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Cardiovascular risk and adrenergic overdrive in the metabolic syndrome
Nutrition, Metabolism & Cardiovascular Diseases (2007) 17, 473e481
www.elsevier.com/locate/nmcd
REVIEW
Cardiovascular risk and adrenergic overdrive in the metabolic syndrome Guido Grassi a,b,c,*, Fosca Quarti-Trevano a, Gino Seravalle b, Raffaella Dell’Oro a a
Clinica Medica, Dipartimento di Medicina Clinica, Prevenzione e Biotecnologie Sanitarie, Universita` Milano-Bicocca, Ospedale San Gerardo dei Tintori, Via Pergolesi 33, 20052 Monza, Milan, Italy b Istituto Auxologico Italiano, Milan, Italy c Centro Interuniversitario di Fisiologia Clinica e Ipertensione, Milan, Italy Received 14 December 2006; received in revised form 15 January 2007; accepted 16 January 2007
KEYWORDS Metabolic syndrome; Sympathetic nervous system; Central sympatholytic drugs; Obesity; Insulin
Abstract Aims: This paper will review the role of the sympathetic nervous system in the pathogenesis of the metabolic syndrome as well as its importance as target of non-pharmacologic and pharmacologic treatment. Data synthesis: Several indices of adrenergic drive, such as plasma norepinephrine, norepinephrine spillover from adrenergic nerve terminals and efferent postganglionic muscle sympathetic nerve traffic, have all shown an increase in the different conditions clustering in metabolic syndrome, such as obesity, hypertension and insulin resistance state. This increase: 1) appears to be potentiated in the metabolic syndrome; and 2) contributes to a large extent at the cardiovascular structural and functional alterations typical of the disease. Based on this evidence, nonpharmacologic life-style interventions as well as drug treatment procedures used in the therapeutic approach to the metabolic syndrome should be aimed at exerting not only favourable haemodynamic and metabolic effects but also pronounced sympathoinhibition. Conclusion: The data reviewed in this paper strongly support the relevance of the sympathetic nervous system in the pathogenesis of the metabolic syndrome and the importance of the sympathomodulation as a specific aim of therapeutic intervention. ª 2007 Elsevier B.V. All rights reserved.
* Corresponding author. Clinica Medica, Dipartimento di Medicina Clinica, Prevenzione e Biotecnologie Sanitarie, Universita ` MilanoBicocca, Ospedale San Gerardo dei Tintori, Via Pergolesi 33, 20052 Monza, Milan, Italy. Tel.: þ39 039 233 374; fax: þ39 039 322 274. E-mail address: [email protected] (G. Grassi). 0939-4753/$ - see front matter ª 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2007.01.004
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Introduction The clinical condition known as ‘‘metabolic syndrome’’, which represents the clustering of several cardiovascular and metabolic risk factors, has received in the past decade growing interest both from investigators and clinicians. This is due in large part to the ‘‘epidemic’’ impact of the disease, the complex pathophysiology, the adverse effects on cardiovascular health as well as the difficulties in (and frequently the disagreement on) the therapeutic approach [1,2]. Further elements of interest (and controversy) are represented by: 1) the difficulties in determining the effective epidemiological ‘‘weight’’ of the disease; and 2) the uncertain about the use of the best definition capable to reflect the overall risk profile associated with the syndrome. Recently a debate in the scientific arena has highlighted the limitations of the concept of ‘‘syndrome’’ [1], since: 1) frequently there is no standardization and uniformity between different laboratories in the determination of the different variables mentioned in the definition; and 2) there is no an unifying pathophysiological background for the disease definition (see below). The above mentioned limitations are strengthened by the evidence reported by two recent studies [3,4], that for both coronary artery disease and the overall cardiovascular risk profile the prognostic information associated with the syndrome is not greater that the sum of its parts. Despite these limitations, the most common definition is the one proposed by the ATP III definition [5,6] can be summarized as follows. One, in the population, the metabolic syndrome is so widespread as to affect about 1 out of 5 individuals. Two, this condition is common in both genders and all ethnic groups, with a high prevalence in both developed and developing countries from all continents. Three, the prevalence is closely age-related, with a peak of up to 40% in middle-age and elderly individuals. Four, only a limited number of subjects fit all of the criteria on which the different definitions are based. And five, no definition has a clear epidemiological edge over another. This implies that the simplest definition may be the most preferable because it would be the most practical. At present, the ATP III definition is the preferred choice, even when the definition recently proposed by the International Diabetes Federation [7] is taken into account. The present paper is aimed at examining the role of sympathetic nervous system in the pathogenesis of the disease as well as in the development of the
G. Grassi et al. target organ damage and cardiovascular risk profile associated with the metabolic syndrome. This will be followed by an analysis of the non-pharmacologic and pharmacologic interventions currently employed in the management of the disease and its complications, again with particular emphasis on the sympathetic hyperactivity as target of the therapeutic interventions.
