Metabolic syndrome and cardiometabolic risk: An update

Abstract

Several lines of evidence show that metabolic syndrome represents an important therapeutic challenge for the forthcoming years. This is because of the epidemic burden of this multifaceted disease, the adverse impact on cardiovascular risk, as well as the problems posed in its management. This paper will provide an up‐to‐date report on metabolic syndrome and cardiometabolic risk, focusing in particular on the epidemiological profile of the disease, the impact on risk profile and target organ damage as well as some of the main pathophysiological features of the condition. The general therapeutic recommendations, provided by the 2007 European Society of Hypertension/European Society of Cardiology Guidelines, will be briefly discussed.

• Antihypertensive treatment
• blood pressure
• cardiovascular risk
• metabolic syndrome
• obesity

Introduction

The clustering of multiple cardiometabolic risk factors such as visceral obesity, hypertriglyceridaemia, low high‐density lipoprotein (HDL)‐cholesterol, hypertension and glucose intolerance, known under the term “metabolic syndrome”, has received during the past few years growing attention in both the clinical and the research perspectives. Several sound reasons justify this interest. Firstly, the syndrome shows a high prevalence in many populations of different countries all around the world [1–5]. Secondly, metabolic syndrome is associated with an increased risk of cardiovascular disease and death, producing a large adverse impact on public health [6–14]. Finally, the disease management is complex and sometimes treatment recommendations [15–18] are not supported by guidelines, because of the lack of specific intervention trials. This appears to be particularly the case for the use of antihypertensive drug treatment in metabolic syndrome with “high‐normal” blood pressure [17],[18]. The present paper provides an updated and comprehensive overview of the prevalence of the disease, its association with an increased cardiovascular risk and greater incidence of target organ damage. This will be followed by a critical analysis of the main pathophysiological features of the metabolic syndrome, thereby allowing, in the final part of the paper, current recommendations for the treatment of the metabolic syndrome to be addressed.

Epidemiological burden of the metabolic syndrome

One of the major difficulties in obtaining a detailed epidemiological picture of the disease is represented by the fact that the definition and nomenclature of the metabolic syndrome have been subject of considerable debate and, not infrequently, disagreement between the experts' opinions [19],[20]. However, taking into account the United States National Cholesterol Education Program Adult Treatment Panel III (ATP III) definition, which was updated in 2005 [21], it is possible to draw the following picture. Firstly, the prevalence of the disease is almost superimposable in European and non‐European countries (about 23–25% of the general population is affected), although higher values have been reported in geographic areas (such as North America), characterized by an increased propensity to obesity reaching sometimes endemic proportions [1–5]. Secondly, the prevalence of the metabolic syndrome increases in both genders with increasing age [2], [4], [5]. Finally, the disease prevalence in people with elevated blood pressure levels is much higher than in the general population [22], a finding that, as it will be discussed later in the text, underscores once again the close links between the two conditions.

As mentioned above, the prevalence of the disease is very similar in different European countries. In Southern Europe, recent findings collected in the context of the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) Study, carried out in the northeast outskirts of the Milan area, indicate that in the general population about 16% of subjects display the disease, with a prevalence greater than 20% in people aged 55 years or more (Figure 1) [23]. In the group of subjects with metabolic syndrome, as a whole hypertension appeared to be the most common component of the disease, followed in sequence by hypertriglyceridaemia, low HDL‐cholesterol, abdominal obesity and lastly impaired fasting glucose (Figure 2) [23]. In reviewing the main epidemiological features of the disease, however, two considerations deserve to be made on the wide heterogeneity of the results of the different studies. The first refers to the fact that the more or less stringent criteria employed for the definition of the disease itself may influence the prevalence data [1]. A head‐to‐head comparison of the figures obtained by employing three different definitions of the disease, the already mentioned ATPIII [21], the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) [24] and the International Diabetes Federation (IDF) [25], has been recently performed in the PAMELA Study. The results of this analysis show that the prevalence of metabolic syndrome may vary considerably when adopting different definitions and criteria (from 16.1% to 22.5%). This is the case also for the metabolic syndrome‐related cardiovascular risk, particularly when unadjusted figures are considered (unpublished data). The second consideration refers to the evidence that a more or a less accurate definition of the disease prevalence frequently depends on the use of more or less sensitive markers of (i) the metabolic state (insulin resistance vs glycaemic levels), (ii) the obese state (waist/hip ratio vs tomographic or densitometric assessment of the adipose tissue distribution) and (iii) the blood pressure elevation (office vs other types of blood pressure measurements).

