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The metabolic syndrome: A vascular perspective
European Journal of Internal Medicine 16 (2005) 314 – 320 www.elsevier.com/locate/ejim
Review article
The metabolic syndrome: A vascular perspective J.T. Tamsma*, I.M. Jazet, E.D. Beishuizen, A.J. Fogteloo, A.E. Meinders, M.V. Huisman Vascular Medicine, Dept. of General Internal Medicine, Leiden University Medical Center, C1-R45, P.O. Box 9600, 2300 RC Leiden, Netherlands Received 20 July 2004; received in revised form 21 December 2004; accepted 20 January 2005
Abstract The metabolic syndrome (MS) is a clustering of cardiovascular risk factors. Current definitions of MS use hypertension, waist circumference, fasting glucose, triglyceride and HDL-cholesterol levels as defining variables. The prevalence of MS is increasing in our society due to lifestyle changes that result in decreased physical activity and increased body weight. Patients with MS have a three times greater risk of coronary heart disease and stroke, and a two to four times greater risk of dying from atherosclerotic coronary heart disease than those without MS. Imaging studies have shown an increased burden and progression of atherosclerosis. Also, MS patients seem to be more vulnerable to events at comparable levels of atherosclerosis. First-line treatment for MS is therapeutic lifestyle intervention, including exercise and weight reduction. Medical intervention strategies using blood pressure-lowering medication, statins, fibrates and metformin seem the most appropriate to date. The effects of thiazolidinediones on cardiovascular endpoints have not been studied to a large extent in the setting of MS. Evidence regarding risk assessment and optimal medical strategies will be an important aspect of vascular research in the coming years. D 2005 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Metabolic syndrome; Atherosclerosis; Cardiovascular disease
Contents 1. 2.
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Introduction. . . . . . . . . . . . . . . . . . . . The metabolic syndrome: definition and criteria . 2.1. Impaired fasting glucose (IFG) . . . . . . 2.2. Insulin resistance or hyperinsulinemia. . . 2.3. Hypertriglyceridemia and HDL-cholesterol 2.4. Hypertension and microalbuminuria. . . . 2.5. Waist circumference . . . . . . . . . . . . 2.6. MS-associated factors . . . . . . . . . . . Vascular perspective—epidemiology . . . . . . . Vascular studies . . . . . . . . . . . . . . . . . Vascular perspective: risk assessment . . . . . . Vascular perspective: treatment . . . . . . . . . . 6.1. Statins . . . . . . . . . . . . . . . . . . . 6.2. Fibrates . . . . . . . . . . . . . . . . . .
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* Corresponding author. E-mail address: [email protected] (J.T. Tamsma). 0953-6205/$ - see front matter D 2005 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2005.01.011
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6.3. Metformin . . . . . . . . 6.4. Thiazolidinediones (TZD) 7. Conclusion . . . . . . . . . . . References . . . . . . . . . . . . . .
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listed in Table 1. The ‘‘calculation rules’’ used in the different classifications are as follows:
1. Introduction In addition to the classic cardiovascular risk factors, the metabolic syndrome (MS) –a clustering of cardiovascular risk factors [1,2] – is increasingly being recognized as an important factor in the pathophysiology of atherosclerosis and as a target of therapy [3]. MS is closely related to presentday changes in lifestyle and their ensuing consequences, such as a lack of physical activity and an increase in body weight. The prevalence of MS has exceeded 20% of the adult population in many countries and is still increasing [4]. Because MS is defined as a clustering of risk factors, some have argued that MS-associated cardiovascular risk is nothing more than the sum of the risks of its defining components. Intriguingly, combinations of risk factors seem to enhance each other. This has been shown in MS, as the syndrome more strongly predicted mortality than did its individual components [5]. Another example of risk enhancement was recently observed for nine environmental risk factors, several reminiscent of MS [6]. In this article, we will address MS from a vascular perspective.