Sympathetic activity in the metabolic syndrome Several are the mechanisms postulated as the major determinants of the syndrome. These include genetic factors, insulin resistance, atherogenic dyslipidemia, visceral obesity and chronic low grade inflammation [8e10]. It is likely that rather than acting independently, the above factors may interact each other, thus making the pathophysiological picture very difficult to be separately analysed [3]. This review article will examine the hypothesis that all the above mentioned mechanisms have a common pathogenetic background in the sympathetic nervous system activation. Indeed evidence has been provided that sympathetic neural influences are involved: 1) in the regulation of energy expenditure, by modulating basal metabolic rate and facilitating the thermogenic response to food intake [11]; and 2) in the homeostatic control of blood pressure values, by modulating heart rate, cardiac output and peripheral vascular resistance [12]. This has led to the hypothesis (schematically depicted in Fig. 1) that the sympathetic nervous system represents the common underlying pathogenetic link among the various components of the metabolic syndrome [11,12]. The data supporting this hypothesis will be reviewed thereafter with regard to the single components as well as to the metabolic syndrome as a separate clinical condition.
High blood pressure Both indirect and direct measures of sympathetic function indicate that a hyperadrenergic state characterizes high blood pressure state [13e15]. The evidence collected so far can be summarized as follows. First, a meta-analysis of the studies based on plasma norepinephrine as a marker of adrenergic function has shown that circulating levels of this substance are greater in hypertensive than in age-matched normotensive patients [13]. Second, direct assessment of muscle sympathetic
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Figure 1 Schematic drawing illustrating the relationships between sympathetic overactivity, the various components of the metabolic syndrome and its complications.
neural outflow in peripheral nerves (peroneal or radial) via the microneurographic technique has documented an increased central adrenergic outflow in hypertension [14]. Finally, studies based on the assessment of the spillover rate of norepinephrine into the systemic circulation, via the so-called norepinephrine radiotracer technique, have documented an increased release of the adrenergic neurotransmitter from nerve terminals in hypertensive states [15]. Some of the peculiar features of the sympathetic overactivity characterizing the hypertensive state deserve to be mentioned. These include the evidence that adrenergic overdrive: 1) affects organs such as the heart, the brain and the kidney that play a key role in the pathogenesis of the disease [15,16]; 2) parallels the degree of the blood pressure elevation as well as of the disease severity [14]; and 3) contributes to the development and progression of the target organ damage, particularly at the cardiac and vascular levels, characterizing hypertension [17]. A further peculiar feature of the neurogenic dysfunction is represented by the evidence that the central sympathetic overdrive is associated at peripheral vascular level with a down-regulation of b-adrenoreceptors [18]. Because these receptors are physiologically involved in facilitating the thermogenic responses to food [19], their dysfunction may explain why hypertensive patients may be more prone to overweight or obesity. Although the mechanisms responsible for the adrenergic overdrive of the hypertensive state are complex, it is likely that reflex, metabolic and humoral factors play a role. These include, for example, a dysfunction in cardiopulmonary receptor modulation of adrenergic drive as well as a state of insulin resistance or the renin-angiotensin-aldosterone activation [19]. The later two humoral factors are probably involved given the evidence that insulin and angiotensin II
exert pronounced sympathoexicitatory effects both in experimental animals and in man [20e22].
Obesity Resting heart rate values have frequently been reported to be elevated in obese individuals, suggesting the occurrence of a hyperadrenergic state [23]. This has been confirmed by evidence that plasma norepinephrine values are increased in subjects with a body mass index >30 Kg/m2 compared to lean individuals [24] and that the augmented circulating levels of the adrenergic neurotransmitter are dependent on a true increase in the sympathetic nerve firing rate, as documented by the results of the microneurographic studies published so far [25,26]. The studies performed over the years on this issue have provided further pathophysiological information, by showing, for example, that visceral (or central) adiposity displays greater levels of sympathetic activation and insulin resistance than the excess of peripheral body fat [27]. Furthermore, evidence has been provided that, when obesity and hypertension are combined in the same subject, the degree of sympathetic activation is further potentiated [26], thereby exposing the cardiovascular system to the adverse effects of a severe hyperadrenergic state. Finally the condition known as ‘‘obstructive sleep apnea’’, which displays a high prevalence in the obese state and is characterized by nocturnal episodes of hypoxemia and hypercapnia accompanied by an elevated risk of sudden death [28], has been documented to potentiate the already elevated sympathetic cardiovascular drive seen in obese patients [29]. As previously mentioned with regard to hypertension, the mechanisms underlying the hyperadrenergic drive in obese individuals include both reflex and
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G. Grassi et al. disease. With regard to the metabolic risk profile, it should be mentioned that insulin may not only be the triggering factor responsible for a hyperadrenergic state, but it may also be the target of the sympathetic stimulation [22]. In other words, insulin and the sympathetic nervous system may reciprocally reinforce each other in a vicious circle, thereby aggravating the deleterious effects their potentiation has on cardiovascular structure and function.
non-reflex factors, such as the condition of insulin resistance, the hyperleptinemic state and the chemoreflex stimulation in the sleep-apnea syndrome and triggered by the hypoxic episodes [21,22,25,28,29].
