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 Abstract The metabolic syndrome (MetS) is characterized by the presence of central obesity,
Metabolic syndrome; impaired glucose metabolism, dyslipidemia and hypertension. Several studies showed that
Endothelial dysfunction; MetS is associated with increased risk for type 2 diabetes mellitus (T2DM) and vascular events.
Lifestyle measures; All components of MetS have adverse effects on the endothelium. Endothelial dysfunction
Statins; plays a role in the pathogenesis of atherosclerosis and might also increase the risk for insulin
Metformin 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 interven-
tions 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 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
The metabolic syndrome (MetS) is characterized by the showed that MetS is associated with increased risk for type
presence of central obesity, impaired fasting glucose (IFG), 2 diabetes mellitus (T2DM) [5] and vascular morbidity and
dyslipidemia and hypertension [1]. The prevalence of MetS 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
* Corresponding author at: Department of Clinical Biochemistry,
Royal Free Hospital Campus, University College Medical School, in patients with or without established vascular disease [8].
University College London (UCL), Pond Street, London NW3 2QG, Endothelial dysfunction also appears to be implicated in the
UK. Tel.: þ44 20 7830 2258; fax: þ44 20 7830 2235. pathogenesis of T2DM [9e11]. Since all components of MetS
E-mail address: [email protected] (D.P. Mikhailidis). 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 141

dysfunction might be more prevalent in patients with MetS that plasma PAI-1 levels and activity rise as the number of
and could play a role in the increased risk for vascular disease MetS components increases [32,33]. Patients with MetS also
and T2DM in this population. have higher circulating levels of the vasoconstrictor agent
We review the prevalence and pathogenesis of endothelial endothelin-1 [34].
dysfunction in MetS. We also discuss the potential effects of Microalbuminuria is more common in patients with MetS
lifestyle measures and pharmacological interventions on [35,36]. In addition, the prevalence of microalbuminuria
endothelial function in patients with MetS. 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
Markers of endothelial function in patients diagnostic criteria of MetS [37].
with MetS

A detailed description of the methods of assessing endo- Pathogenesis of endothelial dysfunction

thelial function is beyond the scope of this review. Several in MetS
relevant comprehensive reviews have been published
[17,18]. In brief, these methods assess: (a) endothelial Several mechanisms are implicated in the pathogenesis of
dysfunction, which is mainly manifested as impaired endothelial dysfunction. Decreased NO availability appears to
vasodilation caused by reduced nitric oxide (NO) avail- play a major role and may result from reduced NO production
ability. Endothelium-dependent vasodilation (EDV) is and/or increased inactivation by reactive oxygen species [17].
evaluated in response to interventions that stimulate NO In addition, reduced availability of other vasodilating agents
release [either pharmacological (mainly acetylcholine) or (including prostacyclin and endothelium-derived hyper-
mechanical (flow-mediated dilation, FMD)] [17,18]. EDV polarizing factors) and/or increased production or activity of
can be assessed in the macrocirculation (either in large vasoconstrictive substances (including endothelin-1 and
coronary arteries with quantitative coronary angiography angiotensin II) are also implicated [17]. All the components of
or in peripheral arteries with ultrasound-measured FMD) MetS can individually impair endothelial function. Several
[17,18]. EDV can also be evaluated in the forearm micro- studies showed that both hypertension [12,38] and T2DM are
circulation (resistance vessels) with venous occlusion associated with endothelial dysfunction [13,39]. Even in
plethysmography [17,18]. EDV assessed in large conduit normotensive subjects, endothelial function progressively
vessels might be more clinically relevant since atheroscle- deteriorates as blood pressure (BP) rises [12]. In some studies,
rosis primarily affects the macrocirculation [17,18]. non-diabetic patients with IFG also showed reduced EDV
However, venous occlusion plethysmography-assessed EDV [40,41] but this was not confirmed by others [42]. Experi-
in the forearm correlates with EDV in the coronary arteries mental glucose loading also impairs endothelial function
and both are associated with increased risk for vascular [43,44] but not in all studies [45]. Besides hypertension and
events [8]. (b) Endothelial activation, i.e. the acquisition of dysglycemia, abdominal obesity is also associated with
inflammatory properties by the endothelium. Endothelial endothelial dysfunction [14,46]. It was also shown that the
activation is evaluated by measuring circulating levels of severity of endothelial dysfunction correlates with the degree
adhesion molecules [soluble intercellular adhesion mole- of visceral adiposity [47]. Impaired endothelial function was
cule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 also reported in patients with low levels of high density lipo-
(sVCAM-1) and E-selectin] and high sensitivity C-reactive protein cholesterol (HDL-C) [16,48]. HDL-C levels indepen-
protein (hsCRP); and (c) endothelial damage, by measuring dently correlate with EDV [16,48]. Reduced EDV was also
serum levels of von Willebrand factor (vWF), tissue plas- reported in patients with elevated triglyceride (TG) levels in
minogen activator (tPA), plasminogen activator inhibitor-1 some [15,49] but not all studies [50,51].