2. The metabolic syndrome: definition and criteria MS has been defined by the WHO, the American National Cholesterol Education Program (NCEP) and the European Group for the Study of Insulin Resistance (EGIR) [3,7,8]. The EGIR definition is a specification of the WHO classification system. MS is defined as a sum of the criteria
1. WHO/EGIR: the presence of impaired fasting glucose or insulin resistance is a prerequisite for the definition. In addition, two or more criteria have to be present. 2. NCEP: three or more criteria are present. A patient can thus be classified or diagnosed as having MS (ICD code: 277.7 [9]). The discussion and studies comparing the classification systems [10 – 15] in order to assess which one to follow in daily practice is beyond the scope of this review. Given the emerging central role for abdominal adiposity [16 – 19], this risk factor will be discussed in some detail. The other criteria will be mentioned only briefly. 2.1. Impaired fasting glucose (IFG) Fasting glucose levels of 5.6 to 5.9 mmol/L have recently been proposed as the cut-off point for IFG as this predicts future diabetes most precisely [20]. The classification systems have not yet adopted this criterion [21] for MS, although the discussion is ongoing [22]. 2.2. Insulin resistance or hyperinsulinemia This aspect is regarded by some as a pathophysiologic key to the metabolic and vascular changes of MS. Insulin has vasoactive properties. Furthermore, hyperinsulinemia has
Table 1 Criteria and definition of the metabolic syndrome Criteria of the metabolic syndrome Glucose Insulin Visceral obesity
Triglycerides HDL-cholesterol
fasting fasting resistance S waist girth S WHR 9 waist girth 9 WHR S 9
Blood pressure Microalbuminuria Definition of the metabolic syndrome
NCEP/ATP III [3]
EGIR-modified WHO [7,8]
>6.1 mmol/L – >102 cm (>94 cm)* – >88 cm – >1.7 mmol/L <1.0 mmol/L <1.3 mmol/L 130/85 mm Hg No
>6.1 mmol/L or DM Upper 25% normal Lowest 25% ‘‘QUICKI’’ 94 cm 0.91 80 cm 0.86 >1.7 mmol/L <0.9 mmol/L <1.0 mmol/L 140/90 mm Hg (WHO 160/90) No (WHO yes)
The presence of 3 or more of the criteria listed above
Hyperinsulinemia, IGT or diabetes and 2 or more of the criteria listed above
Some male patients can develop multiple metabolic risk factors when the waist circumference is only marginally increased. Such patients may have a strong genetic contribution to insulin resistance [3].
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been observed as an independent risk factor for ischemic heart disease [11] and, recently, it was found that insulin resistance was related to coronary calcium scores, a measure of systemic atherosclerosis [23]. A complicating factor is that insulin resistance cannot be established in all patients with MS. 2.3. Hypertriglyceridemia and HDL-cholesterol The hypertriglyceridemia present in MS is thought to result from increased VLDL and VLDL remnant levels that are known to be pro-atherogenic [24]. Related to the higher triglyceride levels are increased concentrations of small dense (sd) LDL [25 – 27]. The pro-atherogenic potential of sd LDL and its association with coronary heart disease have been reviewed comprehensively elsewhere [28]. HDL has an established role in ‘‘reverse cholesterol transport’’ [29]. It has been included as an independent MS criterion notwithstanding the reciprocal relationship between serum triglyceride concentrations and HDL-cholesterol values. 2.4. Hypertension and microalbuminuria Hypertension has already been related to insulin resistance by Reaven [1,30] and is used as a MS criterion. Microalbuminuria is a cardiovascular risk factor, particularly in DM2 and hypertension [31]. Using the WHO criteria, microalbuminuria was found to confer the strongest risk of cardiovascular death of all MS criteria [32]. Despite this observation, microalbuminuria has not been included as a MS-defining criterion in the EGIR and NCEP. 2.5. Waist circumference Table 1 shows different ‘‘truncating values’’ and that the waist –hip ratio (WHR) is not used by the NCEP. It has been argued that the WHR, being an index of relative accumulation of visceral fat, may provide ‘‘misleading’’ information as it could conceal the absolute amount of visceral adipose tissue [16]. Waist circumference correlates well with intra-abdominal, so-called ‘‘visceral’’ adiposity. Intra-abdominal adiposity is seen as a pathophysiologically important factor for the development of the MS [19] and of insulin resistance [33]. It is strongly associated with dyslipidemia [17] and with the risk of developing type 2 diabetes mellitus [34]. In addition, intra-abdominal fat has now been described as a major determinant of the NCEP criteria [18] and as an independent cardiovascular risk factor [35]. This was recently confirmed in the Interheart Study, showing an independent contribution to the risk of myocardial infarction [6]. 2.6. MS-associated factors In addition to the criteria listed in Table 1, there are several factors, often with pro-atherogenic, pro-inflamma-
tory, prothrombotic or antifibrinolytic properties, that are closely associated with MS [36,37]. Examples that have been observed in epidemiological, experimental or clinical studies are plasminogen activator inhibitor-1 (PAI-1) [38,39], tissue plasminogen activator (tPA) [38,40], coagulation factor VII [40] and fibrinogen [38]. The associations between these factors and the MS are not unchallenged [41]. However, some authors support the inclusion of PAI-1, in particular, on the list of official MS criteria [42], and a recent position paper emphasized the role of the prothrombotic and pro-inflammatory state in MS [21].
