metabolic syndrome ( mets ) comprises a cluster of abnormalities , with insulin resistance and adiposity as central features [ 13 ] .
five diagnostic criteria for mets have been identified by the national cholesterol education program adult treatment panel iii ( ncep - atp iii ) , and the presence of any of these three features 
central obesity , dyslipidemia ( high triglycerides , low high - density lipoprotein [ hdl ] cholesterol ) , hypertension , and impaired fasting glucose  is considered sufficient to diagnose the syndrome .
about 24% of us adults have mets , and the prevalence increases with age ( 44% at age 60  years ) .
individuals with mets have an increased burden of cardiovascular disease ( cvd ) [ 68 ] . in the kuopio ischemic heart disease study , lakka et al
.   convincingly showed that men with mets , even in the absence of baseline coronary artery disease ( cad ) or diabetes , had a significantly increased mortality from cad . in the botnia study , mets was defined as the presence of at least two of the following risk factors : obesity , hypertension , dyslipidemia , or microalbuminuria .
cardiovascular mortality was assessed in 3,606 individuals , with a median follow - up of 6.9  years . in women and men ,
respectively , mets was seen in 10% and 15% of participants with normal glucose tolerance , 42% and 64% of those with impaired fasting glucose / impaired glucose tolerance , and 78% and 84% of those with type 2 diabetes mellitus . in individuals with mets ,
the risk for coronary heart disease ( chd ) and stroke was increased threefold ( p  <  0.001 ) and the risk for cardiovascular mortality was increased sixfold ( 12.0% vs 2.2% ; p  <  0.001 ) [ 68 ] . using data from the third national health and nutrition examination survey ( nhanes iii ) ,
alexander et al .   reported that mets is very common , with 44% of the us population over 50  years of age meeting the ncep - atp iii criteria .
individuals with mets without diabetes had higher chd prevalence ( 13.9% ) , and those with both mets and diabetes had the highest prevalence of chd ( 19.2% ) compared with those with neither .
the hoorn study examined 615 men and 749 women aged 50 to 75  years without diabetes or a history of cvd at baseline and reported that the ncep - atp iii definition of mets was associated with about a twofold increase in age - adjusted risk of fatal cvd in men and nonfatal cvd in women [ 68 ] .
the lower but significant risks were also obtained using the world health organization , american college of endocrinology , and european group on insulin resistance definitions of mets .
ford [ 5 , ] using the modified ncep - atp iii criteria on the nhanes cohort , also reported significantly increased prevalence of mets in the us population .
besides the effect on cardiovascular morbidity and mortality , the components of mets have been associated with diabetes .
hanson et al .   used factor analysis to identify the components of mets on 1918 native americans of the pima tribe .
insulin resistance factor was strongly associated with diabetes in a 4-year follow - up . also , the body size and the lipid factor predicted diabetes whereas the blood pressure factor did not . in the west of scotland coronary prevention study ( woscops ) , mets increased the risk for chd events and diabetes .
participants with four or five features of the syndrome had a 3.7-fold increase in risk for chd and a 24.5-fold increase in risk for diabetes compared with those with no features of the syndrome .
the prospective cardiovascular mnster ( procam ) study   also reported a 2.3-fold increased incidence of cvd in participants with mets , and these effects persisted after adjustment for conventional risk factors .
although individual components of mets independently contribute to increased cardiovascular risk , in concert they do not explain the increased propensity of vascular disease in individuals with mets , and the precise mechanisms for this increased propensity remain to be elucidated .
inflammation is pivotal in all phases of atherosclerosis , from foam cell formation to culmination in acute coronary syndromes .
it appears that low - grade chronic inflammation is a central feature of mets and could contribute to increased risks of both cvd and diabetes in mets .
evidence supporting the hypothesis that elevated c - reactive protein ( crp ) levels contribute to increased cardiovascular risk is now available from at least six major prospective studies .