(PAI-1), as well as circulating mature endothelial cells, An increasing number of MetS components is associated
endothelial progenitor cells and endothelial microparticles with more severe impairment in endothelial function
[17,18]. However, some of these markers are not specific of [24,28,52]. Regarding the contribution of each MetS
endothelial dysfunction [17,18]. Circulating levels of component in the pathogenesis of endothelial dysfunction
adhesion molecules increase in inflammatory conditions in patients with MetS, a large study (n Z 1016) reported
[17,18] and PAI-1 levels are associated with insulin resis- that TG levels, waist circumference and diastolic BP inde-
tance, which is an important feature of MetS [19,20]. It was pendently predicted EDV [28]. Waist circumference was
suggested that microalbuminuria might also represent more strongly related to endothelial dysfunction followed
a marker of generalized endothelial dysfunction [21]. by TG levels and diastolic BP [28]. In other reports, only
Several studies showed that EDV is impaired in patients HDL-C levels [23] or BP [52] was independently associated
with MetS [22e27]. In a recent large study in 1016 elderly with reduced FMD in patients with MetS.
subjects, forearm EDV in response to acetylcholine infusion Insulin resistance is an important component of MetS
assessed with venous occlusion plethysmography was [53] although it is not always present [54,55]. Insulin
reduced in MetS [28]. However, FMD in the brachial artery did stimulates the production and release of NO by endothelial
not differ between patients with MetS and control subjects in cells resulting in vasodilation [9,56]. However, the vaso-
the same report [28]. In another recent large study in 1417 dilating action of insulin is attenuated in insulin-resistant
men, MetS was not associated with impaired FMD [29]. states [57,58]. In addition, insulin impaired endothelial
Circulating markers of endothelial dysfunction including function by inducing oxidative stress [59] and stimulated
sICAM-1 [30], tPA antigen [31] and PAI-1 levels and activity the release of endothelin-1 in some studies [60,w1]. Insulin
are also elevated in MetS [26,31e33]. It was also reported 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 healthy subjects or patients with IFG, IGT or T2DM
large study (n Z 1016), acetylcholine-induced vasodilation [w12,w13] but not in all [w15,w16]. Leptin also induces
correlated with insulin resistance whereas FMD did not [28]. NO-independent vasodilation [w17,w18] and leptin levels
Insulin resistance also correlated with sICAM-1, sVCAM-1 directly correlate with EDV in obese patients [w14]. In
and E-selectin levels [w2] and was associated with the patients with MetS, resistin levels correlate with EDV [26]
presence of microalbuminuria [w3]. but this association was not observed in patients with IGT
MetS is considered a pro-inflammatory condition or T2DM [w16].
[29,32,w4]. Several studies showed that hsCRP levels are Serum uric acid levels are raised in MetS [w19,w20].
elevated in MetS [29,32,w4] and rise as the number of MetS Elevated serum uric acid levels appear to be associated
components increases [32,w4]. This pro-inflammatory state with endothelial dysfunction [w19,w21] and may play a role
might play a role in the pathogenesis of endothelial in the increased vascular risk of patients with MetS
dysfunction in MetS, since elevated hsCRP levels are [w20].Table 1
associated with impaired EDV [w5,w6] although not in all It is of interest that endothelial dysfunction might play
studies [w7,w8]. The correlation between hsCRP levels and a role in the pathogenesis of insulin resistance and T2DM
FMD was also observed in patients with MetS [w9]. [9]. Endothelial dysfunction in the skeletal muscle might
Patients with MetS have lower circulating adiponectin lead to decreased blood flow, which in turn could
[26,32,55] and higher resistin [55,w10] and leptin levels contribute to insulin resistance [9]. In prospective studies,
[32]. These alterations in adipokine levels may contribute impaired EDV was associated with increased risk for T2DM
to the development of endothelial dysfunction [w11e in healthy postmenopausal women [10] and in hypertensive
w14]. Adiponectin levels independently correlated with patients [11]. In the general population, circulating
EDV in hypertensive patients [w11] and in some studies in markers of endothelial dysfunction, including sICAM-1,

Table 1 Effects of therapeutic intervention on markers of endothelial function in patients with the metabolic syndrome.