3. Vascular perspective—epidemiology Epidemiological studies have shown that the MS predicts the development of cardiovascular morbidity and mortality [15,43]. Patients with MS have an approximately two to four times higher risk of dying of atherosclerotic disease than individuals without MS [15,32]. A recent survey, which was adjusted for age, gender and other risk factors, reported hazard ratios of 1.40, 1.82 and 2.02 for overall mortality, coronary heart disease mortality and cardiovascular mortality, respectively, for MS. The MS predicted mortality more strongly than its individual components [5]. The San Antonio Heart Study reported comparable to slightly higher hazard ratios. Interestingly, in this cohort, it was observed that gender-modified risk: hazard ratios were higher in women than in men [12]. In addition, MS patients have a three times greater risk of coronary heart disease and stroke [32]. The added risk of MS to cardiovascular disease also seems to occur in patients with diabetes [44]. This may be of interest as many patients with diabetes have MS [32]: in a Finnish cohort, it was observed in 80% of the female and 90% of the male patients [45].
4. Vascular studies The blood vessels of patients with the MS have been studied by echography (arterial intima media thickness, IMT), computer tomography (CT) and angiography. IMT is a measure of atherosclerosis and predicts vascular events, such as a myocardial infarction or stroke. IMT was found to be increased in various groups of patients with MS: in middle-aged men without cardiovascular disease [46], in otherwise healthy patients with hyperinsulinemia without diabetes [47] and in patients with established cardiovascular disease [48]. CT evaluation of coronary arteries showed increased calcium scores (CAC) in MS in a dose-dependent manner. These findings have recently been confirmed [18]. CAC is a known measure for increased whole body ‘‘plaque burden’’ [49], suggesting these coronary findings reflect more widespread atherosclerotic disease. In addition to the presence of vascular damage, progression of vascular damage has also been investigated.
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During a 5-year follow-up study, faster progression of atherosclerosis was found in patients with MS. More plaque formation was observed, as was the development of more stenoses (> 40%) [50]. In postmenopausal women with proven coronary disease and MS, a trend towards faster progression of atherosclerosis was noted during a 2-year angiographic follow-up. Interestingly, when MS was present, significantly more clinical events, such as myocardial infarctions, were observed with similar levels of atherosclerosis at the beginning of the study [51,52].
5. Vascular perspective: risk assessment At the moment, there is no algorithm available to estimate the absolute risk for patients with the MS. In the risk calculators of the UKPDS (glucose, hypertension) and of the International Task Force for Prevention of Coronary Heart Disease (triglycerides, HDL-C, hypertension), some MS criteria are applied. The contribution of MS to cardiovascular risk assessment has been examined in a number of secondary prevention studies. In a study of coronary artery disease patients with increased LDL-cholesterol levels, with or without MS, and in a study of patients without proven coronary disease but with low HDL-cholesterol levels, with or without MS, an additional (relative) risk of approximately 50% was observed [53]. Another study found an even higher increase in relative risk: approximately 70% [54]. The increase was found independent of the Framingham risk score. With regard to risk assessment, another interesting relationship is that between MS and C-reactive protein (CRP), a cardiovascular risk marker. Patients with the syndrome, especially those with abdominal adiposity, have increased CRP levels [55 –57] that add prognostic information about cardiovascular risk [54,58].