Figure 1. Prevalence of the metabolic syndrome in the PAMELA population, accordingly to the subjects' gender and age decades. Data from ref. [23].

Figure 2. Prevalence of the various compounds of the metabolic syndrome in the PAMELA population. BP, Blood pressure; TG, Triglycerides; IFG, Impaired fasting glucose. ↑: Increase. Data from ref. [23].

As far as blood pressure assessment is concerned, in the context of the already mentioned PAMELA study, it has been found that ambulatory blood pressure monitoring and home blood pressure are diagnostic approaches displaying a greater sensitivity than clinic (or sphygmomanometric) blood pressure in estimating the prevalence of the hypertensive state in people with metabolic syndrome [23]. This may depend on the fact that, as discussed in the European Society of Hypertension/European Society of Cardiology 2007 Guidelines for the management of hypertension (which devote a noticeable attention to the problem of metabolic syndrome), blood pressure normality values are lower for ambulatory or home blood than for clinic blood pressure [18]. This may also depend, however, on the finding that 24‐h and home blood pressure are more accurate in reflecting the presence of target organ damage and in providing information on the future development of cardiovascular complications than clinic blood pressure [26].

Total cardiovascular risk

As already mentioned, it is well established that in the metabolic syndrome several cardiovascular risk factors often cluster together, and further that for each of these risk factors there is a continuous relationship with cardiovascular risk [27]. Consequently, attention has been focused on the concept on total (global) cardiovascular risk. Currently, internationally recognized guidelines recommend that the total cardiovascular risk in an individual patient should be assessed and used as the basis for the therapeutic decision [15–18].

The methods used to assess total cardiovascular risk vary among the different guidelines. Those published by the European Society of Hypertension (ESH/ESC) [18] categorize cardiovascular risk according to the presence of other risk factors, target organ damage and associated clinical conditions, such as a history of cardiovascular disease, according to the criteria provided by the Framingham Heart and other studies [28]. Thus, patients can be stratified in terms of an approximate 10‐year added risk of cardiovascular disease as being at low (<10%), medium (15–20%), high (20–30%) or very high (>30%), according to the severity of the hypertensive state and the presence of other risk factors. The presence of additional risk factors, target organ damage or associated clinical conditions can result in patients being at high or very high risk of cardiovascular disease even when blood pressure is normal or “high normal” (i.e. systolic blood pressure 130‐139 mmHg and diastolic blood pressure 85‐89 mmHg). Several studies have shown that in the hypertensive patients a progressively greater number of additional cardiovascular risk factors is associated with a progressively worse prognosis. One such study analysed mortality data for an average follow‐up of 14 years in more than 60,000 male patients with hypertension, showing that the poorer prognosis is associated with the clustering of the various risk factors [29]. Interestingly, this phenomenon occurs not only when blood pressure values are measured by a doctor (“clinic blood pressure”), but also when home and ambulatory blood pressure data are taken into account [30]. This makes the presence of a high blood pressure state of particular relevance in the context of the cardiometabolic syndrome [31].

