QJM Advance Access originally published online on August 9, 2007
QJM 2007 100(9):575-581; doi:10.1093/qjmed/hcm066
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Diabetes, but not the metabolic syndrome, predicts the severity and extent of coronary artery disease in women
From the 1Metabolic Unit, 2Institute of Cardiology and 4Department of Medicine, Kaplan Medical Center, Rehovot, and the Hebrew University Hadassah Medical School, Jerusalem, and 3Department of Statistics, Haifa University, Haifa, Israel
Address correspondence to Professor A. Schattner, Head, Department of Medicine, Kaplan Medical Center, Rehovot 76100, Hebrew University Hadassah Medical School, Jerusalem, Israel. email: amiMD{at}clalit.org.il
Received 27 April 2007 and in revised form 5 June 2007
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Background: Previous studies have suggested that diabetes and metabolic syndrome are significant risk factors for coronary artery disease (CAD). However, in women, their relative importance remains controversial.
Aim: To evaluate risk factors for CAD in women and their association with the severity and extent of coronary angiographic findings.
Methods: We clinically evaluated 243 consecutive female patients with chest pain who underwent coronary angiography. The location and extent of coronary artery occlusions were assessed using the modified Gensini index.
Results: Compared with women with normal coronary arteries (n = 90), those with CAD (n = 153) reported less physical activity (p = 0.001), and had higher prevalences of diabetes (p = 0.046), hypertension (p = 0.002), and the metabolic syndrome (p = 0.001). They also had lower HDL cholesterol levels (p = 0.017), higher levels of triglycerides (p = 0.005), and higher fasting plasma glucose (FPG) (p < 0.001). Physical activity, FPG, serum triglycerides and HDL-cholesterol, but not the metabolic syndrome, were independent predictors of CAD. A score combining the extent and severity of angiographic findings was significantly higher in women with diabetes (p = 0.007), hypertension (p = 0.010) and FPG 
100 mg/dl (p = 0.031), but showed no association with the metabolic syndrome. In a multivariate linear regression analysis, diabetes was an independent predictor of the extent and severity of angiographic score (p = 0.013).
Discussion: Diabetes, fasting plasma glucose and hypertension, but not the metabolic syndrome, were associated with severity of coronary angiographic findings in these women.
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Introduction |
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Cardiovascular disease is the primary cause of death in women. Rates of coronary artery disease (CAD) increase with advancing age in both sexes, although rates in women lag behind those in men by about a decade. Because of their greater age, women with CAD are more likely to have co-morbidities such as diabetes, dyslipidaemia and hypertension. Accordingly, diabetes contributes to coronary events and cardiac death significantly more in women than in men.1,2
There is a significant overlap between diabetes and the metabolic syndrome. The metabolic syndrome is a constellation of lipid and non-lipid factors of metabolic origin associated with insulin resistance: abnormal glucose metabolism, abdominal fat accumulation, hypertension, and typical dyslipidaemia with high triglycerides and low HDL cholesterol.3 In several studies,4–9 but not all,10–12 insulin resistance was also a risk factor for CAD, in men and women. The additive predictive value of metabolic syndrome for cardiovascular diseases is still debated.13
Only a few studies have evaluated the association between glucose intolerance and the severity and extent of coronary atherosclerosis, and women were under-represented in these studies.14–16 We decided to study the risk factors for angiographically-proven CAD in women, and assess whether glucose intolerance and the metabolic syndrome predict the severity and extent of angiographic findings.
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Methods |
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Patients
We studied a group of consecutive female patients with chest pain who underwent coronary angiography at the Institute of Cardiology and Department of Medicine at Kaplan Medical Center, a university hospital serving 300 000 people in central Israel. The inclusion criteria were: (i) referral to coronary angiography, due to chest pain; (ii) age <75 years; (iii) any hormone replacement therapy (HRT) discontinued >1 year prior to angiography. Of the 332 women undergoing angiography, 89 were excluded, due to: age
75 years (n = 33); current or recent HRT (n = 31); and incomplete data (n = 25). Thus, 243 women were included in the final analysis. The study was approved by our local Institutional Review Board.