6. Vascular perspective: treatment Thus far, there have been few studies on MS that focus directly on vascular endpoints. First-line treatment for MS includes therapeutic lifestyle interventions aimed at physical exercise, dietary modifications and weight reduction [21,59]. It is not yet known whether physical exercise and calorie restriction, which help prevent the development of diabetes [60] and have a positive influence on the lipid spectrum [61,62], also have positive effects on atherosclerosis and related vascular wall defects. Recent guidelines emphasize the importance of blood pressure treatment. Since it is believed that blood pressure-lowering itself results in most of the reduction in the associated risk, no particular drug has been identified thus far as being preferable in the setting of MS [21]. Nevertheless, evidence is emerging from several studies that intervention with the renin – angiotensin system (RAS) may be associated with less progression of hypertensive patients to diabetes [63 –
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66]. In addition to antihypertensive treatment, there are certain drugs of particular interest within the framework of MS, four of which will now be discussed. 6.1. Statins The favorable effect of statins on cardiovascular morbidity and mortality is no longer a matter of debate. Particularly in the setting of secondary prevention or in high-risk populations, the favorable influence of these drugs has been established. The MRC Heart Protection Study, for example, showed these effects in all prespecified subgroups including patients with hypertension and diabetes [67]. The role of statins in the primary prevention of patients with MS, however, has not yet been thoroughly elucidated. To assess the role of statins, posthoc analyses have been made from large-scale, randomized, controlled studies. In a secondary prevention trial, patients with MS who were treated with pravastatin achieved a risk reduction similar to that in patients without the syndrome [54]. A post-hoc analysis of the 4S study (patients with an increased serum LDL-cholesterol and proven coronary disease) showed that patients with low HDL-cholesterol and increased serum triglyceride values experienced a high-risk reduction following treatment with simvastatin [68]. To our knowledge, no major randomized, controlled trials have been performed with statins aimed at the primary prevention of patients with the MS. 6.2. Fibrates Fibrates (gemfibrozil, fenofibrate, bezafibrate) act on the peroxisome proliferator activated receptor (PPAR) system and are PPAR-a agonists. PPAR-a agonists are important in the gene regulation of hepatocytes, i.e., their activation decreases triglyceride production. It is well recognized that treatment with fibrates has a positive effect on hyperlipidemia that is characterized by high triglyceride values and low HDL-cholesterol values. The dyslipidemia of patients with the MS has indeed reacted favorably to treatment with fibrates [69 – 72]. No data are yet available on the long-term effects on cardiovascular morbidity and mortality in patients with the MS, whereas, in patients with DM2 on fenofibrate, favorable effects on the progression of coronary atherosclerosis have been observed [73]. 6.3. Metformin A positive influence of metformin on cardiovascular morbidity in DM2 has been observed [74]. Small-scale studies report positive effects of metformin on vascular wall parameters, such as endothelial function, in these patients [75]. Extrapolation of these results to MS is difficult due to a paucity of data. In patients with polycystic ovary syndrome, which is associated with insulin resistance, metformin decreased the serum CRP [76] and, in patients with HIV-
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associated lipodystrophia, it improved the cardiovascular risk markers [77]. There is, however, little direct evidence of a beneficial effect of metformin on vascular endpoints in MS. 6.4. Thiazolidinediones (TZD) This relatively new group of drugs, including troglitazone, pioglitazone and rosiglitazone, also targets the PPARsystem through another agonist: PPAR-g. PPAR-g is an important regulator of the function of fat cells and of inflammatory cells in the atherosclerotic plaque. In fat cells, PPAR-g agonists improve absorption and storage of triglycerides and glucose, resulting in a decrease in serum glucose values and an increase in insulin sensitivity. In experimental studies, they have prevented the progression of atherosclerosis [78 – 80]. Thiazolidinediones might become an attractive intervention in MS, targeting insulin sensitivity and atherosclerosis. The available data on the effects of TZD on the vascular wall in human subjects are in line with the experimental data. Favorable effects of troglitazone and pioglitazone have been described on the progression of IMT of the carotid arteries in DM2 [81,82]. Treatment with rosiglitazone, prescribed to patients without diabetes but with proven coronary disease, resulted in a decrease in inflammatory and endothelial cell-activation parameters [83].
7. Conclusion The MS is a clustering of cardiovascular risk factors. The diagnosis is not difficult to establish using blood pressure, waist circumference and some additional laboratory results. The prevalence of MS is increasing due to changes in lifestyle. Patients with the MS have a two to four times higher risk of dying from atherosclerotic disease. Studies have shown more atherosclerosis and increased rates of its progression in MS patients. Also, these patients seem to be more vulnerable to events at comparable levels of atherosclerosis. Treatment starts with lifestyle intervention: exercise and weight reduction. Medical intervention strategies using blood pressure-lowering agents, statins, fibrates and metformin seem the most appropriate to date; TZD may be added to this list in the future. Evidence regarding risk assessment and optimal medical strategies will be an important aspect of vascular research in the coming years.