Data presented so far strongly suggest that the impact of the metabolic syndrome on cardiovascular risk profile can be particularly unfavourable. This suggestion has been confirmed by the results of a quite large number of cross‐sectional and longitudinal studies showing that the metabolic syndrome is associated with an increased risk of cardiovascular disease and death [6–14]. For example, in the Kuopio Ischaemic Heart Disease Risk Factors Study, performed in a large number of healthy subjects aged 42–60 years who were longitudinally followed‐up for more than 12 years, evidence was provided that the risk of acute coronary fatal events is four times greater in subjects with than without the disease [6]. Similar estimates of risk have been provided by the West of Scotland Coronary Prevention Study (WOSCOPS), whose results highlighted the adverse prognostic relevance of metabolic syndrome and elevated C‐reactive protein values on coronary events [8]. The above‐mentioned data have been confirmed and further expanded by the results of the PAMELA study [23]. Indeed, the Kaplan–Meier survival curves in Figure 3 show that during an average follow‐up of 148 months, patients with metabolic syndrome had a much higher incidence of cardiovascular and all‐cause death than subjects without the disease. Similar results have provided an analysis of the percentage of events, even when subjects affected by diabetes, hypertension or hypercholesterolaemia are excluded from the analysis. Taken together these findings emphasize the long‐term adverse prognostic impact of the disease. They also suggest that the magnitude of the increased risk of metabolic syndrome is much greater than one characterizing each individual component of the disease itself.

Figure 3. Kaplan‐Meier survival curves for cardiovascular death and all‐cause death in subjects without (MS–) and with (MS+) metabolic syndrome. p‐values refer to the statistical difference between the two curves. Modified from ref. [23].

Target organ damage

The 2007 ESH/ESC Guidelines emphasize that, along with traditional cardiovascular risk factors, the presence of subclinical target organ damage confers an increased total cardiovascular risk [18]. Among the different end‐organ damage alterations characterizing the metabolic syndrome (Table I), those specifically involving cardiac function should be regarded as the ones of major clinical relevance, given their close relationship with cardiovascular morbidity and mortality [18],[32].

Table I. Intermediate (surrogate) endpoints of prognostic relevance in hypertension and in metabolic syndrome.

Left ventricular hypertrophy	Arterial stiffness
Diastolic dysfunction	Small arteries media‐to‐lumen ratio
Pulse pressure	Large arteries intima/media thickness
Silent myocardial ischaemia	Endothelial dysfunction
Silent cerebral ischaemia	Insulin resistance
Microalbuminuria/proteinuria	Sympathetic activation
Carotid plaques	Central pressure

Several studies have demonstrated that modifications of left ventricular structure take place in a considerable proportion of patients with the metabolic syndrome [23], [33–39]. Obviously, the precise estimates of prevalence vary considerably from one study to another, depending particularly on the main characteristics of the population examined. In the PAMELA study we found that, when evaluated by echocardiography, patients with metabolic syndrome show a greater left ventricular wall thickness and an increased left ventricular mass index compared with age‐matched individuals without the disease [23]. When we looked at the prevalence of left ventricular hypertrophy, as defined according to common echocardiographic criteria (left ventricular mass index ≥ 125 g/m2 in men and ≥ 110 g/m2 in women), we found that about 27% of the subjects with metabolic syndrome displayed left ventricular hypertrophy (Figure 4) [23]. However, when the same assessment was carried out in selected populations, such as hypertensive or overweight patients referred to a specialist hospital centre, the numbers appeared to be somewhat different and the percentage figures of prevalence greater [39]. This finding emphasizes once again that the haemodynamic overload, i.e. the blood pressure elevation, is an important variable for the development and/or the progression of cardiac organ damage. It also underlines that non‐haemodynamic mechanisms also play a major pathogenetic role. This is further confirmed in the PAMELA study, by the evidence that in patients with metabolic syndrome, values of both left ventricular thickness and left ventricular mass remained greater than those found in subjects without metabolic syndrome even when hypertensive patients were excluded, adjustments for office blood pressure differences were made or matches for 24‐h blood pressure values were performed [23].

Figure 4. Prevalence (%) of left ventricular hypertrophy (LVH) in the subjects of the PAMELA study without (blue bars) and with (grey bars) metabolic syndrome in the whole population samples and in males and females, after exclusion of hypertensive patients or adjustment for 24‐h systolic blood pressure values and in different age decades. Asterisks (*p,0.05) refer to the statistical significance between groups. Data are shown as mean ± SEM. Modified from ref. [23].