Metabolic syndrome The information provided so far on the sympathoexcitatory influences exerted by the single components of the disease suggest that in the metabolic syndrome sympathetic drive to the heart and peripheral circulation may be markedly potentiated. Furthermore, sympathetic activation characterizes another condition frequently detectable in the metabolic syndrome, i.e. the hyperglycemic state or the diabetic condition, particularly when associated to hypertension [30]. The sympathetic potentiation has indeed been confirmed to take place in patients with metabolic syndrome who, when compared with obese or hypertensive patients, almost invariably display greater heart rate values, increased circulating plasma levels of norepinephrine, higher sympathetic nerve firing rates and potentiated systemic norepinephrine spillover from adrenergic nerves (Fig. 2) [22,31,32]. Taken together, these findings provide univocal support for the notion that adrenergic drive is markedly potentiated in the metabolic syndrome and that almost all districts of the cardiovascular system participate in the phenomenon. This potentiation carries adverse prognostic significance, given the evidence that it further aggravates the already elevated cardiovascular and metabolic risk profile characterizing the single components of the
Sympathetic activation and target organ damage in the metabolic syndrome Cardiac hypertrophy A considerable number of studies have demonstrated that modifications of the left ventricular structure take place in a wide proportion of patients with metabolic syndrome [33e36]. Obviously, the precise figures of prevalence vary considerably from one study to another, depending particularly on the main characteristics of the population examined. In the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study, which is a cross-sectional survey carried out by our group in the Brianza area on a large number of subjects belonging to the general population and aged between 25 and 64 years, we found that about 16% had metabolic syndrome, according to the ATP III criteria [4]. These subjects, when evaluated by echocardiography, showed a greater left ventricular wall thickness and an increased left ventricular
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Adrenergic mechanisms and metabolic syndrome mass as index as compared to age-matched individuals without the disease. When the prevalence of the left ventricular hypertrophy, as defined according to common echocardiographic criteria (left ventricular mass 125 g/m2 in men and 100 g/m2 in women) was examined it has been found that about 27% of the subjects with metabolic syndrome display left ventricular hypertrophy. However, when in other studies the same assessment was carried out in selected populations, such as hypertensive or overweight patients referred to a specialist hospital center, the numbers appeared to be somewhat different and the percent figures of prevalence greater [37]. 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, however, that nonhaemodynamic mechanisms play a pathogenetic role. These include the sympathetic nervous system, given the evidence that both in experimental animal and human adrenergic factors may exert trophic effects on myocardium [38]. One of the best sample of these effects is represented by the evidence that in instrumented experimental animals an 8 week systemic infusion of norepinephrine at doses devoid of any blood pressure effect triggered an increase in cardiac mass [39]. In humans, however, the evidence is far from being so clearly defined, although some data have shown that in hypertensive patients with left ventricular hypertrophy the magnitude of the sympathetic activation, quantified via the cardiac norepinephrine spillover approach or the microneurographic nerve traffic recording technique, is much greater than in hypertensive patients who display the same degree of blood pressure elevation but no structural alteration of cardiac muscle [40,41]. Other potential pro-hypertrophic factors should not be disregarded, however. These include, for example, the renin-angiotensin-aldosterone stimulation described in a variety of conditions clustering in the metabolic syndrome, given the evidence that both angiotensin II and aldosterone exert trophy influences on cardiac myocites [42]. They also include however, metabolic factors, such as hyperinsulinemia, considering that insulin exerts marked stimulatory effects on the growth of the connective tissue and cardiac muscle [43].
477 features of large- and medium-size arteries have shown that abnormalities in arterial wall thickness, arterial distensibility and vascular compliance do occur in the metabolic syndrome [44,45]. The alterations appear to be: 1) homogeneously distributed along the vascular tree, with muscle arteries more markedly affected than elastic arteries; 2) detectable in both younger and older patient; and 3) related to a greater extent to an augmented visceral fat accumulation. As already mentioned with regard to cardiac hypertrophy, it is likely that adrenergic (sympathetic overactivity) and metabolic (insulin resistance and hyperleptinemia) factors play a role [44]. However, the contribution of other variables, such as endothelial dysfunction, alterations in the haemocoagulative process as well as the proatherogenic profile of the patients with metabolic syndrome, should also be considered. It is therefore likely that the structural and functional alterations of the arterial vascular tree characterizing the metabolic syndrome represent multifactorial abnormalities involving neural, metabolic and haemodynamic variables. Two other features of the vascular alterations characterizing metabolic syndrome deserve to be mentioned. First, these alterations have an adverse impact on cardiovascular risk profile because they may: 1) favor the cascade of events leading to the appearance and progression of vascular atherosclerotic plaque; 2) contribute to the development of cardiac hypertrophy by increasing cardiac afterload; and 3) when affecting specific vascular districts such as the coronary circulation, promote the occurrence of coronary heart disease to which patients with metabolic syndrome are frequently exposed [44e46]. Second, the above mentioned alterations may favour the development and progression of an increased intima-media thickness when they occur at the level of the carotid arteries. This may explain why patients with metabolic syndrome display, in the longitudinal follow-up of the already mentioned PAMELA Study, a reduced survival rate as compared with agematched subjects without metabolic syndrome [4] (Fig. 3).