Intervention Endothelial Endothelial Endothelial Effect Reference
dysfunction activation damage
Low-fat diet FMD NA PAI-1 Significant improvement [w38,w44]
in both markers
Low-carbohydrate diet FMD NA NA Significant deterioration [w38]
High-carbohydrate meal, FMD at 4 h NA NA Significant improvement [w43]
rich in cereal fiber postprandially
Soy nuts NA NA E-selectin Significant improvement [w45]
Physical exercise FMD NA NA Significant improvement [w54,w55]
(more pronounced with
higher-intensity exercise)
Metformin EDV, FMD NA NA Significant improvement [w61,w62]
in both markers
Rosiglitazone FMD NA NA Significant improvement [22,27]
Pioglitazone NA hsCRP NA Significant improvement [w66]
Atorvastatin FMD sICAM-1 NA Significant improvement [30,w9]
in both markers
Simvastatin NA NA PAI-1 Significant improvement [w72]
Pravastatin NA sICAM-1, sVCAM-1, NA No effect [w73]
E-selectin
Fenofibrate FMD sICAM-1, sVCAM-1 NA Significant improvement [w78ew80]
in all markers
Bezafibrate FMD NA NA Significant improvement [w9]
Nicotinic acid FMD NA NA Significant improvement [w85,w86]
or no change
Ezetimibe combined FMD NA NA Significant improvement [w87]
with statins
Eicosapentaenoic acid NA sICAM-1, sVCAM-1 NA Significant improvement [w89]
in both markers
Irbesartan FMD NA PAI-1 Significant improvement [w94]
in both markers
Oral estradiol NA E-selectin NA Significant improvement [w108]
Transdermal estradiol NA E-selectin NA No change [w108]
FMD Z flow-mediated vasodilation in the brachial artery, NA Z not assessed, PAI-1 Z plasminogen activator inhibitor-1, EDV Z endo-
thelium-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 143

sVCAM-1, E-selectin, tPA antigen and vWF also predicted prospective studies, increased physical activity reduced the
T2DM in some but not all studies [w22ew27]. risk for MetS [w40,w49]. Higher cardiorespiratory fitness,
a marker of increased recent physical activity, is also asso-
ciated with reduced incidence of MetS [w49,w50]. In patients
Therapeutic interventions in MetS e effects on
with MetS, higher cardiorespiratory fitness is also associated
endothelial function Table 1 with reduced risk for vascular and all cause mortality [w51].
Several studies showed that physical activity reduces the
Lifestyle measures prevalence of MetS [w52,w53]. A 3-month physical training
program improved FMD in MetS despite the lack of change in
According to current guidelines, lifestyle measures are the BP, body mass index, plasma lipids or insulin resistance
first-line treatment of MetS [1,w28]. In the Diabetes [w54]. In a recent study in patients with MetS, high-intensity
Prevention Program [3234 overweight patients with IFG or exercise increased FMD more than moderate-intensity
impaired glucose tolerance (IGT); 53% had MetS], lifestyle exercise [w55].
changes reduced the prevalence of MetS [w29]. A reduction Smoking is associated with endothelial dysfunction
in MetS prevalence with lifestyle modification was also [12,w56]. Smoking also appears to increase the risk for insulin
reported in smaller studies [w30,w31]. In overweight resistance, MetS and T2DM [w57]. On the other hand,
patients with IFG or IGT, intensive lifestyle intervention smoking cessation resulted in improvement in endothelial
also reduced the risk for developing MetS [w29] or T2DM function [w58,w59]. Interestingly, even though smoking
[w32,w33]. Regarding diet, a moderately-reduced-energy cessation is associated with a temporary increase in body
diet with a low intake of trans fats, saturated fats and weight [w57], an improvement in insulin sensitivity was
simple sugars and increased consumption of fruits, vege- reported in patients who stopped smoking [w60].
tables and whole grains is recommended for patients with
MetS [1]. Low-fat and low-glycemic load diets appear to Pharmacological treatment
induce similar weight reductions but the former had less
beneficial effects on HDL-C and TG levels [w34,w35]. In the DPP, metformin reduced the risk for developing
However, low-fat diets decrease low density lipoprotein MetS [w29] and T2DM in overweight patients with IFG or
cholesterol (LDL-C) levels more than low-glycemic load IGT but was less protective than lifestyle measures
diets [w34,w35]. Other studies reported more weight loss, [w29,w33]. Moreover, metformin did not reduce the
greater improvement in HDL-C and TG levels and no prevalence of MetS in the same study [w29]. In patients
differences in LDL-C levels with low-glycemic load diets with MetS and normal glucose tolerance, metformin
compared with low-fat diets [w36,w37]. Interestingly, in improved EDV independently of changes in glucose, LDL-C
obese patients, a low-fat diet improved FMD whereas a low- and HDL-C levels, body weight and BP [w61]. In another
carbohydrate diet decreased FMD despite similar weight study in MetS, metformin improved FMD and this
loss [w38]. improvement correlated with the decrease in insulin
In a cross-sectional study, increased intake of fiber was resistance [w62]. Metformin also increased circulating NO
associated with reduced prevalence of MetS [w39]. levels in patients with MetS [w63].