A further element of interest is the evidence that in the PAMELA longitudinal substudy, performed in a cohort of subjects evaluated in the 1990s and re‐examined 10 years later, new‐onset left ventricular hypertrophy was, after a decade of observation, more than doubled in patients with metabolic syndrome as compared with patients without the disease (Figure 5) [40]. Among the predictors of left ventricular hypertrophy, baseline left ventricular mass index and age appeared to be the most significant variables, followed by office systolic blood pressure, body mass index and triglycerides [40].

Figure 5. Left ventricular mass index (LVMI) and prevalence of left ventricular hypertrophy (LVH) in the subjects of the PAMELA study with metabolic syndrome examined in 1991–1992 and reassessed 10 years later. Data are shown as absolute (LVMI) or percentage (LVH) mean values. Data from ref. [40].

Finally, the modifications in left ventricular geometry already described should include another abnormality, i.e. left atrial enlargement. Recent studies have analysed the prevalence and the correlates of left atrial size in populations affected by pathological states clustering in the metabolic syndrome, such as obesity and hypertension, providing evidence that these conditions may represent, although not invariably, sensitive predictors of left atrial dimensions [41–43]. A recent study, performed in more than 2500 untreated and treated uncomplicated essential hypertensive patients, provides evidence that about 30% of these display an increased left atrial diameter on the echocardiographic examination [39]. Interestingly, more than 60% of the patients were affected by metaboli syndrome, highlighting the potential adverse effects of this condition not only on ventricular structure but also on atrial dimensions as well. The clinical implications of these findings are clear, considering that left atrial enlargement is a powerful and independent risk factor for stroke, atrial fibrillation and congestive heart failure [44–46]. It is therefore possible to speculate that the increased cardiovascular risk profile of the metabolic syndrome might be in some way related to this structural alteration of the left atrial chamber.

