumference 80 and 94, Waist Hip Ratio 0.80 and 0.95 for women and men respectively (IDF definition).
components of the MetS among men and more than 1.5-fold higher for the triglyceride component. There was no association with waist circumference or HDL-cholesterol (Table 2). For women, similar associations were found but the association with high blood sugar was weaker; on the other hand, it was stronger regarding blood pressure component. The strength of associations were somewhat attenuated after mutual adjustment for the other metabolic factors and other confounding variables, but the associations with blood pressure remained statistically significant in both sexes and blood sugar in men. Risk of ischemic heart disease was positively associated with the number of MetS components for both men and women with no interaction with sex (P for interaction >0.05; Table 3). With 0 MetS components as the reference group, the multivariate hazard ratio (95% CI) for ischemic heart disease for 3 or more components was 2.57 (1.31e5.03) and 3.10 (1.52e6.32) for 4 or more components. With fewer than 3 components as the reference group, the multivariate hazard ratio (95% CI) associated with 3
components was 1.61 (1.19e2.17). The associations were similar for men and women. The association between the MetS and risk of ischemic heart disease was examined for the total group, stratified by serum total cholesterol levels and smoking status (Table 4). The excess risk of ischemic heart disease associated with the MetS was slightly larger for persons with serum cholesterol levels 200 mg/dL than for those with lower cholesterol levels. The excess risk for IHD associated with the MetS was more evident among smokers than among never smokers. However, significant interaction was found for neither of smoking or hypercholesterolemia with MetS.
Discussion Various studies have been published on the relationship between the MetS and the incidence of IHD, many of which were included in the meta-analysis carried out by Gami
438
M. Talaei et al.
Table 2 Hazard Ratio of metabolic syndrome’s components for ischemic heart disease (MI, Sudden Cardiac Death, and Unstable Angina) in men and women. Crude HR (95% CI)
P-Value
Adjusted HR(95% CI)a
P-Value
(49.6) (58.9) (44.3) (35.9) (14.6)
1.08 1.70 1.04 2.92 2.03
(0.82e1.41) (1.26e2.30) (0.79e1.37) (2.20e3.88) (1.48e2.79)
0.581 <0.001 0.766 <0.001 <0.001
1.02 1.19 1.25 1.70 1.40
(0.71e1.40) (0.75e1.48) (0.93e1.68) (1.25e2.33) (1.01e1.94)
0.979 0.742 0.125 0.001 0.041
636 1751 920 977 388
(21.5) (59.1) (31.1) (33.0) (13.1)
1.45 1.56 1.21 2.81 2.50
(0.96e2.17) (1.05e2.31) (0.82e1.78) (1.93e4.08) (1.65e3.79)
0.078 0.025 0.323 <0.001 <0.001
0.95 1.28 1.25 1.74 1.71
(0.61e1.47) (0.82e1.99) (0.83e1.88) (1.15e2.64) (1.10e2.65)
0.835 0.261 0.271 0.009 0.016
2415 1870 1805 1229 510
(75.8) (58.7) (56.7) (38.6) (16.0)
1.84 1.99 1.08 3.61 1.70
(1.07e3.18) (1.25e3.15) (0.71e1.64) (2.31e5.65) (1.05e2.75)
0.027 0.003 0.699 <0.001 0.029
1.49 1.20 1.25 1.96 1.13
(0.83e2.65) (0.73e1.97) (0.82e1.92) (1.21e3.17) (0.69e1.85)
0.174 0.453 0.295 0.006 0.612
Metabolic Syndrome Components
n (%)
Total Waist circumference Triglyceride HDL-cholesterol Blood pressure Blood sugar
3051 3621 2725 2206 898
Men Waist circumference Triglyceride HDL-cholesterol Blood pressure Blood sugar Women Waist circumference Triglyceride HDL-cholesterol Blood pressure Blood sugar a
Adjusted Model includes age, sex, smoking status and hypercholesterolemia, in addition to the MetS components.