However, this was not confirmed in prospective studies In the Diabetes Reduction Assessment with Ramipril and
[w40,w41]. In patients with MetS, the fiber-rich dietary Rosiglitazone Medication (DREAM) trial, rosiglitazone
approaches to stop hypertension (DASH) diet reduced the reduced the incidence of T2DM in patients with IFG and
prevalence of MetS more than a weight-reducing diet increased the rate of regression to normoglycemia [w64].
emphasizing healthy choices [w42]. This difference was However, there was no change in vascular events and the
independent of weight loss [w42]. In patients with MetS, risk for heart failure increased [w64]. In several studies
consumption of a high-carbohydrate meal, rich in cereal involving patients with MetS, rosiglitazone improved FMD
fiber, improved FMD at 4 h postprandially [w43]. A hypo- [22,27,w65]. The reduction in hsCRP levels and the increase
caloric low-fat diet enriched with whole or refined grains in adiponectin levels correlated with this improvement in
also reduced serum PAI-1 levels in patients with MetS [w44]. endothelial function [27,w65]. In patients with MetS,
In postmenopausal women with MetS, soy nut consumption pioglitazone reduced hsCRP levels but endothelial function
increased plasma NO levels and reduced serum E-selectin was not assessed [w66].
levels more than a control diet [w45]. Subgroup analyses of both primary and secondary
The Mediterranean diet appears to induce similar prevention trials showed that statins reduce vascular
weight loss as low-carbohydrate diets and greater than events in patients with MetS [w67ew69]. In some trials,
low-fat diets [w37]. In cross-sectional studies, the Medi- statins conferred greater risk reduction in patients with
terranean diet is associated with reduced prevalence of MetS [w69]. In patients with MetS, atorvastatin reduced the
MetS [w46]. The Mediterranean diet also reduced the risk prevalence of MetS [w70,w71], increased FMD [w9] and
for MetS in some prospective studies [w47] but not in reduced sICAM-1 levels [30]. Simvastatin reduced serum
others [w48]. In patients with MetS, Mediterranean diet PAI-1 activity in patients with MetS [w72] whereas pravas-
enriched with nuts reduced the prevalence of MetS more tatin did not affect sICAM-1, sVCAM-1 or E-selectin levels
than a low-fat diet [w48]. In contrast, Mediterranean diet [w73]. These limited data suggest that different statins
enriched with virgin olive oil and the low-fat had similar might not have the same effect on endothelial function in
effects [w48]. patients with MetS. However, no comparative studies
A daily minimum of 30 min moderate-intensity physical assessed whether one statin improves endothelial function
activity is recommended in patients with MetS [1]. In more than others.
144 K. Tziomalos et al.

A post-hoc subgroup analysis of the bezafibrate infarction addition, both orlistat [w77,w101] and sibutramine reduced
prevention (BIP) study showed that bezafibrate reduces the the prevalence of MetS [w31] but their effects on endo-
risk for myocardial infarction (MI) in patients with estab- thelial function in these patients are unclear.
lished coronary heart disease (CHD) [w74]. Other post-hoc Estradiol stimulates NO production and improves
analyses of the same study suggested that bezafibrate endothelial function [w102ew105]. Interestingly, these
reduces the risk for T2DM in obese patients [w75] and in effects of estradiol appear to be carried out through its
patients with IFG [w76]. Fenofibrate reduced the prevalence association with HDL particles [w102]. Other atheropro-
of MetS [w70,w71,w77]. In addition, fenofibrate increased tective effects of HDL, such as macrophage cholesterol
FMD [w78,w79] and reduced sICAM-1 and sVCAM-1 levels in efflux, also appear to be enhanced by HDL-associated
patients with MetS [w80]. Bezafibrate also increased FMD estradiol esters [w106]. Oral hormone therapy appears to
[w9]. The combination of statins and fibrates also increased have more beneficial effects on circulating levels of
FMD more than either monotherapy in patients with mixed adhesion molecules, PAI-1 and tPA than transdermal
dyslipidemia [w81]. However, switching from atorvastatin to hormone therapy [w107]. However, the former increased
bezafibrate in patients with MetS was associated with hsCRP levels more than the latter [w107]. In post-
a reduction in EDV [w82]. menopausal women with MetS, oral estradiol lowered
Nicotinic acid (NA) might be useful in the management circulating E-selectin levels whereas transdermal estradiol
of combined dyslipidemia in MetS [w83]. A post-hoc analysis had no effect [w108].