Therapeutic implications Life-style changes
Vascular alterations Several studies using various and sophisticated approaches to assess the structural and functional
Most guidelines on the prevention of cardiovascular disease recommend a treatment based on lifestyle modifications for the metabolic syndrome [5,47,48]. This includes: 1) a reduction in body
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In obese subjects exposed to 16 weeks of a low energy diet, a modest reduction in body weight was accompanied by a marked reduction in both plasma norepinephrine and muscle sympathetic nerve traffic with a concomitant recovery of the impaired baroreflex ability to modulate sympathetic tone [52]. This is in line with the data collected in middle-aged obese individuals with a metabolic syndrome, in whom a 7% reduction in body weight by implementation of a hypocaloric diet significantly reduced the norepinephrine spillover rate and muscle sympathetic nerve activity while enhancing the baroreflex ability to modulate the sinus node activity and improving the metabolic syndrome components [53].
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Figure 3 KaplaneMeier survival curves for cardiovascular death and all cause death in subjects without (MS) and with (MSþ) metabolic syndrome. Figure modified from Ref. [4], by permission.
weight via a low-calorie diet and an increase in physical activity; and 2) a reduction in the consumption of animal products and an increase in the consumption of vegetables, fish oil, and foods rich in polyunsaturated fat. The rationale for lifestyle modifications for the metabolic syndrome is well established. Even a modest weight loss (7% to 10% of body weight) results in a decrease in fat mass, blood pressure, plasma glucose, low-density lipoproteins, and plasma triglycerides, thereby favorably affecting all components of the metabolic syndrome [49]. In addition, similar beneficial effects have been observed in subjects exposed to exercise programs and lifestyle modifications, which have been shown to markedly reduce the incidence of new-onset diabetes, thereby offsetting a major risk factor in individuals with a metabolic syndrome [50,51]. Furthermore, these modifications also reduce the risk of developing hypertension, which is extremely high in subjects whose blood pressure is in the high normal range as is most often the case in the metabolic syndrome [5,50]. Finally, lifestyle modifications favorably affect the sympathetic hyperactivity characterizing the metabolic syndrome as well as its components.
In the metabolic syndrome, drug treatment is usually recommended when there is hypertension, diabetes, or frank dyslipidemia, i.e. conditions in which antihypertensive, antidiabetic, and lipid lowering agents have been shown to exert cardiovascular protective effects [5]. As far as antihypertensive drug treatment is concerned, preferred antihypertensive drugs in the treatment of the metabolic syndrome are calcium channel antagonists, ACE inhibitors, and angiotensin II antagonists because they are lipid neutral and more effective than diuretics and b-blockers in preventing progression or favoring regression of left ventricular hypertrophy, small vessel alterations, and subclinical atherosclerosis, i.e. organ alterations common in the metabolic syndrome [5,47]. ACE inhibitors and angiotensin II antagonists, however, have special advantages, including: 1) a lower incidence of new-onset diabetes compared with calcium antagonists [54]; 2) a reduced incidence of new-onset diabetes when tested against placebo, which suggests that their mechanism of action is truly antidiabetogenic [54]; and 3) a sustained antiproteinuric effect [47]. Based on the mechanistic evidence reported above, use of sympathoinhibitory drugs should also be considered. Sympathoinhibition cannot be obtained by calcium antagonists whose administration is accompanied by an increase, or at best, no change in sympathetic activity [55]. It can, however, be obtained by administration of ACE inhibitors or angiotensin II antagonists because their ability to act against the renin-angiotensin system opposes the sympathoexcitatory effects of angiotensin II [55]. This has recently been confirmed by our group in a study in which a consistent reduction in sympathetic nerve traffic was detected in obese hypertensive subjects following a 12 week
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Figure 4 Effects of an angiotensin II receptor antagonist (candesartan) or a diuretic (HCTZ) treatment on muscle sympathetic nerve traffic (MSNA) and insulin resistance (IRI) in obese hypertensives. Data, shown as means SEM, refer to values obtained before (B) and following 12 weeks (wks) of treatment (T). Asterisks (*p < 0.05, **p < 0.01) refer to the statistical significance between groups. Figure modified from Ref. [57], by permission.
administration of an angiotensin II receptor antagonist (Fig. 4) [56]. A more direct and powerful sympathoinhibition, however, can be achieved by peripheral sympathomoderating agents, such as a1-receptor blockers, and by drugs acting centrally on a2-adrenergic or I1 imidazoline receptors [55,57].
Conclusions The metabolic syndrome represents a condition characterized by the clustering of alterations in glucose, lipid metabolism, and blood pressure. The mechanisms responsible for the appearance and progression of the disease are multifold and complex. A primary role, however, should be ascribed to the sympathetic activation, which is a hallmark of the disease as well as of several of its most common components (visceral obesity and blood pressure elevation). Treatment of the metabolic syndrome is based on lifestyle modifications and on use of drugs that are effective in reducing the haemodynamic, metabolic and neuroadrenergic abnormalities commonly characterizing the disease.