Pathophysiological features

Although a variety of metabolic, antropometric, haemodynamic, genetic, inflammatory and vascular abnormalities have been suggested in explaining the chain of events leading to the development and progression of the metabolic syndrome [47–53], the exact mechanisms responsible for the disease still remain largely undefined. It is well accepted that abnormalities in the adipose tissue morphology, increased storage of triglycerides in the skeletal muscle and hepatic tissue, alterations in muscle glucose disposal as well as in insulin metabolism play a major role [48]. Three other factors, however, should be mentioned. The first one refers to the genetic background with the evidence that genes codifying for insulin receptors may be linked to the insulin‐resistant state [54]. Candidate genes for the metabolic syndrome, however, are multifold and include angiotensin‐converting enzyme, endothelial nitric oxide synthase, peroxisome proliferators‐activator receptor γ as well as interleukine‐6 [54–56]. Recently, information on the genetic background of the syndrome has been considerably expanded with the evidence that genes codifying for β‐adrenergic receptors may be involved [54]. Data collected in the context of the already mentioned PAMELA study have allowed to advance the hypothesis that an overexpression of the genes codifying for alpha‐1 adrenoreceptors may also participate [57]. The second pathogenetic factor that has received particular attention in the past few years has been an overactivity of the immune system, leading to accumulation of macrofages and other inflammatory cells within the adipose tissue [49],[58],[59]. The third and final theory, non‐mutually exclusive of the previous ones, says that alteration in the sympathetic function, which regulates both cardiovascular and metabolic variables, represents the “primum movens” of the disease thereby acting as the “driving force” of the complex chain of events involved in the development and progression of the disease [47–60]. The hypothesis is strengthened by the evidence that a number of components of metabolic syndrome and this condition per se are associated with an increased activity of the sympathetic nervous system (Figure 6, panel A). Obesity, for example, is accompanied by an increased number of sympathetic neural bursts (detected via the microneurographic technique) to skeletal muscle tissue, which occurs in the absence of an increase in blood pressure and is amplified if the augmented body weight is of the visceral type (Figure 6, panel B) [61],[62]. Furthermore, an increased number of sympathetic bursts to skeletal muscle tissue as well as an increased level of plasma norepinephrine spillover from the neuroeffector junctions into the plasma reservoir (detected via the radiolabeled norepinephrine technique) has been seen in essential hypertension even when the blood pressure elevation is of a mild nature, with a further increase if the elevation in blood pressure and the increase in body weight take place concomitantly (Figure 6, panel C) [63]. Finally, the metabolic syndrome is associated with markers of sympathetic hyperactivity such as an increase in heart rate and recent studies have provided direct evidence that muscle sympathetic nerve traffic is increased as well [64]. This can be seen in Figure 6, panel D, which shows the number of muscle sympathetic bursts to be greater in individuals with a metabolic syndrome based on the ATP III criteria as compared with those without metabolic syndrome. This is the case also if subjects with hypertension are excluded from both groups. It is further the case in subjects with diseases that already cause a pronounced sympathetic activation. For example, in subjects in whom congestive heart failure markedly increases sympathetic activity, a further augmentation of the adrenergic overdrive takes place when the metabolic syndrome is additionally present [65]. The mechanisms responsible for the sympathetic activation accompanying metabolic syndrome have not been fully elucidated. Evidence is available, however, that insulin is a powerful sympatho‐stimulating factor, which suggests that the hyperinsulinaemia resulting from the insulin‐resistance state typical of metabolic syndrome may play a major role [47],[60]. The sympathetic nervous system, on the other hand, can trigger insulin resistance primarily through its vascular effects, i.e. skeletal muscle vasoconstriction, which increases the distance insulin has to travel to reach the cell membrane where it favours entrance of glucose into the intracellular compartment. Thus, insulin resistance and sympathetic activity are linked in a positive feedback fashion that leads to their reciprocal reinforcement. It is not known which factor is activated first, the so‐called “chicken and egg question”, but some authors have defended the causative role of the sympathetic nervous system, which is also suggested by a study by Japanese investigators who have shown that 10 years before developing a marked increase in blood pressure subjects had an increase in plasma norepinephrine but not in plasma insulin levels [47],[60]. Otherfactors may contribute to the sympathetic activation occurring in metabolic syndrome. They include leptin, which is increased in obesity and has been shown to act as a powerful sympatho‐stimulator [47]. The endothelial system may be involved as well because its impairment in metabolic syndrome causes a reduction in nitric oxide and an increase in endothelin secretion with less sympatho‐inhibitory and more sympatho‐excitatory influences, respectively [47],[60]. Sleep apnoea, which frequently occurs in obesity, may also play a role because of its sympatho‐stimulating effect via the hypoxic activation of the chemoreceptor reflex [66–68].

Figure 6. Values of muscle sympathetic nerve activity (MSNA) in obesity. Panel A, data in controls (C) and in obese (O) subjects; Panel B in visceral (CO) and peripheral (PO) overweight; Panel C, in the obese state (O+ HT); panel D, in the metabolic syndrome state (MS). Asterisks (*p<0.05, **p< 0.01) refer to the statistical significance between groups. Data from refs [61–64].

Whatever the mechanisms, the sympathetic activation occurring in metabolic syndrome is likely to contribute to its damaging effects on the cardiovascular system [47],[60]. Indeed, an increased activity of the sympathetic nervous system (i) unfavourably modulates cardiac metabolism, triggering an increase in cardiac cell volume and cardiac hypertrophy for any given pressure, (ii) has an arrhythmogenic effect thereby increasing the risk of sudden death, (iii) promotes an increase in diastolic and systolic blood pressure throughout vasoconstriction and extensive artery wall thickening and (iv) triggers the down‐regulation of alpha‐adrenoreceptors with production or exacerbation of weight gain. The association of metabolic syndrome with sympathetic nervous system hyperactivity strongly suggests that drug‐induced suppression of the hyperadrenergic function could be a beneficial type of intervention.