of the Coronary Drug Project showed that NA reduces the
risk for non-fatal MI and all cause mortality in patients with Bariatric surgery
CHD and MetS [w84]. In patients with MetS, NA increased
FMD [w85]. However, no change in FMD was observed with
Bariatric surgery results in resolution of MetS in most cases
NA treatment in another study that included patients with
[w109,w110]. Bariatric surgery also appears to be more
MetS [w86].
effective than lifestyle modifications and pharmacological
In patients with MetS, ezetimibe plus atorvastatin
treatment in reducing the prevalence of MetS [w111]. In
10 mg/day reduced LDL-C levels and improved EDV more
obese patients, bariatric surgery improved EDV and reduced
than atorvastatin 40 mg/day [w87]. In another study, eze-
E-selectin, vWF and PAI-1 levels [w112ew114] whereas the
timibe plus simvastatin 10 mg/day prevented the post-fat-
effects on sICAM-1 and sVCAM-1 levels were inconsistent
load decline in FMD more than simvastatin 80 mg/day alone
[w113,w114]. In patients with MetS, a reduction in albu-
[w88]. In patients with MetS, eicosapentaenoic acid
minuria was observed after bariatric surgery [w115].
reduced plasma sICAM-1 and sVCAM-1 levels [w89].
However, bariatric surgery in patients with MetS was asso-
Subgroup analyses of secondary prevention trials
ciated with longer hospitalization [w116].
showed that angiotensin converting enzyme inhibitors
(ACE-I) reduce vascular events in patients with MetS
[w90]. In hypertensive patients, ACE-I and angiotensin Conclusions
receptor blockers (ARB) appear to reduce the risk for T2DM
whereas diuretics and beta-blockers appear to increase it Endothelial dysfunction is observed in patients with MetS.
[w91]. Calcium-channel blockers have a neutral effect Abdominal obesity, dyslipidemia, hypertension and
[w91]. However, in the placebo-controlled DREAM trial, impaired glucose metabolism appear to contribute to the
ramipril did not reduce the incidence of T2DM or vascular pathogenesis of endothelial dysfunction in these patients.
disease in patients with IFG [w92]. However, more Limited data suggest that both lifestyle measures and
patients assigned to ramipril regressed to normoglycemia pharmacological intervention might partly restore endo-
[w92]. In a recent subgroup analysis of the Antihyperten- thelial function in MetS. It is also unclear whether an
sive and Lipid-Lowering Treatment to Prevent Heart improvement in endothelial function will reduce vascular
Attack Trial (ALLHAT) trial, treatment of patients with risk in patients with MetS.
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, Conflict of interest
patients assigned to lisinopril had higher systolic BP during
follow-up than those receiving chlorthalidone [w93]. The This review was written independently; no company or
risk for T2DM and vascular events was similar in patients institution supported it financially. Some of the authors
with MetS treated with amlodipine and those assigned to have attended conferences, given lectures and partici-
either chlorthalidone or lisinopril [w93]. Regarding the pated in advisory boards or trials sponsored by various
effects of antihypertensive treatment on endothelial pharmaceutical companies. Konstantinos Tziomalos is
function in MetS, a study reported improvement in FMD supported by a grant from the Hellenic Atherosclerosis
and reduction in plasma PAI-1 levels with irbesartan Society.
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 Appendix A
agent alone [w95ew97]. Supplemental material
In obese patients with IGT, treatment with orlistat
reduced the risk for T2DM [w98]. Both orlistat and sibutr- Supplementary information for this manuscript can be
amine improved FMD in obese patients [w99,w100]. In downloaded at doi:10.1016/j.numecd.2009.08.006.
Endothelial dysfunction in metabolic syndrome 145

References different states of glucose tolerance. The Insulin Resistance

Atherosclerosis Study (IRAS). Arterioscler Thromb Vasc Biol
1999;19:562e8.
[1] Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, [20] Potter van Loon BJ, Kluft C, Radder JK, Blankenstein MA,
Franklin BA, et al. Diagnosis and management of the Meinders AE. The cardiovascular risk factor plasminogen
metabolic syndrome: an American Heart Association/National activator inhibitor type 1 is related to insulin resistance.
