Endothelial dysfunction in metabolic syndrome: Prevalence, pathogenesis and management

Nutrition, Metabolism & Cardiovascular Diseases (2010) 20, 140e146 available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/nmcd

REVIEW

Endothelial dysfunction in metabolic syndrome: Prevalence, pathogenesis and management K. Tziomalos a,b, V.G. Athyros c, A. Karagiannis c, D.P. Mikhailidis a,b,* a

Department of Clinical Biochemistry (Vascular Prevention Clinic), Royal Free Hospital Campus, University College Medical School, University College London (UCL), London, UK b Department of Surgery, Royal Free Hospital Campus, University College Medical School, University College London (UCL), London, UK c Second Propedeutic Department of Internal Medicine, Aristotle University, Hippokration Hospital, Thessaloniki, Greece Received 9 March 2009; received in revised form 9 June 2009; accepted 3 August 2009

KEYWORDS Metabolic syndrome; Endothelial dysfunction; Lifestyle measures; Statins; Metformin

Abstract The metabolic syndrome (MetS) is characterized by the presence of central obesity, impaired glucose metabolism, dyslipidemia and hypertension. Several studies showed that MetS is associated with increased risk for type 2 diabetes mellitus (T2DM) and vascular events. All components of MetS have adverse effects on the endothelium. Endothelial dysfunction plays a role in the pathogenesis of atherosclerosis and might also increase the risk for insulin resistance and T2DM. We review the prevalence and pathogenesis of endothelial dysfunction in MetS. We also discuss the potential effects of lifestyle measures and pharmacological interventions on endothelial function in these patients. It remains to be established whether improving endothelial function in MetS will reduce the risk for T2DM and vascular events. ª 2009 Elsevier B.V. All rights reserved.

Introduction The metabolic syndrome (MetS) is characterized by the presence of central obesity, impaired fasting glucose (IFG), dyslipidemia and hypertension [1]. The prevalence of MetS

* Corresponding author at: Department of Clinical Biochemistry, Royal Free Hospital Campus, University College Medical School, University College London (UCL), Pond Street, London NW3 2QG, UK. Tel.: þ44 20 7830 2258; fax: þ44 20 7830 2235. E-mail address: [email protected] (D.P. Mikhailidis).

is approximately 34.6% in the United States [2], 17.8e34.0% in Europe [3,4] and 12.8e41.1% in Asia [3]. Several studies showed that MetS is associated with increased risk for type 2 diabetes mellitus (T2DM) [5] and vascular morbidity and mortality [6]. Endothelial dysfunction appears to play a role in the pathogenesis of atherosclerosis [7,8]. Prospective studies showed that endothelial dysfunction predicts vascular events in patients with or without established vascular disease [8]. Endothelial dysfunction also appears to be implicated in the pathogenesis of T2DM [9e11]. Since all components of MetS have adverse effects on the endothelium [12e16], endothelial

0939-4753/$ - see front matter ª 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2009.08.006

Endothelial dysfunction in metabolic syndrome dysfunction might be more prevalent in patients with MetS and could play a role in the increased risk for vascular disease and T2DM in this population. We review the prevalence and pathogenesis of endothelial dysfunction in MetS. We also discuss the potential effects of lifestyle measures and pharmacological interventions on endothelial function in patients with MetS.