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Review article
The metabolic syndrome: A vascular perspective J.T. Tamsma*, I.M. Jazet, E.D. Beishuizen, A.J. Fogteloo, A.E. Meinders, M.V. Huisman Vascular Medicine, Dept. of General Internal Medicine, Leiden University Medical Center, C1-R45, P.O. Box 9600, 2300 RC Leiden, Netherlands Received 20 July 2004; received in revised form 21 December 2004; accepted 20 January 2005
Abstract The metabolic syndrome (MS) is a clustering of cardiovascular risk factors. Current definitions of MS use hypertension, waist circumference, fasting glucose, triglyceride and HDL-cholesterol levels as defining variables. The prevalence of MS is increasing in our society due to lifestyle changes that result in decreased physical activity and increased body weight. Patients with MS have a three times greater risk of coronary heart disease and stroke, and a two to four times greater risk of dying from atherosclerotic coronary heart disease than those without MS. Imaging studies have shown an increased burden and progression of atherosclerosis. Also, MS patients seem to be more vulnerable to events at comparable levels of atherosclerosis. First-line treatment for MS is therapeutic lifestyle intervention, including exercise and weight reduction. Medical intervention strategies using blood pressure-lowering medication, statins, fibrates and metformin seem the most appropriate to date. The effects of thiazolidinediones on cardiovascular endpoints have not been studied to a large extent in the setting of MS. Evidence regarding risk assessment and optimal medical strategies will be an important aspect of vascular research in the coming years. D 2005 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Metabolic syndrome; Atherosclerosis; Cardiovascular disease
Contents 1. 2.
3. 4. 5. 6.
Introduction. . . . . . . . . . . . . . . . . . . . The metabolic syndrome: definition and criteria . 2.1. Impaired fasting glucose (IFG) . . . . . . 2.2. Insulin resistance or hyperinsulinemia. . . 2.3. Hypertriglyceridemia and HDL-cholesterol 2.4. Hypertension and microalbuminuria. . . . 2.5. Waist circumference . . . . . . . . . . . . 2.6. MS-associated factors . . . . . . . . . . . Vascular perspective—epidemiology . . . . . . . Vascular studies . . . . . . . . . . . . . . . . . Vascular perspective: risk assessment . . . . . . Vascular perspective: treatment . . . . . . . . . . 6.1. Statins . . . . . . . . . . . . . . . . . . . 6.2. Fibrates . . . . . . . . . . . . . . . . . .
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* Corresponding author. E-mail address: [email protected] (J.T. Tamsma). 0953-6205/$ - see front matter D 2005 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2005.01.011
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6.3. Metformin . . . . . . . . 6.4. Thiazolidinediones (TZD) 7. Conclusion . . . . . . . . . . . References . . . . . . . . . . . . . .
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listed in Table 1. The ‘‘calculation rules’’ used in the different classifications are as follows:
1. Introduction In addition to the classic cardiovascular risk factors, the metabolic syndrome (MS) –a clustering of cardiovascular risk factors [1,2] – is increasingly being recognized as an important factor in the pathophysiology of atherosclerosis and as a target of therapy [3]. MS is closely related to presentday changes in lifestyle and their ensuing consequences, such as a lack of physical activity and an increase in body weight. The prevalence of MS has exceeded 20% of the adult population in many countries and is still increasing [4]. Because MS is defined as a clustering of risk factors, some have argued that MS-associated cardiovascular risk is nothing more than the sum of the risks of its defining components. Intriguingly, combinations of risk factors seem to enhance each other. This has been shown in MS, as the syndrome more strongly predicted mortality than did its individual components [5]. Another example of risk enhancement was recently observed for nine environmental risk factors, several reminiscent of MS [6]. In this article, we will address MS from a vascular perspective.