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481 [53] Straznicky NE, Lambert EA, Lambert GW, Masuo K, Esler MD, Nestel PJ. Effects of dietary weight loss of sympathetic activity and cardiac risk factors associated with the metabolic syndrome. J Clin Endocrinol Metab 2005;90:5998e6005. [54] Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens 2006;24:3e10. [55] Grassi G. Counteracting the sympathetic nervous system in essential hypertension. Curr Opin Nephrol Hypertens 2004; 13:513e9. [56] Grassi G, Seravalle G, Dell’Oro R, Quarti Trevano F, Bombelli M, Scopelliti F, et al. Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: results of the CROSS study. J Hypertens 2003;21: 1761e9. [57] Pessina AC, Ciccariello L, Perrone F, Stoico V, Gussoni G, Scotti A, et al. Clinical efficacy and tolerability of alphablocker doxazozin as add-on therapy in patients with hypertension and impaired glucose metabolism. Nutr Metab Cardiovasc Dis 2006;16:137e47.
www.elsevier.com/locate/nmcd
REVIEW
Cardiovascular risk and adrenergic overdrive in the metabolic syndrome Guido Grassi a,b,c,*, Fosca Quarti-Trevano a, Gino Seravalle b, Raffaella Dell’Oro a a
Clinica Medica, Dipartimento di Medicina Clinica, Prevenzione e Biotecnologie Sanitarie, Universita` Milano-Bicocca, Ospedale San Gerardo dei Tintori, Via Pergolesi 33, 20052 Monza, Milan, Italy b Istituto Auxologico Italiano, Milan, Italy c Centro Interuniversitario di Fisiologia Clinica e Ipertensione, Milan, Italy Received 14 December 2006; received in revised form 15 January 2007; accepted 16 January 2007
KEYWORDS Metabolic syndrome; Sympathetic nervous system; Central sympatholytic drugs; Obesity; Insulin
Abstract Aims: This paper will review the role of the sympathetic nervous system in the pathogenesis of the metabolic syndrome as well as its importance as target of non-pharmacologic and pharmacologic treatment. Data synthesis: Several indices of adrenergic drive, such as plasma norepinephrine, norepinephrine spillover from adrenergic nerve terminals and efferent postganglionic muscle sympathetic nerve traffic, have all shown an increase in the different conditions clustering in metabolic syndrome, such as obesity, hypertension and insulin resistance state. This increase: 1) appears to be potentiated in the metabolic syndrome; and 2) contributes to a large extent at the cardiovascular structural and functional alterations typical of the disease. Based on this evidence, nonpharmacologic life-style interventions as well as drug treatment procedures used in the therapeutic approach to the metabolic syndrome should be aimed at exerting not only favourable haemodynamic and metabolic effects but also pronounced sympathoinhibition. Conclusion: The data reviewed in this paper strongly support the relevance of the sympathetic nervous system in the pathogenesis of the metabolic syndrome and the importance of the sympathomodulation as a specific aim of therapeutic intervention. ª 2007 Elsevier B.V. All rights reserved.
* Corresponding author. Clinica Medica, Dipartimento di Medicina Clinica, Prevenzione e Biotecnologie Sanitarie, Universita ` MilanoBicocca, Ospedale San Gerardo dei Tintori, Via Pergolesi 33, 20052 Monza, Milan, Italy. Tel.: þ39 039 233 374; fax: þ39 039 322 274. E-mail address: [email protected] (G. Grassi). 0939-4753/$ - see front matter ª 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2007.01.004
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Introduction The clinical condition known as ‘‘metabolic syndrome’’, which represents the clustering of several cardiovascular and metabolic risk factors, has received in the past decade growing interest both from investigators and clinicians. This is due in large part to the ‘‘epidemic’’ impact of the disease, the complex pathophysiology, the adverse effects on cardiovascular health as well as the difficulties in (and frequently the disagreement on) the therapeutic approach [1,2]. Further elements of interest (and controversy) are represented by: 1) the difficulties in determining the effective epidemiological ‘‘weight’’ of the disease; and 2) the uncertain about the use of the best definition capable to reflect the overall risk profile associated with the syndrome. Recently a debate in the scientific arena has highlighted the limitations of the concept of ‘‘syndrome’’ [1], since: 1) frequently there is no standardization and uniformity between different laboratories in the determination of the different variables mentioned in the definition; and 2) there is no an unifying pathophysiological background for the disease definition (see below). The above mentioned limitations are strengthened by the evidence reported by two recent studies [3,4], that for both coronary artery disease and the overall cardiovascular risk profile the prognostic information associated with the syndrome is not greater that the sum of its parts. Despite these limitations, the most common definition is the one proposed by the ATP III definition [5,6] can be summarized as follows. One, in the population, the metabolic syndrome is so widespread as to affect about 1 out of 5 individuals. Two, this condition is common in both genders and all ethnic groups, with a high prevalence in both developed and developing countries from all continents. Three, the prevalence is closely age-related, with a peak of up to 40% in middle-age and elderly individuals. Four, only a limited number of subjects fit all of the criteria on which the different definitions are based. And five, no definition has a clear epidemiological edge over another. This implies that the simplest definition may be the most preferable because it would be the most practical. At present, the ATP III definition is the preferred choice, even when the definition recently proposed by the International Diabetes Federation [7] is taken into account. The present paper is aimed at examining the role of sympathetic nervous system in the pathogenesis of the disease as well as in the development of the
G. Grassi et al. target organ damage and cardiovascular risk profile associated with the metabolic syndrome. This will be followed by an analysis of the non-pharmacologic and pharmacologic interventions currently employed in the management of the disease and its complications, again with particular emphasis on the sympathetic hyperactivity as target of the therapeutic interventions.