Markers of endothelial function in patients with MetS A detailed description of the methods of assessing endothelial function is beyond the scope of this review. Several relevant comprehensive reviews have been published [17,18]. In brief, these methods assess: (a) endothelial dysfunction, which is mainly manifested as impaired vasodilation caused by reduced nitric oxide (NO) availability. Endothelium-dependent vasodilation (EDV) is evaluated in response to interventions that stimulate NO release [either pharmacological (mainly acetylcholine) or mechanical (flow-mediated dilation, FMD)] [17,18]. EDV can be assessed in the macrocirculation (either in large coronary arteries with quantitative coronary angiography or in peripheral arteries with ultrasound-measured FMD) [17,18]. EDV can also be evaluated in the forearm microcirculation (resistance vessels) with venous occlusion plethysmography [17,18]. EDV assessed in large conduit vessels might be more clinically relevant since atherosclerosis primarily affects the macrocirculation [17,18]. However, venous occlusion plethysmography-assessed EDV in the forearm correlates with EDV in the coronary arteries and both are associated with increased risk for vascular events [8]. (b) Endothelial activation, i.e. the acquisition of inflammatory properties by the endothelium. Endothelial activation is evaluated by measuring circulating levels of adhesion molecules [soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and E-selectin] and high sensitivity C-reactive protein (hsCRP); and (c) endothelial damage, by measuring serum levels of von Willebrand factor (vWF), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), as well as circulating mature endothelial cells, endothelial progenitor cells and endothelial microparticles [17,18]. However, some of these markers are not specific of endothelial dysfunction [17,18]. Circulating levels of adhesion molecules increase in inflammatory conditions [17,18] and PAI-1 levels are associated with insulin resistance, which is an important feature of MetS [19,20]. It was suggested that microalbuminuria might also represent a marker of generalized endothelial dysfunction [21]. Several studies showed that EDV is impaired in patients with MetS [22e27]. In a recent large study in 1016 elderly subjects, forearm EDV in response to acetylcholine infusion assessed with venous occlusion plethysmography was reduced in MetS [28]. However, FMD in the brachial artery did not differ between patients with MetS and control subjects in the same report [28]. In another recent large study in 1417 men, MetS was not associated with impaired FMD [29]. Circulating markers of endothelial dysfunction including sICAM-1 [30], tPA antigen [31] and PAI-1 levels and activity are also elevated in MetS [26,31e33]. It was also reported

141 that plasma PAI-1 levels and activity rise as the number of MetS components increases [32,33]. Patients with MetS also have higher circulating levels of the vasoconstrictor agent endothelin-1 [34]. Microalbuminuria is more common in patients with MetS [35,36]. In addition, the prevalence of microalbuminuria increases when more MetS components are present [35,36]. It should also be noted that according to the World Health Organization (WHO), microalbuminuria is one of the diagnostic criteria of MetS [37].

Pathogenesis of endothelial dysfunction in MetS Several mechanisms are implicated in the pathogenesis of endothelial dysfunction. Decreased NO availability appears to play a major role and may result from reduced NO production and/or increased inactivation by reactive oxygen species [17]. In addition, reduced availability of other vasodilating agents (including prostacyclin and endothelium-derived hyperpolarizing factors) and/or increased production or activity of vasoconstrictive substances (including endothelin-1 and angiotensin II) are also implicated [17]. All the components of MetS can individually impair endothelial function. Several studies showed that both hypertension [12,38] and T2DM are associated with endothelial dysfunction [13,39]. Even in normotensive subjects, endothelial function progressively deteriorates as blood pressure (BP) rises [12]. In some studies, non-diabetic patients with IFG also showed reduced EDV [40,41] but this was not confirmed by others [42]. Experimental glucose loading also impairs endothelial function [43,44] but not in all studies [45]. Besides hypertension and dysglycemia, abdominal obesity is also associated with endothelial dysfunction [14,46]. It was also shown that the severity of endothelial dysfunction correlates with the degree of visceral adiposity [47]. Impaired endothelial function was also reported in patients with low levels of high density lipoprotein cholesterol (HDL-C) [16,48]. HDL-C levels independently correlate with EDV [16,48]. Reduced EDV was also reported in patients with elevated triglyceride (TG) levels in some [15,49] but not all studies [50,51]. An increasing number of MetS components is associated with more severe impairment in endothelial function [24,28,52]. Regarding the contribution of each MetS component in the pathogenesis of endothelial dysfunction in patients with MetS, a large study (n Z 1016) reported that TG levels, waist circumference and diastolic BP independently predicted EDV [28]. Waist circumference was more strongly related to endothelial dysfunction followed by TG levels and diastolic BP [28]. In other reports, only HDL-C levels [23] or BP [52] was independently associated with reduced FMD in patients with MetS. Insulin resistance is an important component of MetS [53] although it is not always present [54,55]. Insulin stimulates the production and release of NO by endothelial cells resulting in vasodilation [9,56]. However, the vasodilating action of insulin is attenuated in insulin-resistant states [57,58]. In addition, insulin impaired endothelial function by inducing oxidative stress [59] and stimulated the release of endothelin-1 in some studies [60,w1]. Insulin resistance was independently associated with reduced EDV