Clinical evaluation
All women had a physical examination with anthropometric measurements, and answered a detailed questionnaire about CAD risk factors including: physical activity, age at menopause, family history of cardiovascular disease and cardiovascular risk factors, hypertension, smoking and diabetes. All medications received prior to coronary angiography were recorded. Laboratory tests were done on admission or within 1 month prior to elective angiography, and included renal and liver function tests, fasting lipid profile and fasting plasma glucose (FPG). Previous CAD was defined as at least one of the following, occurring >6 months before the index angiography: acute myocardial infarction, positive effort test or cardiac scan, abnormal coronary angiography. The metabolic syndrome was defined as the presence of three or more of the following criteria: FPG 5.6 mmol/l or previous diagnosis of diabetes, HDL cholesterol <1.3 mmol/l, triglycerides 1.7 mmol/l, hypertension (blood pressure 130/85 mmHg or use of antihypertensive drug therapy) and overweight.3 Since data on waist circumference were not available, we used body mass index (BMI) >27 kg/m2 as defining overweight and obesity for this analysis. Diabetes was diagnosed according to the American Diabetes Association (ADA) criteria.17 Impaired fasting glucose (IFG) was defined as FPG 5.6–6.9 mmol/l and no diabetes treatment.17
Assessment of angiographic CAD
All subjects underwent catheterization and coronary angiography, using standard techniques. During cardiac catheterization, nitroglycerine was administrated routinely in all cases suspected of having coronary spasm. Angiograms were assessed independently by two experienced interventional cardiologists who were blinded to patients’ clinical parameters. Angiography results were divided into two groups: (i) obstructive and non-obstructive lesions (defined as <50% obstruction); (ii) normal coronary angiography (NCA). All angiographies included in group 1 were assessed by the modified Gensini index as previously described.18,19 Briefly, location, degree of stenosis (severity), and number of occluded segments (extent) were evaluated. Coronary vasculature was divided into 27 coronary segments, and each involved segment was weighted by a value from 0.5 (least important) to 5.0 (critical location), reflecting the location of coronary artery lesions. The severity (percentage of stenosis) was weighted as follows: <25%, 2; 26–50%, 4; 51–75%, 8; 76–90%, 16; 91–99%, 32; 100%, 64. Extent was determined by the number of occluded segments (from 1 to 27) and constitutes score III. Score II is the sum of the weighted severity for all involved segments. The product of the weights for location and severity is the total weight for each arterial segment, and the sum of all segments involved constitutes Score I (the modified Gensini index), reflecting location, severity and extent.19
Statistical analyses
Statistical analyses used SAS statistical software, version 9.1. Continuous variables were expressed as means ± SD and comparison between groups used the t test. Categorical variables were compared using the 
2 test. The values for coronary artery angiographic scores I and II were log-transformed. The effects of independent predictors on log-transformed angiographic scores I and II were evaluated by multiple linear regression analysis. A multiple logistic regression analysis was done to determine predictors of ischaemic heart disease at coronary angiography. The variables included in the analysis of predictors for CAD were: origin, physical activity, smoking, diabetes, hypertension, family history of CAD/diabetes/hypertension, age at coronary angiography, triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol, BMI and FPG. Differences and associations were considered statistically significant at a p value of <0.05.
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Results |
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Among the 243 participants, 90 women (37%) had normal coronary arteries (NCA group) and 153 had angiographically-proven CAD. Baseline characteristics of the two groups are shown in Table 1. Women with CAD were significantly older (p < 0.001) and had more hypertension (p = 0.002), more diabetes (p = 0.046), higher FPG and more IFG (29/80, 36% vs. 16/58, 28%), compared with the NCA group. FPG was also higher in women without diabetes in the CAD group than in the NCA group (5.3 ± 0.7 vs. 5.1 ± 0.8 mmol/l, p = 0.028). The CAD group had significantly higher levels of triglycerides and lower HDL cholesterol, but no significant differences in current smoking, BMI, total cholesterol and LDL cholesterol levels. Metabolic syndrome was diagnosed in 69.9% of the CAD group compared with 38.9% of the NCA group (p = 0.001).