et al., consisting of 43 cohorts and 17,2573 participants. The meta-analysis concluded that MetS itself, apart from its components, increases the risk of cardiovascular events 1.78 times; and 1.54 times after adjustment. They even suggested that in addition to targeting individual cardiovascular risk factors, primary prevention trials should study interventions that address the MetS as a single entity. However, all the longitudinal studies evaluated in this meta-analysis, except for the two conducted in Turkey and Japan, were carried out in Western countries [5]. Another meta-analysis performed by Galassi et al. evaluated 21 cohort studies reached similar conclusions [15]. The findings of the current study in an Iranian population identified a slightly higher crude risk, but the adjusted risk was similar to those previously reported and contrasted with study from Pakistan which showed no association using NCEPATPIII criteria [16]. The magnitude of risk was similar to those observed in other Asian populations (except for Turkey, mostly from East Asia), ranged from 1.7 to 3 [2,17e20]. In addition, the ICS considered serious IHD events. The strength of the association of the MetS with cardiovascular events in East Asian populations were considerably higher than from our study, which was more similar to those from Western populations. On the other hand, the positive effect of adding risk factors one by one to the predictive models of CVD and IHD (dose response effect) which was observed in various studies [2,18,19,21,22], and to some extent is evident in the present study, indicate partly the non-dominance of MetS and suggest the use of a continuous metabolic score [23e25]. Furthermore, the prediction power of the MetS in the ICS was very close to that of blood pressure and serum glucose level, which shows that MetS might not be more effective than these two components independently.
Moreover, whether the adverse impact on health by MetS is greater than the sum of its parts remains unclear [6,7,26]. In spite of the recommendations by WHO and others to define the criterion for abdominal obesity locally [15,27], the two Iranian published studies presented inconsistent results [28,29] and there remains no agreement on the cut point for waist circumference in Iran. It is strongly believed that abdominal obesity plays a pivotal role in MetS [15,30,31], but in ICS although the WC was significantly higher in the group later affected by IHD, abdominal obesity as defined according to both ATPIII or IDF was not associated with risk of IHD. This finding is in line with those studies which indicate Asian data favors the ATPIII definition for Asian populations [4]. However, further study on central obesity index is required in Iran. On balance, until sufficient data from developing countries become available and the definition of the MetS components in these countries, including Iran, are agreed upon, the impact of the MetS can not be adequately assessed. This study tried to fulfill partly this need. In their extensive review, Kahn et al. recommended that until much needed research is completed, clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the MetS [31]. The present study determined the MetS risk for women to be slightly higher than in men. The meta-analysis carried out by Gami et al. similarly suggested the risk of incident CVD events to be higher in women (RR Z 2.63 vs. 1.98) [5], which is in agreement with data from a meta-analysis by Galassi et al. [7]. In contrast, the relation between the MetS and the prevalence of CHD was significant only in men in a Turkish population [17]. The Tehran Lipid and Glucose Study (TLGS), which is among the few Iranian studies analyzing the relationship between the MetS and CVD, also reported higher risk for men [32], but this may be the result
Metabolic syndrome and ischemic heart disease in Iran Table 3
439
Hazard Ratio of ischemic heart disease according to the number of Metabolic syndrome’s components.
n (%) Total subjects No. of metabolic 0 1 2 3 4þ 3þ P for trend
Person-years
No. of Events
Crude HR (95% CI)
Multivariable HR (95% CI)
factors 729 (11.9) 1476 (24.0) 1750 (28.5) 1380 (22.5) 811 (13.2) 2191 (36)
2740 5769 6717 5333 3171 8505
10 38 51 58 52 110
1 1.72 (0.86e3.46) 1.97 (1.00e3.90)* 2.85 (1.45e5.58)y 4.44 (2.25e8.76)z 3.43 (1.79e6.55)z P < 0.001
1 1.56 (0.77e3.16) 1.80 (0.90e3.59)x 2.29 (1.15e4.59)* 3.10 (1.52e6.32)y 2.57 (1.31e5.03)y 0.005