142

K. Tziomalos et al.

in most studies [46,57] but not in all [24,29]. In a recent large study (n Z 1016), acetylcholine-induced vasodilation correlated with insulin resistance whereas FMD did not [28]. Insulin resistance also correlated with sICAM-1, sVCAM-1 and E-selectin levels [w2] and was associated with the presence of microalbuminuria [w3]. MetS is considered a pro-inflammatory condition [29,32,w4]. Several studies showed that hsCRP levels are elevated in MetS [29,32,w4] and rise as the number of MetS components increases [32,w4]. This pro-inflammatory state might play a role in the pathogenesis of endothelial dysfunction in MetS, since elevated hsCRP levels are associated with impaired EDV [w5,w6] although not in all studies [w7,w8]. The correlation between hsCRP levels and FMD was also observed in patients with MetS [w9]. Patients with MetS have lower circulating adiponectin [26,32,55] and higher resistin [55,w10] and leptin levels [32]. These alterations in adipokine levels may contribute to the development of endothelial dysfunction [w11e w14]. Adiponectin levels independently correlated with EDV in hypertensive patients [w11] and in some studies in

Table 1

healthy subjects or patients with IFG, IGT or T2DM [w12,w13] but not in all [w15,w16]. Leptin also induces NO-independent vasodilation [w17,w18] and leptin levels directly correlate with EDV in obese patients [w14]. In patients with MetS, resistin levels correlate with EDV [26] but this association was not observed in patients with IGT or T2DM [w16]. Serum uric acid levels are raised in MetS [w19,w20]. Elevated serum uric acid levels appear to be associated with endothelial dysfunction [w19,w21] and may play a role in the increased vascular risk of patients with MetS [w20].Table 1 It is of interest that endothelial dysfunction might play a role in the pathogenesis of insulin resistance and T2DM [9]. Endothelial dysfunction in the skeletal muscle might lead to decreased blood flow, which in turn could contribute to insulin resistance [9]. In prospective studies, impaired EDV was associated with increased risk for T2DM in healthy postmenopausal women [10] and in hypertensive patients [11]. In the general population, circulating markers of endothelial dysfunction, including sICAM-1,

Effects of therapeutic intervention on markers of endothelial function in patients with the metabolic syndrome.

Intervention

Endothelial dysfunction

Endothelial activation

Endothelial damage

Effect

Reference

Low-fat diet

FMD

NA

PAI-1

[w38,w44]

Low-carbohydrate diet High-carbohydrate meal, rich in cereal fiber Soy nuts Physical exercise

FMD FMD at 4 h postprandially NA FMD

NA NA

NA NA

Significant improvement in both markers Significant deterioration Significant improvement

NA NA

E-selectin NA

Metformin

EDV, FMD

NA

NA

Rosiglitazone Pioglitazone Atorvastatin

FMD NA FMD

NA hsCRP sICAM-1

NA NA NA

Simvastatin Pravastatin

NA NA

PAI-1 NA

Fenofibrate

FMD

NA sICAM-1, sVCAM-1, E-selectin sICAM-1, sVCAM-1

Bezafibrate Nicotinic acid

FMD FMD

NA NA

NA NA

Ezetimibe combined with statins Eicosapentaenoic acid

FMD

NA

NA

NA

sICAM-1, sVCAM-1

NA

Irbesartan

FMD

NA

PAI-1

Oral estradiol Transdermal estradiol

NA NA

E-selectin E-selectin

NA NA

NA

[w38] [w43]

Significant improvement Significant improvement (more pronounced with higher-intensity exercise) Significant improvement in both markers Significant improvement Significant improvement Significant improvement in both markers Significant improvement No effect