2. The metabolic syndrome: definition and criteria MS has been defined by the WHO, the American National Cholesterol Education Program (NCEP) and the European Group for the Study of Insulin Resistance (EGIR) [3,7,8]. The EGIR definition is a specification of the WHO classification system. MS is defined as a sum of the criteria
1. WHO/EGIR: the presence of impaired fasting glucose or insulin resistance is a prerequisite for the definition. In addition, two or more criteria have to be present. 2. NCEP: three or more criteria are present. A patient can thus be classified or diagnosed as having MS (ICD code: 277.7 [9]). The discussion and studies comparing the classification systems [10 – 15] in order to assess which one to follow in daily practice is beyond the scope of this review. Given the emerging central role for abdominal adiposity [16 – 19], this risk factor will be discussed in some detail. The other criteria will be mentioned only briefly. 2.1. Impaired fasting glucose (IFG) Fasting glucose levels of 5.6 to 5.9 mmol/L have recently been proposed as the cut-off point for IFG as this predicts future diabetes most precisely [20]. The classification systems have not yet adopted this criterion [21] for MS, although the discussion is ongoing [22]. 2.2. Insulin resistance or hyperinsulinemia This aspect is regarded by some as a pathophysiologic key to the metabolic and vascular changes of MS. Insulin has vasoactive properties. Furthermore, hyperinsulinemia has
Table 1 Criteria and definition of the metabolic syndrome Criteria of the metabolic syndrome Glucose Insulin Visceral obesity
Triglycerides HDL-cholesterol
fasting fasting resistance S waist girth S WHR 9 waist girth 9 WHR S 9
Blood pressure Microalbuminuria Definition of the metabolic syndrome
NCEP/ATP III [3]
EGIR-modified WHO [7,8]
>6.1 mmol/L – >102 cm (>94 cm)* – >88 cm – >1.7 mmol/L <1.0 mmol/L <1.3 mmol/L 130/85 mm Hg No
>6.1 mmol/L or DM Upper 25% normal Lowest 25% ‘‘QUICKI’’ 94 cm 0.91 80 cm 0.86 >1.7 mmol/L <0.9 mmol/L <1.0 mmol/L 140/90 mm Hg (WHO 160/90) No (WHO yes)
The presence of 3 or more of the criteria listed above
Hyperinsulinemia, IGT or diabetes and 2 or more of the criteria listed above
Some male patients can develop multiple metabolic risk factors when the waist circumference is only marginally increased. Such patients may have a strong genetic contribution to insulin resistance [3].
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been observed as an independent risk factor for ischemic heart disease [11] and, recently, it was found that insulin resistance was related to coronary calcium scores, a measure of systemic atherosclerosis [23]. A complicating factor is that insulin resistance cannot be established in all patients with MS. 2.3. Hypertriglyceridemia and HDL-cholesterol The hypertriglyceridemia present in MS is thought to result from increased VLDL and VLDL remnant levels that are known to be pro-atherogenic [24]. Related to the higher triglyceride levels are increased concentrations of small dense (sd) LDL [25 – 27]. The pro-atherogenic potential of sd LDL and its association with coronary heart disease have been reviewed comprehensively elsewhere [28]. HDL has an established role in ‘‘reverse cholesterol transport’’ [29]. It has been included as an independent MS criterion notwithstanding the reciprocal relationship between serum triglyceride concentrations and HDL-cholesterol values. 2.4. Hypertension and microalbuminuria Hypertension has already been related to insulin resistance by Reaven [1,30] and is used as a MS criterion. Microalbuminuria is a cardiovascular risk factor, particularly in DM2 and hypertension [31]. Using the WHO criteria, microalbuminuria was found to confer the strongest risk of cardiovascular death of all MS criteria [32]. Despite this observation, microalbuminuria has not been included as a MS-defining criterion in the EGIR and NCEP. 2.5. Waist circumference Table 1 shows different ‘‘truncating values’’ and that the waist –hip ratio (WHR) is not used by the NCEP. It has been argued that the WHR, being an index of relative accumulation of visceral fat, may provide ‘‘misleading’’ information as it could conceal the absolute amount of visceral adipose tissue [16]. Waist circumference correlates well with intra-abdominal, so-called ‘‘visceral’’ adiposity. Intra-abdominal adiposity is seen as a pathophysiologically important factor for the development of the MS [19] and of insulin resistance [33]. It is strongly associated with dyslipidemia [17] and with the risk of developing type 2 diabetes mellitus [34]. In addition, intra-abdominal fat has now been described as a major determinant of the NCEP criteria [18] and as an independent cardiovascular risk factor [35]. This was recently confirmed in the Interheart Study, showing an independent contribution to the risk of myocardial infarction [6]. 2.6. MS-associated factors In addition to the criteria listed in Table 1, there are several factors, often with pro-atherogenic, pro-inflamma-
tory, prothrombotic or antifibrinolytic properties, that are closely associated with MS [36,37]. Examples that have been observed in epidemiological, experimental or clinical studies are plasminogen activator inhibitor-1 (PAI-1) [38,39], tissue plasminogen activator (tPA) [38,40], coagulation factor VII [40] and fibrinogen [38]. The associations between these factors and the MS are not unchallenged [41]. However, some authors support the inclusion of PAI-1, in particular, on the list of official MS criteria [42], and a recent position paper emphasized the role of the prothrombotic and pro-inflammatory state in MS [21].