Metabolic syndrome No 3955 (64.4) Yes 2191 (35.6)
15228 8505
99 110
1 2.00 (1.52e2.63)z
1 1.61 (1.19e2.17)y
factors 564 (19.0) 939 (31.7) 848 (28.6) 432 (14.6) 178 (6.0) 610 (20.6)
2128 3630 3225 1742 682 2425
10 28 33 30 16 46
1 1.66 (0.80e3.43) 2.09 (1.02e4.25)* 3.44 (1.66e6.99)y 5.17 (2.34e11.40)z 3.88 (1.95e7.70)z P < 0.001
1 1.30 (0.62e2.70) 1.46 (0.71e3.02) 1.93 (0.92e4.06)x 2.47 (1.09e4.06)* 2.09 (1.03e4.25)* 0.143
Metabolic syndrome No 2351 (79.4) Yes 610 (20.6)
8983 2425
71 46
1 2.33 (1.60e3.38)z
1 1.58 (1.06e2.35)*
factors 165 (5.2) 537 (16.9) 702 (22.0) 902 (28.3) 948 (29.8) 633 (19.9) 1581 (49.6)
612 2139 2751 3492 3591 2489 6080
0 10 10 18 28 36 64
1 1.48 (0.68e3.23) 2.33 (1.13e4.82)* 4.30 (2.12e8.72)z 3.13 (1.60e6.13)y P < 0.001
e e 1 1.35 (0.60e3.06) 1.80 (0.83e3.88) 2.43 (1.14e5.19)* 2.09 (1.01e4.30)* 0.066
Metabolic syndrome No 1604 (50.4) Yes 1581 (49.6)
6244 6080
28 64
1 2.49 (1.58e3.86)z
1 1.72(1.08e2.74)*
Men No. of metabolic 0 1 2 3 4þ 3þ P for trend
Women No. of metabolic 0 1 1a 2 3 4þ 3þ P for trend
HR indicates hazard ratios, Ischemic Heart Disease include: MI, SCD, USA. Test for significance: xP < 0.1, *P < 0.05, yP < 0.01, zP < 0.001. Multivariable HR adjusted for age, sex, serum total cholesterol, cigarette smoking and for women, menopausal status. a There was no event in women who did not have any of the metabolic syndrome components; so, this stratum merged with women with only one component.
of the cross-sectional nature of that study. Similarly, the Framingham Offspring Study reported the relative risk of CVD events in men was two times higher than that for women which was attributed to the premenopausal and perimenopausal status of most of the female participants [3]. However, the Hoorn Cohort Study which was carried out on individuals older than 50 demonstrated similar pattern [33]. A Japanese study also reported almost similar risks (HR 2.4 vs. 2.3 in men and women respectively) [18]. According to the ICS findings, both smoking and hypercholesterolemia strengthened the relationship between MetS and incident IHD, although no significant interaction was observed, suggesting the relationship is additive and
not multiplicative. A recent report from China reported a dose response relationship between the severity of smoking and exacerbation of MetS effect on IHD. As in the current study, an interaction was also not observed [34]. However, data from Japan identified similar results in terms of smoking, but in this case there was a significant interaction between the MetS and hypercholesterolemia on incident IHD [18]. In a recent report of 34 cohort studies in the Asia-Pacific region, smoking exacerbated the association between total cholesterol and the risk of IHD and mitigated the protective effects of HDL-C on coronary risk, interacting with both [35]. There is therefore a clear need to study the relations among MetS and other risk factors and
440
M. Talaei et al.
Table 4 Multivariable Hazard Ratio of ischemic heart disease associated with metabolic syndrome, stratified by serum total cholesterol Levels and smoking status. Crude HR (95% CI)
Multivariable HR (95% CI)
1.75 (1.04e2.93)*
1.60 (0.93e2.57)x
Serum total cholesterol 200 mg/dL Metabolic syndrome P for interaction
1.86 (1.33e259)z
1.77 (1.24e2.53)y 0.092
Never smokers Metabolic syndrome
1.86 (1.35e2.57)z
1.52 (1.07e2.16)*
Smokers Metabolic syndrome P for interaction
3.29 (1.94e5.56)z
1.98 (1.13e3.48)* 0.244
Serum total cholesterol <200 mg/dL Metabolic syndrome
HR indicates hazard ratios. Test for significance: xP < 0.1, *P < 0.05, yP < 0.01, zP < 0.001. Multivariable HR adjusted for the same variables shown in Table 2 except for the stratified variables.
the incidence of IHD, as has been emphasized in other studies [31].
Limitation Although the loss-to-follow up rate was remarkable, characteristics of subjects lost to follow-up did not differed except for WC and BP components that the differences were just around 3%. Hence it seems unlikely that losses to follow up could have introduced serious bias, however, it is still a limitation for this study. The role of treatment of metabolic syndrome and its components as well as successfulness of such treatments was not investigated during follow up. This shortcoming might have changed strength of associations and could be a subject for further research. In addition, no data were collected on subclinical coronary artery disease because of resource limitations.