Heart, Lung, and Blood Institute Scientific Statement. Metabolism 1993;42:945e9.
Circulation 2005;112:2735e52. [21] Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T,
[2] Ford ES. Prevalence of the metabolic syndrome defined by the Kofoed-Enevoldsen A. Albuminuria reflects widespread
International Diabetes Federation among adults in the U.S. vascular damage. The Steno hypothesis. Diabetologia 1989;32:
Diabetes Care 2005;28:2745e9. 219e26.
[3] Grundy SM. Metabolic syndrome pandemic. Arterioscler [22] Esposito K, Ciotola M, Carleo D, Schisano B, Saccomanno F,
Thromb Vasc Biol 2008;28:629e36. Sasso FC, et al. Effect of rosiglitazone on endothelial function
[4] Athyros VG, Ganotakis ES, Elisaf M, Mikhailidis DP. The prev- and inflammatory markers in patients with the metabolic
alence of the metabolic syndrome using the National Choles- syndrome. Diabetes Care 2006;29:1071e6.
terol Educational Program and International Diabetes [23] Dell’Omo G, Penno G, Pucci L, Mariani M, Del PS, Pedrinelli R.
Federation definitions. Curr Med Res Opin 2005;21:1157e9. Abnormal capillary permeability and endothelial dysfunction
[5] Ford ES, Li C, Sattar N. Metabolic syndrome and incident in hypertension with comorbid Metabolic Syndrome. Athero-
diabetes: current state of the evidence. Diabetes Care 2008; sclerosis 2004;172:383e9.
31:1898e904. [24] Hamburg NM, Larson MG, Vita JA, Vasan RS, Keyes MJ,
[6] Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK, Widlansky ME, et al. Metabolic syndrome, insulin resistance,
et al. Metabolic syndrome and risk of incident cardiovascular and brachial artery vasodilator function in Framingham
events and death: a systematic review and meta-analysis of Offspring participants without clinical evidence of cardiovas-
longitudinal studies. J Am Coll Cardiol 2007;49:403e14. cular disease. Am J Cardiol 2008;101:82e8.
[7] Ross R. Atherosclerosisdan inflammatory disease. N Engl [25] Lteif AA, Han K, Mather KJ. Obesity, insulin resistance, and
J Med 1999;340:115e26. the metabolic syndrome: determinants of endothelial
[8] Kullo IJ, Malik AR. Arterial ultrasonography and tonometry as dysfunction in whites and blacks. Circulation 2005;112:32e8.
adjuncts to cardiovascular risk stratification. J Am Coll Cardiol [26] Bahia L, Aguiar LG, Villela N, Bottino D, Godoy-Matos AF,
2007;49:1413e26. Geloneze B, et al. Relationship between adipokines, inflam-
[9] Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal rela- mation, and vascular reactivity in lean controls and obese
tionships between insulin resistance and endothelial subjects with metabolic syndrome. Clinics 2006;61:433e40.
dysfunction: molecular and pathophysiological mechanisms. [27] Bahia L, Aguiar LG, Villela N, Bottino D, Godoy-Matos AF,
Circulation 2006;113:1888e904. Geloneze B, et al. Adiponectin is associated with improve-
[10] Rossi R, Cioni E, Nuzzo A, Origliani G, Modena MG. Endothelial- ment of endothelial function after rosiglitazone treatment in
dependent vasodilation and incidence of type 2 diabetes in non-diabetic individuals with metabolic syndrome. Athero-
a population of healthy postmenopausal women. Diabetes sclerosis 2007;195:138e46.
Care 2005;28:702e7. [28] Lind L. Endothelium-dependent vasodilation, insulin resis-
[11] Perticone F, Maio R, Sciacqua A, Andreozzi F, Iemma G, tance and the metabolic syndrome in an elderly cohort: the
Perticone M, et al. Endothelial dysfunction and C-reactive Prospective Investigation of the Vasculature in Uppsala
protein are risk factors for diabetes in essential hypertension. Seniors (PIVUS) study. Atherosclerosis 2008;196:795e802.
Diabetes 2008;57:167e71. [29] Title LM, Lonn E, Charbonneau F, Fung M, Mather KJ, Verma S,
[12] Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS, et al. Relationship between brachial artery flow-mediated
Keaney Jr JF, et al. Clinical correlates and heritability of flow- dilatation, hyperemic shear stress, and the metabolic
mediated dilation in the community: the Framingham Heart syndrome. Vasc Med 2008;13:263e70.