3. Vascular perspective—epidemiology Epidemiological studies have shown that the MS predicts the development of cardiovascular morbidity and mortality [15,43]. Patients with MS have an approximately two to four times higher risk of dying of atherosclerotic disease than individuals without MS [15,32]. A recent survey, which was adjusted for age, gender and other risk factors, reported hazard ratios of 1.40, 1.82 and 2.02 for overall mortality, coronary heart disease mortality and cardiovascular mortality, respectively, for MS. The MS predicted mortality more strongly than its individual components [5]. The San Antonio Heart Study reported comparable to slightly higher hazard ratios. Interestingly, in this cohort, it was observed that gender-modified risk: hazard ratios were higher in women than in men [12]. In addition, MS patients have a three times greater risk of coronary heart disease and stroke [32]. The added risk of MS to cardiovascular disease also seems to occur in patients with diabetes [44]. This may be of interest as many patients with diabetes have MS [32]: in a Finnish cohort, it was observed in 80% of the female and 90% of the male patients [45].
4. Vascular studies The blood vessels of patients with the MS have been studied by echography (arterial intima media thickness, IMT), computer tomography (CT) and angiography. IMT is a measure of atherosclerosis and predicts vascular events, such as a myocardial infarction or stroke. IMT was found to be increased in various groups of patients with MS: in middle-aged men without cardiovascular disease [46], in otherwise healthy patients with hyperinsulinemia without diabetes [47] and in patients with established cardiovascular disease [48]. CT evaluation of coronary arteries showed increased calcium scores (CAC) in MS in a dose-dependent manner. These findings have recently been confirmed [18]. CAC is a known measure for increased whole body ‘‘plaque burden’’ [49], suggesting these coronary findings reflect more widespread atherosclerotic disease. In addition to the presence of vascular damage, progression of vascular damage has also been investigated.
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During a 5-year follow-up study, faster progression of atherosclerosis was found in patients with MS. More plaque formation was observed, as was the development of more stenoses (> 40%) [50]. In postmenopausal women with proven coronary disease and MS, a trend towards faster progression of atherosclerosis was noted during a 2-year angiographic follow-up. Interestingly, when MS was present, significantly more clinical events, such as myocardial infarctions, were observed with similar levels of atherosclerosis at the beginning of the study [51,52].
5. Vascular perspective: risk assessment At the moment, there is no algorithm available to estimate the absolute risk for patients with the MS. In the risk calculators of the UKPDS (glucose, hypertension) and of the International Task Force for Prevention of Coronary Heart Disease (triglycerides, HDL-C, hypertension), some MS criteria are applied. The contribution of MS to cardiovascular risk assessment has been examined in a number of secondary prevention studies. In a study of coronary artery disease patients with increased LDL-cholesterol levels, with or without MS, and in a study of patients without proven coronary disease but with low HDL-cholesterol levels, with or without MS, an additional (relative) risk of approximately 50% was observed [53]. Another study found an even higher increase in relative risk: approximately 70% [54]. The increase was found independent of the Framingham risk score. With regard to risk assessment, another interesting relationship is that between MS and C-reactive protein (CRP), a cardiovascular risk marker. Patients with the syndrome, especially those with abdominal adiposity, have increased CRP levels [55 –57] that add prognostic information about cardiovascular risk [54,58].