Sympathetic activity in the metabolic syndrome Several are the mechanisms postulated as the major determinants of the syndrome. These include genetic factors, insulin resistance, atherogenic dyslipidemia, visceral obesity and chronic low grade inflammation [8e10]. It is likely that rather than acting independently, the above factors may interact each other, thus making the pathophysiological picture very difficult to be separately analysed [3]. This review article will examine the hypothesis that all the above mentioned mechanisms have a common pathogenetic background in the sympathetic nervous system activation. Indeed evidence has been provided that sympathetic neural influences are involved: 1) in the regulation of energy expenditure, by modulating basal metabolic rate and facilitating the thermogenic response to food intake [11]; and 2) in the homeostatic control of blood pressure values, by modulating heart rate, cardiac output and peripheral vascular resistance [12]. This has led to the hypothesis (schematically depicted in Fig. 1) that the sympathetic nervous system represents the common underlying pathogenetic link among the various components of the metabolic syndrome [11,12]. The data supporting this hypothesis will be reviewed thereafter with regard to the single components as well as to the metabolic syndrome as a separate clinical condition.
High blood pressure Both indirect and direct measures of sympathetic function indicate that a hyperadrenergic state characterizes high blood pressure state [13e15]. The evidence collected so far can be summarized as follows. First, a meta-analysis of the studies based on plasma norepinephrine as a marker of adrenergic function has shown that circulating levels of this substance are greater in hypertensive than in age-matched normotensive patients [13]. Second, direct assessment of muscle sympathetic
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Figure 1 Schematic drawing illustrating the relationships between sympathetic overactivity, the various components of the metabolic syndrome and its complications.
neural outflow in peripheral nerves (peroneal or radial) via the microneurographic technique has documented an increased central adrenergic outflow in hypertension [14]. Finally, studies based on the assessment of the spillover rate of norepinephrine into the systemic circulation, via the so-called norepinephrine radiotracer technique, have documented an increased release of the adrenergic neurotransmitter from nerve terminals in hypertensive states [15]. Some of the peculiar features of the sympathetic overactivity characterizing the hypertensive state deserve to be mentioned. These include the evidence that adrenergic overdrive: 1) affects organs such as the heart, the brain and the kidney that play a key role in the pathogenesis of the disease [15,16]; 2) parallels the degree of the blood pressure elevation as well as of the disease severity [14]; and 3) contributes to the development and progression of the target organ damage, particularly at the cardiac and vascular levels, characterizing hypertension [17]. A further peculiar feature of the neurogenic dysfunction is represented by the evidence that the central sympathetic overdrive is associated at peripheral vascular level with a down-regulation of b-adrenoreceptors [18]. Because these receptors are physiologically involved in facilitating the thermogenic responses to food [19], their dysfunction may explain why hypertensive patients may be more prone to overweight or obesity. Although the mechanisms responsible for the adrenergic overdrive of the hypertensive state are complex, it is likely that reflex, metabolic and humoral factors play a role. These include, for example, a dysfunction in cardiopulmonary receptor modulation of adrenergic drive as well as a state of insulin resistance or the renin-angiotensin-aldosterone activation [19]. The later two humoral factors are probably involved given the evidence that insulin and angiotensin II
exert pronounced sympathoexicitatory effects both in experimental animals and in man [20e22].
Obesity Resting heart rate values have frequently been reported to be elevated in obese individuals, suggesting the occurrence of a hyperadrenergic state [23]. This has been confirmed by evidence that plasma norepinephrine values are increased in subjects with a body mass index >30 Kg/m2 compared to lean individuals [24] and that the augmented circulating levels of the adrenergic neurotransmitter are dependent on a true increase in the sympathetic nerve firing rate, as documented by the results of the microneurographic studies published so far [25,26]. The studies performed over the years on this issue have provided further pathophysiological information, by showing, for example, that visceral (or central) adiposity displays greater levels of sympathetic activation and insulin resistance than the excess of peripheral body fat [27]. Furthermore, evidence has been provided that, when obesity and hypertension are combined in the same subject, the degree of sympathetic activation is further potentiated [26], thereby exposing the cardiovascular system to the adverse effects of a severe hyperadrenergic state. Finally the condition known as ‘‘obstructive sleep apnea’’, which displays a high prevalence in the obese state and is characterized by nocturnal episodes of hypoxemia and hypercapnia accompanied by an elevated risk of sudden death [28], has been documented to potentiate the already elevated sympathetic cardiovascular drive seen in obese patients [29]. As previously mentioned with regard to hypertension, the mechanisms underlying the hyperadrenergic drive in obese individuals include both reflex and
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G. Grassi et al. disease. With regard to the metabolic risk profile, it should be mentioned that insulin may not only be the triggering factor responsible for a hyperadrenergic state, but it may also be the target of the sympathetic stimulation [22]. In other words, insulin and the sympathetic nervous system may reciprocally reinforce each other in a vicious circle, thereby aggravating the deleterious effects their potentiation has on cardiovascular structure and function.
non-reflex factors, such as the condition of insulin resistance, the hyperleptinemic state and the chemoreflex stimulation in the sleep-apnea syndrome and triggered by the hypoxic episodes [21,22,25,28,29].