Study. Circulation 2004;109:613e9. [30] Blanco-Colio LM, Martin-Ventura JL, de TE, Farsang C,
[13] McVeigh GE, Brennan GM, Johnston GD, McDermott BJ, Gaw A, Gensini G, et al. Elevated ICAM-1 and MCP-1 plasma
McGrath LT, Henry WR, et al. Impaired endothelium-dependent levels in subjects at high cardiovascular risk are diminished
and independent vasodilation in patients with type 2 (non-insulin- by atorvastatin treatment. Atorvastatin on Inflammatory
dependent) diabetes mellitus. Diabetologia 1992;35:771e6. Markers study: a substudy of Achieve Cholesterol Targets
[14] Brook RD, Bard RL, Rubenfire M, Ridker PM, Rajagopalan S. Fast with Atorvastatin Stratified Titration. Am Heart J 2007;
Usefulness of visceral obesity (waist/hip ratio) in predicting 153:881e8.
vascular endothelial function in healthy overweight adults. [31] Anand SS, Yi Q, Gerstein H, Lonn E, Jacobs R, Vuksan V, et al.
Am J Cardiol 2001;88:1264e9. Relationship of metabolic syndrome and fibrinolytic dysfunc-
[15] Lupattelli G, Lombardini R, Schillaci G, Ciuffetti G, Marchesi S, tion to cardiovascular disease. Circulation 2003;108:420e5.
Siepi D, et al. Flow-mediated vasoactivity and circulating adhe- [32] You T, Nicklas BJ, Ding J, Penninx BW, Goodpaster BH,
sion molecules in hypertriglyceridemia: association with small, Bauer DC, et al. The metabolic syndrome is associated with
dense LDL cholesterol particles. Am Heart J 2000;140:521e6. circulating adipokines in older adults across a wide range of
[16] Kuvin JT, Patel AR, Sidhu M, Rand WM, Sliney KA, Pandian NG, adiposity. J Gerontol A Biol Sci Med Sci 2008;63:414e9.
et al. Relation between high-density lipoprotein cholesterol and [33] Mertens I, Verrijken A, Michiels JJ, Van der PM, Ruige JB, Van
peripheral vasomotor function. Am J Cardiol 2003;92:275e9. Gaal LF. Among inflammation and coagulation markers, PAI-1
[17] Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and is a true component of the metabolic syndrome. Int J Obes
dysfunction: testing and clinical relevance. Circulation 2007; (Lond) 2006;30:1308e14.
115:1285e95. [34] Piatti PM, Monti LD, Conti M, Baruffaldi L, Galli L, Phan CV,
[18] Barac A, Campia U, Panza JA. Methods for evaluating endo- et al. Hypertriglyceridemia and hyperinsulinemia are potent
thelial function in humans. Hypertension 2007;49:748e60. inducers of endothelin-1 release in humans. Diabetes 1996;45:
[19] Festa A, D’Agostino Jr R, Mykkanen L, Tracy RP, Zaccaro DJ, 316e21.
Hales CN, et al. Relative contribution of insulin and its [35] Leoncini G, Ratto E, Viazzi F, Vaccaro V, Parodi D, Parodi A,
precursors to fibrinogen and PAI-1 in a large population with et al. Metabolic syndrome is associated with early signs of
146 K. Tziomalos et al.

organ damage in nondiabetic, hypertensive patients. J Intern [48] Lupattelli G, Marchesi S, Roscini AR, Siepi D, Gemelli F,
Med 2005;257:454e60. Pirro M, et al. Direct association between high-density lipo-
[36] Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, protein cholesterol and endothelial function in hyperlipemia.
Fonseca V, et al. The metabolic syndrome and chronic kidney Am J Cardiol 2002;90:648e50.
disease in U.S. adults. Ann Intern Med 2004;140:167e74. [49] Lundman P, Eriksson MJ, Stuhlinger M, Cooke JP, Hamsten A,
[37] Alberti KG, Zimmet PZ. Definition, diagnosis and classification Tornvall P. Mild-to-moderate hypertriglyceridemia in young
of diabetes mellitus and its complications. Part 1: diagnosis men is associated with endothelial dysfunction and increased
and classification of diabetes mellitus provisional report of plasma concentrations of asymmetric dimethylarginine. J Am
a WHO consultation. Diabet Med 1998;15:539e53. Coll Cardiol 2001;38:111e6.
[38] Panza JA, Quyyumi AA, Brush Jr JE, Epstein SE. Abnormal [50] Schnell GB, Robertson A, Houston D, Malley L, Anderson TJ.
endothelium-dependent vascular relaxation in patients with Impaired brachial artery endothelial function is not predicted
essential hypertension. N Engl J Med 1990;323:22e7. by elevated triglycerides. J Am Coll Cardiol 1999;33:2038e43.