Conclusion MetS based on NECP-ATPIII definition is a major determinant of ischemic heart disease among Iranian men and women but current international cut-off points for waist circumference failed to define central obesity as a predictor of IHD. Furthermore, the number of the constituent factors provides informative graded assessment of risk. High blood pressure is the most individual important component. The excess risk associated with the MetS was slightly larger among smokers and hypercholesterolemics.
Acknowledgement The baseline survey as a part of Isfahan Healthy Heart Program (IHHP) was supported by a grant (No. 31309304) from the Iranian Budget and Planning Organization and the Ministry of Health in Iran. Isfahan Cardiovascular Research Centre, affiliated to Isfahan University of Medical Sciences, supported the biannual follow-ups. We thank the personnel of Isfahan Cardiovascular Research Centre, especially those in the Surveillance Department and IHHP Evaluation
Committee for their close cooperation. Moreover, we owe a debt of gratitude to Dr. Majid Ahsan regarding his technical assistance for converting dates in Persian calendar (Solar Hejri) to Gregorian.
References [1] Sarrafzadegan N, Kelishadi R, Esmaillzadeh A, Mohammadifard N, Rabiei K, Roohafza H, et al. Do lifestyle interventions work in developing countries? Findings from the Isfahan healthy heart program in the Islamic Republic of Iran. Bull World Health Organ 2009;87:39e50. [2] Park HS, Cho SI, Song YM, Sung J. Multiple metabolic risk factors and total and cardiovascular mortality in men with low prevalence of obesity. Atherosclerosis 2006 Jul;187(1): 123e30. [3] Wilson PWF, D’Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005;112(20): 3066e72. [4] Pan WH, Yeh WT, Weng LC. Epidemiology of metabolic syndrome in Asia. Asia Pac J Clin Nutr 2008;17(Suppl. 1):37e42. [5] Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK, et al. Metabolic sydrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007;49(4):403e14. [6] Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care 2005;28(7): 1769e78. [7] Galassi A, Reynolds K, He J. Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. Am J Med 2006; 119(10):812e9. [8] Sarraf-Zadegan N, Sadri G, Malek AH, Baghaei M, Mohammadi FN, Shahrokhi S, et al. Isfahan Healthy Heart Programme: a comprehensive integrated community-based programme for cardiovascular disease prevention and control. Design, methods and initial experience. Acta Cardiol 2003; 58(4):309e20. [9] Vartiainen E, Laatikainen T. Isfahan Healthy heart Program (IHHP): external evaluation 12.5.-18.5.2009 [Internet] [cited 2009 Jun 25]. Isfahan: Isfahan Cardiovascular Research Center. Available from: http://ihhp.mui.ac.ir/ihhp/sounds/ 1656/1656_0.pdf; 2009.
Metabolic syndrome and ischemic heart disease in Iran [10] Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome. An American heart Association/National heart, Lung, and blood Institute Scientific statement. Executive summary. Cardiol Rev 2005;13(6):322e7. [11] Yang G, Rao C, Ma J, Wang L, Wan X, Dubrovsky G, et al. Validation of verbal autopsy procedures for adult deaths in China. Int J Epidemiol 2006;35(3):741e8. [12] Kumar R, Thakur JS, Rao BT, Singh MM, Bhatia SP. Validity of verbal autopsy in determining causes of adult deaths. Indian J Public Health 2006;50(2):90e4. [13] Luepker RV, Apple FS, Christenson RH, Crow RS, Fortmann SP, Goff D, et al. Case definitions for acute coronary heart disease in epidemiology and clinical research studies: a statement from the AHA Council on Epidemiology and prevention; AHA Statistics Committee; World heart Federation Council on Epidemiology and prevention; the European Society of Cardiology Working group on Epidemiology and prevention; Centers for disease control and prevention; and the national heart, Lung, and blood Institute. Circulation 2003;108(20): 2543e9. [14] Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-STsegment elevation myocardial infarctione2002: summary article: a report of the American College of Cardiology/American heart association Task Force on Practice guidelines (Committee on the management of patients