Metabolic syndrome The information provided so far on the sympathoexcitatory influences exerted by the single components of the disease suggest that in the metabolic syndrome sympathetic drive to the heart and peripheral circulation may be markedly potentiated. Furthermore, sympathetic activation characterizes another condition frequently detectable in the metabolic syndrome, i.e. the hyperglycemic state or the diabetic condition, particularly when associated to hypertension [30]. The sympathetic potentiation has indeed been confirmed to take place in patients with metabolic syndrome who, when compared with obese or hypertensive patients, almost invariably display greater heart rate values, increased circulating plasma levels of norepinephrine, higher sympathetic nerve firing rates and potentiated systemic norepinephrine spillover from adrenergic nerves (Fig. 2) [22,31,32]. Taken together, these findings provide univocal support for the notion that adrenergic drive is markedly potentiated in the metabolic syndrome and that almost all districts of the cardiovascular system participate in the phenomenon. This potentiation carries adverse prognostic significance, given the evidence that it further aggravates the already elevated cardiovascular and metabolic risk profile characterizing the single components of the
Sympathetic activation and target organ damage in the metabolic syndrome Cardiac hypertrophy A considerable number of studies have demonstrated that modifications of the left ventricular structure take place in a wide proportion of patients with metabolic syndrome [33e36]. Obviously, the precise figures of prevalence vary considerably from one study to another, depending particularly on the main characteristics of the population examined. In the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study, which is a cross-sectional survey carried out by our group in the Brianza area on a large number of subjects belonging to the general population and aged between 25 and 64 years, we found that about 16% had metabolic syndrome, according to the ATP III criteria [4]. These subjects, when evaluated by echocardiography, showed a greater left ventricular wall thickness and an increased left ventricular
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Adrenergic mechanisms and metabolic syndrome mass as index as compared to age-matched individuals without the disease. When the prevalence of the left ventricular hypertrophy, as defined according to common echocardiographic criteria (left ventricular mass 125 g/m2 in men and 100 g/m2 in women) was examined it has been found that about 27% of the subjects with metabolic syndrome display left ventricular hypertrophy. However, when in other studies the same assessment was carried out in selected populations, such as hypertensive or overweight patients referred to a specialist hospital center, the numbers appeared to be somewhat different and the percent figures of prevalence greater [37]. 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, however, that nonhaemodynamic mechanisms play a pathogenetic role. These include the sympathetic nervous system, given the evidence that both in experimental animal and human adrenergic factors may exert trophic effects on myocardium [38]. One of the best sample of these effects is represented by the evidence that in instrumented experimental animals an 8 week systemic infusion of norepinephrine at doses devoid of any blood pressure effect triggered an increase in cardiac mass [39]. In humans, however, the evidence is far from being so clearly defined, although some data have shown that in hypertensive patients with left ventricular hypertrophy the magnitude of the sympathetic activation, quantified via the cardiac norepinephrine spillover approach or the microneurographic nerve traffic recording technique, is much greater than in hypertensive patients who display the same degree of blood pressure elevation but no structural alteration of cardiac muscle [40,41]. Other potential pro-hypertrophic factors should not be disregarded, however. These include, for example, the renin-angiotensin-aldosterone stimulation described in a variety of conditions clustering in the metabolic syndrome, given the evidence that both angiotensin II and aldosterone exert trophy influences on cardiac myocites [42]. They also include however, metabolic factors, such as hyperinsulinemia, considering that insulin exerts marked stimulatory effects on the growth of the connective tissue and cardiac muscle [43].
477 features of large- and medium-size arteries have shown that abnormalities in arterial wall thickness, arterial distensibility and vascular compliance do occur in the metabolic syndrome [44,45]. The alterations appear to be: 1) homogeneously distributed along the vascular tree, with muscle arteries more markedly affected than elastic arteries; 2) detectable in both younger and older patient; and 3) related to a greater extent to an augmented visceral fat accumulation. As already mentioned with regard to cardiac hypertrophy, it is likely that adrenergic (sympathetic overactivity) and metabolic (insulin resistance and hyperleptinemia) factors play a role [44]. However, the contribution of other variables, such as endothelial dysfunction, alterations in the haemocoagulative process as well as the proatherogenic profile of the patients with metabolic syndrome, should also be considered. It is therefore likely that the structural and functional alterations of the arterial vascular tree characterizing the metabolic syndrome represent multifactorial abnormalities involving neural, metabolic and haemodynamic variables. Two other features of the vascular alterations characterizing metabolic syndrome deserve to be mentioned. First, these alterations have an adverse impact on cardiovascular risk profile because they may: 1) favor the cascade of events leading to the appearance and progression of vascular atherosclerotic plaque; 2) contribute to the development of cardiac hypertrophy by increasing cardiac afterload; and 3) when affecting specific vascular districts such as the coronary circulation, promote the occurrence of coronary heart disease to which patients with metabolic syndrome are frequently exposed [44e46]. Second, the above mentioned alterations may favour the development and progression of an increased intima-media thickness when they occur at the level of the carotid arteries. This may explain why patients with metabolic syndrome display, in the longitudinal follow-up of the already mentioned PAMELA Study, a reduced survival rate as compared with agematched subjects without metabolic syndrome [4] (Fig. 3).