these are the physician s health study ( phs ) , women s healthy study ( whs ) , atherosclerosis risk in communities ( aric ) study , and air force / texas coronary atherosclerosis prevention study ( afcaps / texcaps )   in the united states and the monitoring trends and determinants on cardiovascular diseases / cooperative health research in the region of augsburg ( monica / kora augsburg )   and the age gene / environment susceptibility ( ages)-reykjavik   studies in europe . the largest of the american cohorts is the whs , a prospective evaluation of 27,939 initially healthy american women who underwent high - sensitivity crp ( hscrp ) evaluation along with a full lipid panel and framingham risk assessment and were monitored over a period of 8.3  years for the occurrence of first - ever cardiovascular events .
overall , baseline hscrp levels in the whs were a strong predictor of future vascular events ; the relative risks for those with lowest to highest quintiles of hscrp at baseline were 1.0 , 1.8 , 2.3 , 3.2 , and 4.5 ( p  <  0.001 ) .
after adjustment for age , smoking , diabetes , blood pressure , and hormone replacement therapy , the risk in the top quintile of hscrp was 2.3 ( 95% ci , 1.63.4 ) .
a combined approach , using both a lipid panel and hscrp , provided improved prediction of cardiovascular event  free survival .
most importantly , hscrp levels remained a highly significant predictor of risk in the whs after adjustment for the framingham risk score .
data on hscrp from the phs and whs have been corroborated by similar analyses from other large cohorts from the united states and europe . in a case - cohort analysis of 12,819 apparently healthy middle - aged men and women participating in the aric study over a 6-year follow - up period , the relative risks of incident chd for those with baseline hscrp levels less than 1.0 , 1.0 to 3.0 , and greater than 3.0  mg / l were 1.0 , 1.6 , and 2.5 , respectively , after adjusting for age , gender , and ethnicity .
almost identical data were derived from a prospective evaluation of 3435 german men participating in the monica / kora augsburg cohort study , in which 191 incident coronary events occurred during 6.6  years of follow - up . in this study of men , as in the whs study of women , hscrp levels at baseline were independently associated with incident coronary events .
these effects remained significant ( p < 0.001 ) after adjustment for framingham risk score .
although this prospective study used an hscrp cut - point for relative risk of 2.0 rather than 3.0 , and thus would tend to underestimate effects compared with other cohorts , a highly significant fully adjusted odds ratio of 1.5 was observed . within the afcaps / texcaps analysis of 5,742 apparently healthy individuals enrolled in a randomized primary prevention trial of lovastatin versus placebo , each quartile increase in baseline hscrp was associated with a 21% increase in the risk of a first cardiovascular event ( 95% ci , 441% ) , an effect that again persisted after control for all individual components of the framingham risk score .
similarly , in an analysis of 1,666 individuals free of cvd enrolled in the pravastatin inflammation / crp evaluation ( prince ) study , hscrp levels correlated modestly with 10-year framingham risk scores yet showed minimal relation to any individual component of the score itself .
furthermore , it has been proposed that hscrp be added as a clinical criterion for mets and for creation of an hscrp - modified chd risk score . with regard to mets , yudkin et al .
, conducted z - score analyses in a study 107 nondiabetic individuals and found a very significant correlation between inflammatory markers and several features of the mets .
crp levels were shown to be strongly associated with insulin resistance calculated from the homeostatic model assessment , blood pressure , low hdl , and triglycerides , and also to levels of the proinflammatory cytokines interleukin-6 ( il-6 ) and tumor necrosis factor ( tnf ) .
there is a linear relationship between the number of metabolic features and increasing levels of hscrp .
furthermore , festa et al . , in the insulin resistance and atherosclerosis study ( iras ) , showed that hscrp was positively correlated with body mass index , waist circumference , blood pressure , triglycerides , cholesterol , low - density lipoprotein ( ldl ) cholesterol , plasma glucose , and fasting insulin , and that it was inversely correlated with hdl cholesterol and the insulin sensitivity index .
the strongest associations were observed between crp levels , central adiposity , and insulin resistance .
the largest study to date that examined the association between inflammation and mets was nhanes iii . in a representative sample of the us population ( 8570 participants >
20  years of age ) , individuals with mets , defined using ncep - atp iii criteria , were more likely than those without the syndrome to have elevated levels of markers of inflammation such as crp , fibrinogen , and leukocyte count .