[w45] [w54,w55]

Significant improvement in all markers Significant improvement Significant improvement or no change Significant improvement

[w78ew80]

Significant improvement in both markers Significant improvement in both markers Significant improvement No change

[w89]

[w61,w62] [22,27] [w66] [30,w9] [w72] [w73]

[w9] [w85,w86] [w87]

[w94] [w108] [w108]

FMD Z flow-mediated vasodilation in the brachial artery, NA Z not assessed, PAI-1 Z plasminogen activator inhibitor-1, EDV Z endothelium-dependent vasodilation in the forearm assessed with venous occlusion plethysmography, hsCRP Z high sensitivity C-reactive protein, sICAM-1 Z soluble intercellular adhesion molecule-1, sVCAM-1 Z soluble vascular cell adhesion molecule-1.

Endothelial dysfunction in metabolic syndrome sVCAM-1, E-selectin, tPA antigen and vWF also predicted T2DM in some but not all studies [w22ew27].

Therapeutic interventions in MetS e effects on endothelial function Table 1 Lifestyle measures According to current guidelines, lifestyle measures are the first-line treatment of MetS [1,w28]. In the Diabetes Prevention Program [3234 overweight patients with IFG or impaired glucose tolerance (IGT); 53% had MetS], lifestyle changes reduced the prevalence of MetS [w29]. A reduction in MetS prevalence with lifestyle modification was also reported in smaller studies [w30,w31]. In overweight patients with IFG or IGT, intensive lifestyle intervention also reduced the risk for developing MetS [w29] or T2DM [w32,w33]. Regarding diet, a moderately-reduced-energy diet with a low intake of trans fats, saturated fats and simple sugars and increased consumption of fruits, vegetables and whole grains is recommended for patients with MetS [1]. Low-fat and low-glycemic load diets appear to induce similar weight reductions but the former had less beneficial effects on HDL-C and TG levels [w34,w35]. However, low-fat diets decrease low density lipoprotein cholesterol (LDL-C) levels more than low-glycemic load diets [w34,w35]. Other studies reported more weight loss, greater improvement in HDL-C and TG levels and no differences in LDL-C levels with low-glycemic load diets compared with low-fat diets [w36,w37]. Interestingly, in obese patients, a low-fat diet improved FMD whereas a lowcarbohydrate diet decreased FMD despite similar weight loss [w38]. In a cross-sectional study, increased intake of fiber was associated with reduced prevalence of MetS [w39]. However, this was not confirmed in prospective studies [w40,w41]. In patients with MetS, the fiber-rich dietary approaches to stop hypertension (DASH) diet reduced the prevalence of MetS more than a weight-reducing diet emphasizing healthy choices [w42]. This difference was independent of weight loss [w42]. In patients with MetS, consumption of a high-carbohydrate meal, rich in cereal fiber, improved FMD at 4 h postprandially [w43]. A hypocaloric low-fat diet enriched with whole or refined grains also reduced serum PAI-1 levels in patients with MetS [w44]. In postmenopausal women with MetS, soy nut consumption increased plasma NO levels and reduced serum E-selectin levels more than a control diet [w45]. The Mediterranean diet appears to induce similar weight loss as low-carbohydrate diets and greater than low-fat diets [w37]. In cross-sectional studies, the Mediterranean diet is associated with reduced prevalence of MetS [w46]. The Mediterranean diet also reduced the risk for MetS in some prospective studies [w47] but not in others [w48]. In patients with MetS, Mediterranean diet enriched with nuts reduced the prevalence of MetS more than a low-fat diet [w48]. In contrast, Mediterranean diet enriched with virgin olive oil and the low-fat had similar effects [w48]. A daily minimum of 30 min moderate-intensity physical activity is recommended in patients with MetS [1]. In