Therapeutic implications Life-style changes
Vascular alterations Several studies using various and sophisticated approaches to assess the structural and functional
Most guidelines on the prevention of cardiovascular disease recommend a treatment based on lifestyle modifications for the metabolic syndrome [5,47,48]. This includes: 1) a reduction in body
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In obese subjects exposed to 16 weeks of a low energy diet, a modest reduction in body weight was accompanied by a marked reduction in both plasma norepinephrine and muscle sympathetic nerve traffic with a concomitant recovery of the impaired baroreflex ability to modulate sympathetic tone [52]. This is in line with the data collected in middle-aged obese individuals with a metabolic syndrome, in whom a 7% reduction in body weight by implementation of a hypocaloric diet significantly reduced the norepinephrine spillover rate and muscle sympathetic nerve activity while enhancing the baroreflex ability to modulate the sinus node activity and improving the metabolic syndrome components [53].
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weight via a low-calorie diet and an increase in physical activity; and 2) a reduction in the consumption of animal products and an increase in the consumption of vegetables, fish oil, and foods rich in polyunsaturated fat. The rationale for lifestyle modifications for the metabolic syndrome is well established. Even a modest weight loss (7% to 10% of body weight) results in a decrease in fat mass, blood pressure, plasma glucose, low-density lipoproteins, and plasma triglycerides, thereby favorably affecting all components of the metabolic syndrome [49]. In addition, similar beneficial effects have been observed in subjects exposed to exercise programs and lifestyle modifications, which have been shown to markedly reduce the incidence of new-onset diabetes, thereby offsetting a major risk factor in individuals with a metabolic syndrome [50,51]. Furthermore, these modifications also reduce the risk of developing hypertension, which is extremely high in subjects whose blood pressure is in the high normal range as is most often the case in the metabolic syndrome [5,50]. Finally, lifestyle modifications favorably affect the sympathetic hyperactivity characterizing the metabolic syndrome as well as its components.
In the metabolic syndrome, drug treatment is usually recommended when there is hypertension, diabetes, or frank dyslipidemia, i.e. conditions in which antihypertensive, antidiabetic, and lipid lowering agents have been shown to exert cardiovascular protective effects [5]. As far as antihypertensive drug treatment is concerned, preferred antihypertensive drugs in the treatment of the metabolic syndrome are calcium channel antagonists, ACE inhibitors, and angiotensin II antagonists because they are lipid neutral and more effective than diuretics and b-blockers in preventing progression or favoring regression of left ventricular hypertrophy, small vessel alterations, and subclinical atherosclerosis, i.e. organ alterations common in the metabolic syndrome [5,47]. ACE inhibitors and angiotensin II antagonists, however, have special advantages, including: 1) a lower incidence of new-onset diabetes compared with calcium antagonists [54]; 2) a reduced incidence of new-onset diabetes when tested against placebo, which suggests that their mechanism of action is truly antidiabetogenic [54]; and 3) a sustained antiproteinuric effect [47]. Based on the mechanistic evidence reported above, use of sympathoinhibitory drugs should also be considered. Sympathoinhibition cannot be obtained by calcium antagonists whose administration is accompanied by an increase, or at best, no change in sympathetic activity [55]. It can, however, be obtained by administration of ACE inhibitors or angiotensin II antagonists because their ability to act against the renin-angiotensin system opposes the sympathoexcitatory effects of angiotensin II [55]. This has recently been confirmed by our group in a study in which a consistent reduction in sympathetic nerve traffic was detected in obese hypertensive subjects following a 12 week
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administration of an angiotensin II receptor antagonist (Fig. 4) [56]. A more direct and powerful sympathoinhibition, however, can be achieved by peripheral sympathomoderating agents, such as a1-receptor blockers, and by drugs acting centrally on a2-adrenergic or I1 imidazoline receptors [55,57].
Conclusions The metabolic syndrome represents a condition characterized by the clustering of alterations in glucose, lipid metabolism, and blood pressure. The mechanisms responsible for the appearance and progression of the disease are multifold and complex. A primary role, however, should be ascribed to the sympathetic activation, which is a hallmark of the disease as well as of several of its most common components (visceral obesity and blood pressure elevation). Treatment of the metabolic syndrome is based on lifestyle modifications and on use of drugs that are effective in reducing the haemodynamic, metabolic and neuroadrenergic abnormalities commonly characterizing the disease.
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