[ 12 , 14 ] evaluated inter - relationships between crp , mets , and incident cardiovascular events among 14,719 apparently healthy women who were followed for an 8-year period for myocardial infarction , stroke , coronary revascularization , or cardiovascular death ; 24% of the cohort had mets at study entry . at baseline ,
median crp levels for those with zero , one , two , three , four , or five characteristics of the metabolic syndrome were 0.68 , 1.09 , 1.93 , 3.01 , 3.88 , and 5.75  mg / l , respectively ( p for trend < 0.0001 ) . over the 8-year follow - up , cardiovascular event - free survival rates based on crp levels above or below 3.0  mg /
l were similar to survival rates based on having three or more characteristics of mets .
at all levels of severity of mets , crp added prognostic information on subsequent risk .
additive effects for crp were also observed for those with four or five characteristics of mets .
thus , in this study , those who had hscrp levels of less than 3  mg / l without mets had the best cardiovascular survival , whereas those who had hscrp levels greater than 3  mg / l with mets had the worst cardiovascular survival .
an almost identical additive interaction between hscrp , mets , and subsequent vascular risk was observed in woscops , a randomized intervention trial of pravastatin that monitored 6447 middle - aged men over a 5-year period . in woscops ,
mg / l at baseline was highly predictive of incident vascular events after stratification by the presence or absence of mets . specifically , the observed relative risks of future coronary events in the low - crp / mets - absent , high - crp / mets - absent , low - crp / mets - present , and high - crp / mets - present subgroups within woscops were 1.0 ( referent ) , 1.6 , 1.6 , and 2.8 , respectively ( p  <  0.05 ) .
studied 4,017 men and women  65  years of age without baseline congestive heart failure ( chf ) or diabetes participating in the cardiovascular health study , an observational study with 12.2  years follow - up and 966 cases of incident chf .
baseline crp / mets or il-6/mets were defined as presence of three of six components , with elevated crp ( 3 
mg / l ) or il-6 ( 2.21  pg / ml ) as a sixth component added to ncep - atp iii criteria .
mets and elevated inflammation markers were independently associated with chf risk ( hazard ratio = 1.32 [ 95% ci , 1.161.51 ] for mets ; 1.53 [ 95% ci , 1.341.75 ] for crp ; and 1.37 [ 95% ci , 1.191.55 ] for il-6 ) .
there was a 20% relative excess risk attributed to the combination of mets and crp ( 95% ci , 44% to 88% ) .
crp / mets and il-6/mets definitions reclassified 18% and 13% , respectively , of participants as having mets .
both crp / mets and il-6/mets increased risk of chf by 60% compared with those without mets . in this study ,
mets and inflammation markers provided additive information on chf risk in this elderly cohort . in a cross - sectional study of 3,873 individuals ( weighted to 156 million ) aged  18  years participating in the nhanes 19992000
, participants were classified as having diabetes , mets according to modified ncep - atp iii criteria , or neither condition by low ( < 1 
mg / l ) , intermediate ( 13  mg / l ) , or high ( > 3 
reported that after adjusting for age , gender , smoking , and total cholesterol , compared with those with neither mets nor diabetes and low crp levels , the odd ratios of cvd were 1.99 ( 95% ci , 1.103.59 ) for those with no disease and high crp levels and 2.67 ( 95% ci , 1.305.48 ) for those with mets and intermediate crp .
persons with mets but high crp had an or of 3.33 ( 95% ci , 1.806.16 ) , similar to those with diabetes and low crp ( 3.21 ; 95% ci , 1.278.09 ) .
the likelihood of cvd was highest in those with diabetes who had intermediate crp levels ( 6.01 ; 95% ci , 2.5414.20 ) and in those with diabetes and high crp ( 7.73 ; 95% ci , 3.9914.95 ) .