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Women with NCA did significantly more physical activity (p = 0.001) and had received more frequent HRT in the past than the CAD group (32.2% vs. 10.5%, p < 0.001), although age at menopause was similar in the two groups. Both ethnicity and the frequency of a family history of CAD, diabetes or hypertension, were similar when comparing the groups.
In the CAD group, 62 women (40.5%) had a previous history of ischaemic heart disease. More women in the CAD group were receiving statins (76.8% vs. 44.8%, p < 0.001), ACE inhibitors (60.8% vs. 34.1%, p < 0.001), aspirin (92.2% vs. 58.0%, p < 0.001), beta-blockers (90.1% vs. 60.0%, p < 0.001), sulfonylurea (17.8% vs. 5.6%, p = 0.008), metformin (22.9% vs. 6.8%, p = 0.001), and insulin (7.8% vs. 0%, p = 0.005), compared with the NCA group. Following angiography, 41/153 (27%) of the CAD group underwent percutaneous coronary intervention.
We tested several multivariate models for predicting angiographically proven CAD. Those with the best performance are shown in Table 2. Physical activity <30 min/week, age at coronary angiography, FPG and HDL cholesterol were all predictors of CAD in model 1. In model 2, triglycerides replaced HDL cholesterol. Adjusting for statin usage did not change the association between angiographically-proven CAD and lipid variables.
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Quantitative analysis of coronary angiographies was done in all women with abnormal coronary angiography, yielding three scores (see Methods). The associations between angiographic findings and baseline clinical characteristics are presented in Table 3. Women with diabetes had more severe angiographic disease compared with women without diabetes, as demonstrated by an increase in all three scores. Increased FPG was also associated with more extensive angiographic disease and with more severe lesions. Women with hypertension, compared with women without hypertension, also had more extensive angiographic disease with more severe lesions. However, we found no association between the angiographic scores and the existence of the metabolic syndrome, high triglycerides, low HDL cholesterol and the combination of high BMI and elevated triglycerides (Table 3).
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In a multiple linear regression analysis of angiographic score II, diabetes and hypertension were independent predictors of the extent and severity of CAD (Table 4). The R2 value for this model was 0.19. In multivariate linear regression analysis of angiographic score I (combining severity, extent and location of coronary artery occlusions), diabetes was an independent predictor (p = 0.005), but hypertension was not (p = 0.2)
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Discussion |
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Diabetes, glucose intolerance and metabolic syndrome were very common in our study population of women referred for angiography for evaluation of chest pain. The prevalence was especially high in women with angiographically-proven CAD, in whom 46% had diabetes (in about half of them previously undiagnosed or untreated), 36% had IFG levels and 70% had metabolic syndrome. These data, higher than those of some previous studies,15,20 imply that women with CAD have an extremely high prevalence of glucose intolerance and metabolic syndrome.
Another central finding of our study is that diabetes and increased FPG were also risk factors for more severe CAD in women. Women with diabetes (compared with non-diabetic women) had significantly higher angiographic scores in all scores examined, and FPG 5.6 mmol/l was also associated with increased score II (severity and extent) and score III (extent only) (Table 3). Moreover, diabetes and hypertension were both independent predictors of coronary artery disease severity. Although metabolic syndrome was more prevalent in women with CAD than in the NCA group, it was neither an independent predictor of CAD nor of coronary angiography findings. Thus, our findings strongly suggest that diabetes, but not the metabolic syndrome, is independently associated with CAD in women.