143 prospective studies, increased physical activity reduced the risk for MetS [w40,w49]. Higher cardiorespiratory fitness, a marker of increased recent physical activity, is also associated with reduced incidence of MetS [w49,w50]. In patients with MetS, higher cardiorespiratory fitness is also associated with reduced risk for vascular and all cause mortality [w51]. Several studies showed that physical activity reduces the prevalence of MetS [w52,w53]. A 3-month physical training program improved FMD in MetS despite the lack of change in BP, body mass index, plasma lipids or insulin resistance [w54]. In a recent study in patients with MetS, high-intensity exercise increased FMD more than moderate-intensity exercise [w55]. Smoking is associated with endothelial dysfunction [12,w56]. Smoking also appears to increase the risk for insulin resistance, MetS and T2DM [w57]. On the other hand, smoking cessation resulted in improvement in endothelial function [w58,w59]. Interestingly, even though smoking cessation is associated with a temporary increase in body weight [w57], an improvement in insulin sensitivity was reported in patients who stopped smoking [w60].

Pharmacological treatment In the DPP, metformin reduced the risk for developing MetS [w29] and T2DM in overweight patients with IFG or IGT but was less protective than lifestyle measures [w29,w33]. Moreover, metformin did not reduce the prevalence of MetS in the same study [w29]. In patients with MetS and normal glucose tolerance, metformin improved EDV independently of changes in glucose, LDL-C and HDL-C levels, body weight and BP [w61]. In another study in MetS, metformin improved FMD and this improvement correlated with the decrease in insulin resistance [w62]. Metformin also increased circulating NO levels in patients with MetS [w63]. In the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial, rosiglitazone reduced the incidence of T2DM in patients with IFG and increased the rate of regression to normoglycemia [w64]. However, there was no change in vascular events and the risk for heart failure increased [w64]. In several studies involving patients with MetS, rosiglitazone improved FMD [22,27,w65]. The reduction in hsCRP levels and the increase in adiponectin levels correlated with this improvement in endothelial function [27,w65]. In patients with MetS, pioglitazone reduced hsCRP levels but endothelial function was not assessed [w66]. Subgroup analyses of both primary and secondary prevention trials showed that statins reduce vascular events in patients with MetS [w67ew69]. In some trials, statins conferred greater risk reduction in patients with MetS [w69]. In patients with MetS, atorvastatin reduced the prevalence of MetS [w70,w71], increased FMD [w9] and reduced sICAM-1 levels [30]. Simvastatin reduced serum PAI-1 activity in patients with MetS [w72] whereas pravastatin did not affect sICAM-1, sVCAM-1 or E-selectin levels [w73]. These limited data suggest that different statins might not have the same effect on endothelial function in patients with MetS. However, no comparative studies assessed whether one statin improves endothelial function more than others.