with unstable angina). Circulation 2002;106(14):1893e900. [15] Alberti KGM, Zimmet P, Shaw J. The metabolic syndromeea new worldwide definition. Lancet 2005;366(9491):1059e62. [16] Wierzbicki AS, Nishtar S, Lumb PJ, Lambert-Hammill M, Crook MA, Marber MS, et al. Waist circumference, metabolic syndrome and coronary artery disease in a Pakistani cohort. Int J Cardiol 2008;128(1):77e82. [17] Onat A, Ceyhan Kk, Basar O, Erer B, Toprak S, Sansoy V. Metabolic syndrome: major impact on coronary risk in a population with low cholesterol levelsea prospective and crosssectional evaluation. Atherosclerosis 2002;165(2):285e92. [18] Iso H, Sato S, Kitamura A, Imano H, Kiyama M, Yamagishi K, et al. Metabolic syndrome and the risk of ischemic heart disease and stroke among Japanese men and women. Stroke 2007;38(6):1744e51. [19] Chien KL, Hsu HC, Sung FC, Su TC, Chen MF, Lee YT. Metabolic syndrome as a risk factor for coronary heart disease and stroke: an 11-year prospective cohort in Taiwan community. Atherosclerosis 2007;194(1):214e21. [20] Thomas GN, Schooling CM, McGhee SM, Ho SY, Cheung BM, Wat NM, et al. Metabolic syndrome increases all-cause and vascular mortality: the Hong Kong cardiovascular risk factor study. Clin Endocrinol (Oxf) 2007;66(5):666e71. [21] Eberly LE, Prineas R, Cohen JD, Vazquez G, Zhi X, Neaton JD, et al. Metabolic syndrome: risk factor distribution and 18-year mortality in the multiple risk factor intervention trial. Diabetes Care 2006 1;29(1):123e30.
441 [22] McNeill AM, Rosamond WD, Girman CJ, Golden SH, Schmidt MI, East HE, et al. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study. Diabetes Care 2005;28(2):385e90. [23] Hillier TA, Rousseau A, Lange C, Lepinay P, Cailleau M, Novak M, et al. Practical way to assess metabolic syndrome using a continuous score obtained from principal components analysis. Diabetologia 2006;49(7):1528e35. [24] Does diagnosis of the metabolic syndrome detect further men at high risk of cardiovascular death beyond those identified by a conventional cardiovascular risk score? The DECODE Study. Eur J Cardiovasc Prev Rehabil 2007;14(2):192e9. [25] Woodward M, Tunstall-Pedoe H. The metabolic syndrome is not a sensible tool for predicting the risk of coronary heart disease. Eur J Cardiovasc Prev Rehabil 2009;16(2):210e4. [26] Nilsson PM. Cardiovascular risk in the metabolic syndrome: fact or fiction? Curr Cardiol Rep 2007;9(6):479e85. [27] World Health Organization (WHO). Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 2000;894. i-253. [28] Delavari A, Forouzanfar MH, Alikhani S, Sharifian A, Kelishadi R. The First nationwide study of the prevalence of the metabolic syndrome and optimal cut-off points of waist circumference in the middle east: the national survey of risk factors for non-communicable diseases of Iran. Diabetes Care; 2009:dc08e1800. [29] Esteghamati A, Ashraf H, Rashidi A, Meysamie A. Waist circumference cut-off points for the diagnosis of metabolic syndrome in Iranian adults. Diabetes Res Clin Pract 2008; 82(1):104e7. [30] Zimmet P, Alberti KG, Serrano Rios M. A New International Diabetes Federation (IDF) worldwide definition of the metabolic syndrome: the rationale and the results. Revista Espanola de Cardiologia 2005;58(12):1371e5. [31] Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005;28(9): 2289e304. [32] Zabetian A, Hadaegh F, Azizi F. Relationship between metabolic syndrome and its components with coronary heart disease in Iranian men and women. Exp Clin Endocrinol Diabetes 2008;116(9):525e31. [33] Dekker JM, Girman C, Rhodes T, Nijpels G, Stehouwer CDA, Bouter LM, et al. Metabolic syndrome and 10-year cardiovascular disease risk in the Hoorn study. Circulation 2005;112(5): 666e73. [34] He Y, Lam TH, Jiang B, Wang J, Sai X, Fan L, et al. Combined effects of tobacco smoke exposure and metabolic syndrome on cardiovascular risk in older residents of China. J Am Coll Cardiol 2009;53(4):363e71. [35] Nakamura K, Barzi F, Huxley R, Lam TH, Suh I, Woo J, et al. Does cigarette smoking exacerbate the effect of total cholesterol and high-density lipoprotein cholesterol on the risk of cardiovascular diseases? Heart 2009;95(11):909e16.