These intriguing findings complement and add to several recent studies suggesting that diabetes and hyperglycaemia, but not the metabolic syndrome, are associated with the severity of CAD. In a study of 437 patients (35% women), a detailed quantitative assessment of the severity of coronary atherosclerosis identified diabetes as independent predictor of CAD severity.14 Metabolic syndrome was not examined. In another angiographic study, postprandial glucose was an independent predictor, but the 107 women (20%) were not analysed separately.16 In the Women's Angiographic Vitamin and Estrogen (WAVE) trial, women with and without metabolic syndrome had similar baseline minimum and average lumen diameters.21 Baseline angiographic findings in the Women's Ischemia Syndrome Evaluation (WISE) study also revealed only a slight increase in stenoses 50% in women with metabolic syndrome.22 A small study found an association between post-challenge hyperinsulinaemia and the number of diseased coronary arteries, but no quantitative coronary analysis was done.23 The strengths of our study include the relatively large group of consecutive women studied and the detailed quantitative analysis of coronary angiographies including even minimal stenoses of <25% in both proximal and distal portions of coronary arteries. Although such non-obstructive lesions have no clinical implications at time of catheterization, they reflect more accurately the severity of the atherosclerotic process.
Diabetes is a strong risk factor for CAD events and mortality in women.1,2 Insulin resistance has a major role in the pathogenesis of type 2 diabetes, and hence the majority of patients with type 2 diabetes and IFG have insulin resistance. Numerous data also suggest that insulin resistance has a central role in atherosclerosis.4–9,24 The metabolic syndrome is a constellation of three or more of five components, all of which relate to some extent to insulin resistance; however, this diagnosis may be based on numerous combinations that differ in the degree of correlation with this trait. In a critical evaluation of the metabolic syndrome it had a low overall sensitivity and specificity for identifying subjects with insulin resistance.25,26 However, enlarged waist circumference reflecting increased intra-abdominal fat and increased triglycerides correlated significantly with insulin sensitivity index in non-diabetic patients.27 The limitations of the metabolic syndrome diagnostic criteria may partly explain the inconsistency observed between different studies evaluating its role as an independent predictor of CAD.28–30 This controversial issue has been the focus of a recent ongoing debate.13
In the present study, women with CAD had higher triglycerides and lower HDL cholesterol, but no significant differences in LDL cholesterol levels, compared with women with NCA. In a multivariate analysis, high triglycerides and low HDL were predictors of angiographically-proven CAD. The Lipid Research Clinics’ Follow-Up and the Framingham studies yielded similar findings.31–33 In the latter study, HDL was a stronger predictor of CVD death in women aged 50–69 than total cholesterol, and high HDL neutralized the increased risk usually associated with increased total or LDL cholesterol.33 The significance of increased triglycerides in predicting coronary events in women was also confirmed by other studies.34–36 All these data suggest that low levels of HDL and high triglycerides are important risk factors for CAD in women.
Physical inactivity was a strong independent risk factor for angiographic proven CAD, yet was not associated with the extent and severity of CAD in our patients. In a large Finnish study of people without cardiovascular disease at baseline, physical activity had strong, independent, and inverse association with CAD prevalence in both genders.37 In another recent study, higher self-reported physical fitness scores in women were independently associated with fewer risk factors, less severe angiographic CAD, and reduced cardiovascular events.38
Limitations of our study include lack of data on waist circumference, an indicator of intra-abdominal fat. The association between abdominal obesity and both insulin resistance and CAD is stronger than the corresponding association between BMI and these two conditions.39 In post-menopausal women, central and peripheral fat mass have contrasting effect on the progression of aortic calcification, and women with general obesity tend to have less progression compared with those who have central obesity.40 These data suggest that in women, even more than in men, abdominal obesity is a stronger predictor of morbidity than is BMI. In another study, enlarged waist combined with elevated triglycerides was associated with a 4.7-fold increase in the risk of fatal cardiovascular events.34 We included only women referred for angiography, which may have created a bias towards a high-risk profile, and may partly explain the relatively high prevalence of women with diabetes and IFG. Another limitation was that the use of medications, especially statins, was more prevalent in the CAD group and may have affected the results. However, controlling for statin therapy in the multivariate model did not change our results. Finally, coronary angiography may under-estimate atherosclerotic plaque burden, compared with methods such as intravascular ultrasound.
In conclusion, we found a significantly higher prevalence of diabetes, hyperglycaemia and metabolic syndrome in women with angiographically-proven CAD, compared with women with normal coronary arteries. The extent and severity of coronary artery disease in women were strongly associated with diabetes and fasting glucose levels, but not with the metabolic syndrome.
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