6. Vascular perspective: treatment Thus far, there have been few studies on MS that focus directly on vascular endpoints. First-line treatment for MS includes therapeutic lifestyle interventions aimed at physical exercise, dietary modifications and weight reduction [21,59]. It is not yet known whether physical exercise and calorie restriction, which help prevent the development of diabetes [60] and have a positive influence on the lipid spectrum [61,62], also have positive effects on atherosclerosis and related vascular wall defects. Recent guidelines emphasize the importance of blood pressure treatment. Since it is believed that blood pressure-lowering itself results in most of the reduction in the associated risk, no particular drug has been identified thus far as being preferable in the setting of MS [21]. Nevertheless, evidence is emerging from several studies that intervention with the renin – angiotensin system (RAS) may be associated with less progression of hypertensive patients to diabetes [63 –
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66]. In addition to antihypertensive treatment, there are certain drugs of particular interest within the framework of MS, four of which will now be discussed. 6.1. Statins The favorable effect of statins on cardiovascular morbidity and mortality is no longer a matter of debate. Particularly in the setting of secondary prevention or in high-risk populations, the favorable influence of these drugs has been established. The MRC Heart Protection Study, for example, showed these effects in all prespecified subgroups including patients with hypertension and diabetes [67]. The role of statins in the primary prevention of patients with MS, however, has not yet been thoroughly elucidated. To assess the role of statins, posthoc analyses have been made from large-scale, randomized, controlled studies. In a secondary prevention trial, patients with MS who were treated with pravastatin achieved a risk reduction similar to that in patients without the syndrome [54]. A post-hoc analysis of the 4S study (patients with an increased serum LDL-cholesterol and proven coronary disease) showed that patients with low HDL-cholesterol and increased serum triglyceride values experienced a high-risk reduction following treatment with simvastatin [68]. To our knowledge, no major randomized, controlled trials have been performed with statins aimed at the primary prevention of patients with the MS. 6.2. Fibrates Fibrates (gemfibrozil, fenofibrate, bezafibrate) act on the peroxisome proliferator activated receptor (PPAR) system and are PPAR-a agonists. PPAR-a agonists are important in the gene regulation of hepatocytes, i.e., their activation decreases triglyceride production. It is well recognized that treatment with fibrates has a positive effect on hyperlipidemia that is characterized by high triglyceride values and low HDL-cholesterol values. The dyslipidemia of patients with the MS has indeed reacted favorably to treatment with fibrates [69 – 72]. No data are yet available on the long-term effects on cardiovascular morbidity and mortality in patients with the MS, whereas, in patients with DM2 on fenofibrate, favorable effects on the progression of coronary atherosclerosis have been observed [73]. 6.3. Metformin A positive influence of metformin on cardiovascular morbidity in DM2 has been observed [74]. Small-scale studies report positive effects of metformin on vascular wall parameters, such as endothelial function, in these patients [75]. Extrapolation of these results to MS is difficult due to a paucity of data. In patients with polycystic ovary syndrome, which is associated with insulin resistance, metformin decreased the serum CRP [76] and, in patients with HIV-
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associated lipodystrophia, it improved the cardiovascular risk markers [77]. There is, however, little direct evidence of a beneficial effect of metformin on vascular endpoints in MS. 6.4. Thiazolidinediones (TZD) This relatively new group of drugs, including troglitazone, pioglitazone and rosiglitazone, also targets the PPARsystem through another agonist: PPAR-g. PPAR-g is an important regulator of the function of fat cells and of inflammatory cells in the atherosclerotic plaque. In fat cells, PPAR-g agonists improve absorption and storage of triglycerides and glucose, resulting in a decrease in serum glucose values and an increase in insulin sensitivity. In experimental studies, they have prevented the progression of atherosclerosis [78 – 80]. Thiazolidinediones might become an attractive intervention in MS, targeting insulin sensitivity and atherosclerosis. The available data on the effects of TZD on the vascular wall in human subjects are in line with the experimental data. Favorable effects of troglitazone and pioglitazone have been described on the progression of IMT of the carotid arteries in DM2 [81,82]. Treatment with rosiglitazone, prescribed to patients without diabetes but with proven coronary disease, resulted in a decrease in inflammatory and endothelial cell-activation parameters [83].
7. Conclusion The MS is a clustering of cardiovascular risk factors. The diagnosis is not difficult to establish using blood pressure, waist circumference and some additional laboratory results. The prevalence of MS is increasing due to changes in lifestyle. Patients with the MS have a two to four times higher risk of dying from atherosclerotic disease. Studies have shown more atherosclerosis and increased rates of its progression in MS patients. Also, these patients seem to be more vulnerable to events at comparable levels of atherosclerosis. Treatment starts with lifestyle intervention: exercise and weight reduction. Medical intervention strategies using blood pressure-lowering agents, statins, fibrates and metformin seem the most appropriate to date; TZD may be added to this list in the future. Evidence regarding risk assessment and optimal medical strategies will be an important aspect of vascular research in the coming years.
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