144 A post-hoc subgroup analysis of the bezafibrate infarction prevention (BIP) study showed that bezafibrate reduces the risk for myocardial infarction (MI) in patients with established coronary heart disease (CHD) [w74]. Other post-hoc analyses of the same study suggested that bezafibrate reduces the risk for T2DM in obese patients [w75] and in patients with IFG [w76]. Fenofibrate reduced the prevalence of MetS [w70,w71,w77]. In addition, fenofibrate increased FMD [w78,w79] and reduced sICAM-1 and sVCAM-1 levels in patients with MetS [w80]. Bezafibrate also increased FMD [w9]. The combination of statins and fibrates also increased FMD more than either monotherapy in patients with mixed dyslipidemia [w81]. However, switching from atorvastatin to bezafibrate in patients with MetS was associated with a reduction in EDV [w82]. Nicotinic acid (NA) might be useful in the management of combined dyslipidemia in MetS [w83]. A post-hoc analysis of the Coronary Drug Project showed that NA reduces the risk for non-fatal MI and all cause mortality in patients with CHD and MetS [w84]. In patients with MetS, NA increased FMD [w85]. However, no change in FMD was observed with NA treatment in another study that included patients with MetS [w86]. In patients with MetS, ezetimibe plus atorvastatin 10 mg/day reduced LDL-C levels and improved EDV more than atorvastatin 40 mg/day [w87]. In another study, ezetimibe plus simvastatin 10 mg/day prevented the post-fatload decline in FMD more than simvastatin 80 mg/day alone [w88]. In patients with MetS, eicosapentaenoic acid reduced plasma sICAM-1 and sVCAM-1 levels [w89]. Subgroup analyses of secondary prevention trials showed that angiotensin converting enzyme inhibitors (ACE-I) reduce vascular events in patients with MetS [w90]. In hypertensive patients, ACE-I and angiotensin receptor blockers (ARB) appear to reduce the risk for T2DM whereas diuretics and beta-blockers appear to increase it [w91]. Calcium-channel blockers have a neutral effect [w91]. However, in the placebo-controlled DREAM trial, ramipril did not reduce the incidence of T2DM or vascular disease in patients with IFG [w92]. However, more patients assigned to ramipril regressed to normoglycemia [w92]. In a recent subgroup analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) trial, treatment of patients with MetS with chlorthalidone was associated with a higher risk of developing T2DM but with a lower risk for vascular events than treatment with lisinopril [w93]. However, patients assigned to lisinopril had higher systolic BP during follow-up than those receiving chlorthalidone [w93]. The risk for T2DM and vascular events was similar in patients with MetS treated with amlodipine and those assigned to either chlorthalidone or lisinopril [w93]. Regarding the effects of antihypertensive treatment on endothelial function in MetS, a study reported improvement in FMD and reduction in plasma PAI-1 levels with irbesartan despite the lack of fall in BP [w94]. In dyslipidemic patients with hypertension or T2DM, statins or fibrates combined with ACE-I or ARB improved FMD more than each agent alone [w95ew97]. In obese patients with IGT, treatment with orlistat reduced the risk for T2DM [w98]. Both orlistat and sibutramine improved FMD in obese patients [w99,w100]. In

K. Tziomalos et al. addition, both orlistat [w77,w101] and sibutramine reduced the prevalence of MetS [w31] but their effects on endothelial function in these patients are unclear. Estradiol stimulates NO production and improves endothelial function [w102ew105]. Interestingly, these effects of estradiol appear to be carried out through its association with HDL particles [w102]. Other atheroprotective effects of HDL, such as macrophage cholesterol efflux, also appear to be enhanced by HDL-associated estradiol esters [w106]. Oral hormone therapy appears to have more beneficial effects on circulating levels of adhesion molecules, PAI-1 and tPA than transdermal hormone therapy [w107]. However, the former increased hsCRP levels more than the latter [w107]. In postmenopausal women with MetS, oral estradiol lowered circulating E-selectin levels whereas transdermal estradiol had no effect [w108].

Bariatric surgery Bariatric surgery results in resolution of MetS in most cases [w109,w110]. Bariatric surgery also appears to be more effective than lifestyle modifications and pharmacological treatment in reducing the prevalence of MetS [w111]. In obese patients, bariatric surgery improved EDV and reduced E-selectin, vWF and PAI-1 levels [w112ew114] whereas the effects on sICAM-1 and sVCAM-1 levels were inconsistent [w113,w114]. In patients with MetS, a reduction in albuminuria was observed after bariatric surgery [w115]. However, bariatric surgery in patients with MetS was associated with longer hospitalization [w116].

Conclusions Endothelial dysfunction is observed in patients with MetS. Abdominal obesity, dyslipidemia, hypertension and impaired glucose metabolism appear to contribute to the pathogenesis of endothelial dysfunction in these patients. Limited data suggest that both lifestyle measures and pharmacological intervention might partly restore endothelial function in MetS. It is also unclear whether an improvement in endothelial function will reduce vascular risk in patients with MetS.

Conflict of interest This review was written independently; no company or institution supported it financially. Some of the authors have attended conferences, given lectures and participated in advisory boards or trials sponsored by various pharmaceutical companies. Konstantinos Tziomalos is supported by a grant from the Hellenic Atherosclerosis Society.

Appendix A Supplemental material Supplementary information for this manuscript can be downloaded at doi:10.1016/j.numecd.2009.08.006.

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