Therapeutic implications

Preventive measures should always be the primary approach in intervention in patients with metabolic syndrome. This is particularly the case when the single risk factor components of the metabolic syndrome are present but their values are still in the high‐normal range well below, however, those requiring immediate drug treatment. This is the case, for example, for blood pressure values <140/90 mmHg but higher than 125/75 mmHg. The same considerations can be applied for impaired glucose tolerance or for a body weight increase that does not yet result in obesity. In these instances clear recommendations exist to start with non‐pharmacological interventions (physical exercise, hypocaloric diet, diet modifications, etc.) aimed at improving metabolic profile, reducing body weight and decreasing blood pressure [69],[70]. It is interesting to note that several of the lifestyle interventions can favourably affect not only the cardiovascular risk profile of the patients but also some pathophysiological characteristics of the disease [60],[71]. In practice, however, non‐pharmacological interventions are not always sufficiently successful. It is for instance well known how difficult it is to correct overweight in the long‐term. Similar problems are faced in the preventive approach to hypertension and diabetes mellitus type 2. Accordingly, the vast majority of patients with hypertension and/or diabetes mellitus type 2 require pharmacological treatment, in spite of all the good intentions with respect to prevention and lifestyle improvements. Once established, drug treatment has to be followed daily, and usually for the rest of the patient's life. The problem is more complex in individuals with metabolic syndrome who do not present with diabetes or hypertension. There is, however, a growing opinion that drug treatment may be more often needed also in such patients because of the compelling therapeutic aim to reduce the risk of developing diabetes and hypertension as well as to obtain regression or delay progression of subclinical organ damage [17],[18]. The following is a brief summary of the position of the 2007 Guidelines of the European Society of Hypertension and the European Society of Cardiology on this matter and other Guidelines recently issued on the topic [15–18].

The above‐mentioned Guidelines recommend that in hypertensive subjects with the metabolic syndrome, diagnostic procedures should be more extensive than usual because of the higher prevalence of multiple organ damage and increased levels of inflammatory markers. Intense lifestyle measures should be adopted and antihypertensive drug treatment instituted whenever blood pressure is ≥140/90 mmHg, by preferably blocking the renin–angiotensin system with the addition, when needed, of a calcium antagonist or a low dose thiazide diuretic. Beta‐blocking agents (particularly those of the old generations) are not recommended, given the evidence that these compounds (and also thiazide diuretics at higher dosage) may favour the development of new‐onset diabetes mellitus, as data collected in “old” and “new” clinical trials indicate [71],[72]. Administration of a renin–angiotensin system blocker is advisable when blood pressure is still in the high‐normal range, in order to protect against organ damage and prevent new‐onset diabetes or hypertension, but cannot be generally recommended at present. Similarly, antidiabetic drug treatment should be instituted in metabolic syndrome patients with type 2 diabetes, but no firm recommendation can as yet be given on use of antidiabetic drugs or insulin sensitizers in subjects who only have an impaired glucose tolerance. A lower incidence of events has been reported in subjects who were given a statin, which suggests that lipid lowering treatment may also be considered. Pharmacological approaches to subjects with the metabolic syndrome who are not hypertensive or diabetic are worth being investigated in consideration of the fact that, at variance with results of clinical trials, in real life adherence to lifestyle modifications is low and persistent reduction in body weight rare. Taken together, these considerations stress once again the importance of an adequate control of blood pressure in patients with metabolic syndrome, trying to achieve targets close to 125/75 mmHg, as recent Guidelines suggest [17],[18],[71]. Finally, Guidelines also emphasize the need of (i) an adequate cholesterol control via statins and other lipid‐lowering drugs, (ii) antiplatelet drugs and (iii) insulin‐sensitizing therapies as well as antidiabetic agents [17],[18]. Such a therapeutic approach would allow us to adequately address the multifaceted aspects of the metabolic syndrome [18],[71].

Conflict of interest: none.