[39] Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA. [51] Chowienczyk PJ, Watts GF, Wierzbicki AS, Cockcroft JR,
Impaired nitric oxide-mediated vasodilation in patients with Brett SE, Ritter JM. Preserved endothelial function in patients
non-insulin-dependent diabetes mellitus. J Am Coll Cardiol with severe hypertriglyceridemia and low functional lipopro-
1996;27:567e74. tein lipase activity. J Am Coll Cardiol 1997;29:964e8.
[40] Rodriguez CJ, Miyake Y, Grahame-Clarke C, Di Tullio MR, [52] Ghiadoni L, Penno G, Giannarelli C, Plantinga Y, Bernardini M,
Sciacca RR, Boden-Albala B, et al. Relation of plasma glucose Pucci L, et al. Metabolic syndrome and vascular alterations
and endothelial function in a population-based multiethnic in normotensive subjects at risk of diabetes mellitus.
sample of subjects without diabetes mellitus. Am J Cardiol Hypertension 2008;51:440e5.
2005;96:1273e7. [53] Reaven GM. Banting lecture 1988. Role of insulin resistance in
[41] Vehkavaara S, Seppala-Lindroos A, Westerbacka J, Groop PH, human disease. Diabetes 1988;37:1595e607.
Yki-Jarvinen H. In vivo endothelial dysfunction characterizes [54] Sierra-Johnson J, Johnson BD, Allison TG, Bailey KR,
patients with impaired fasting glucose. Diabetes Care 1999; Schwartz GL, Turner ST. Correspondence between the adult
22:2055e60. treatment panel III criteria for metabolic syndrome and insulin
[42] Henry RM, Ferreira I, Kostense PJ, Dekker JM, Nijpels G, resistance. Diabetes Care 2006;29:668e72.
Heine RJ, et al. Type 2 diabetes is associated with impaired [55] Hivert MF, Sullivan LM, Fox CS, Nathan DM, D’Agostino Sr RB,
endothelium-dependent, flow-mediated dilation, but impaired Wilson PW, et al. Associations of adiponectin, resistin, and
glucose metabolism is not; The Hoorn Study. Atherosclerosis tumor necrosis factor-alpha with insulin resistance. J Clin
2004;174:49e56. Endocrinol Metab 2008;93:3165e72.
[43] Beckman JA, Goldfine AB, Gordon MB, Creager MA. Ascorbate [56] Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD.
restores endothelium-dependent vasodilation impaired by acute Insulin-mediated skeletal muscle vasodilation is nitric oxide
hyperglycemia in humans. Circulation 2001;103:1618e23. dependent. A novel action of insulin to increase nitric oxide
[44] Title LM, Cummings PM, Giddens K, Nassar BA. Oral glucose release. J Clin Invest 1994;94:1172e9.
loading acutely attenuates endothelium-dependent vasodila- [57] Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G,
tion in healthy adults without diabetes: an effect prevented Baron AD. Obesity/insulin resistance is associated with
by vitamins C and E. J Am Coll Cardiol 2000;36:2185e91. endothelial dysfunction. Implications for the syndrome of
[45] Houben AJ, Schaper NC, de Haan CH, Huvers FC, Slaaf DW, de insulin resistance. J Clin Invest 1996;97:2601e10.
Leeuw PW, et al. Local 24-h hyperglycemia does not affect [58] Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased
endothelium-dependent or -independent vasoreactivity in effect of insulin to stimulate skeletal muscle blood flow in
humans. Am J Physiol 1996;270:H2014e20. obese man. A novel mechanism for insulin resistance. J Clin
[46] Perticone F, Ceravolo R, Candigliota M, Ventura G, Iacopino S, Invest 1990;85:1844e52.
Sinopoli F, et al. Obesity and body fat distribution induce [59] Arcaro G, Cretti A, Balzano S, Lechi A, Muggeo M, Bonora E,
endothelial dysfunction by oxidative stress: protective effect et al. Insulin causes endothelial dysfunction in humans: sites
of vitamin C. Diabetes 2001;50:159e65. and mechanisms. Circulation 2002;105:576e82.
[47] Arcaro G, Zamboni M, Rossi L, Turcato E, Covi G, Armellini F, [60] Cardillo C, Nambi SS, Kilcoyne CM, Choucair WK, Katz A,
et al. Body fat distribution predicts the degree of endothelial Quon MJ, et al. Insulin stimulates both endothelin and nitric
dysfunction in uncomplicated obesity. Int J Obes Relat Metab oxide activity in the human forearm. Circulation 1999;100:
Disord 1999;23:936e42. 820e5.