.   showed in the nurses health study and health professionals follow - up study that whereas mets was a strong predictor of chd in both men and women , crp was additive in men only .
it should be emphasized that in this study , a modified definition of mets was used because waist circumference , blood pressure , and glucose were not available at baseline . in a smaller japanese study by takeno et al .   of 461 patients with acute myocardial infarction , crp levels were additive to mets in predicting future major adverse cardiac events .
furthermore , recent investigation relating increased crp levels and mets in 1,044 older ( 65  years ) individuals has also led to the conclusion that mets is associated with low - grade systemic inflammation and that the association is mainly supported by a strong independent correlation between waist circumference and high hscrp levels .
collectively , all these studies support the hypothesis that an increased crp level in the setting of mets confers an increased risk of future cardiovascular events .
additionally , a genome - wide association study has been performed among 6,345 apparently healthy women in whom 336,108 single nucleotide proteins were evaluated as potential determinants of plasma crp concentration .
overall , seven loci that associate with plasma crp at levels achieving genome - wide statistical significance were found .
two of these loci ( gckr and hnf1a ) are suspected or known to be associated with maturity - onset diabetes of the young , one is a gene - desert region on 12q23.2 , and the remaining four loci are in or near the leptin receptor protein gene , the apolipoprotein e gene , the il-6 receptor protein gene , or the crp gene itself .
the protein products of six of these seven loci are directly involved in mets , insulin resistance , -cell function , weight homeostasis , and/or premature atherothrombosis .
thus , it was concluded that common variations in several genes involved in metabolic and inflammatory regulation have significant effects on crp levels , consistent with the identification of crp as a useful biomarker of risk for incident vascular disease and diabetes .
these findings have sparked increased discussion about the formal addition of hscrp to the criteria of mets .
in addition to the prognostic information that hscrp evaluation might add to the current definition of mets , there are several other practical benefits of hscrp measurement . first , hscrp is strongly associated with components of mets that are difficult to measure in routine clinical practice , such as impaired fibrinolysis and insulin resistance [ 19 , 20 ] .
also , the widespread availability of commercial assays for hscrp has made its measurement simple and inexpensive .
in addition , as hscrp does not display diurnal variation and demonstrates long - term stability comparable with cholesterol , it can be reliably evaluated with a single nonfasting measurement [ 29 , 30 ] .
the addition of hscrp measurement to our present diagnosis of the mets may significantly improve the early detection of risk for future diabetes and cardiovascular events in individuals .
overall , it appears that in individuals with mets , an elevated crp confers a greater risk for cardiovascular events by activation of monocytes and induction of endothelial cell dysfunction .
endothelial dysfunction ( ed ) is now recognized to play a critical role in the initiation and progression of atherosclerotic vascular disease [ 3335 ] .
furthermore , endothelial function assessment by brachial flow - mediated dilatation is a surrogate marker of cardiovascular risk [ 36 , 37 ] and has been shown to be decreased in mets [ 3843 ] .
previous studies have shown that obesity , low hdl cholesterol , impaired glucose tolerance , hypertriglyceridemia , and hypertension are associated with decreased endothelium - dependent vasodilatation [ 44 , 45 ] .
an impressive amount of data now implicates crp in inducing endothelial cell activation and dysfunction in vitro as well as in vivo [ 4852 ] .
several observations demonstrated that crp levels correlated inversely with endothelial vasoreactivity in vivo [ 53 , 54].the most compelling data implicating crp as a determinant of ed were studies demonstrating that human crp reduced basal and stimulated nitric oxide release from arterial and venous endothelial cells [ 55 , 56 ] .
our group has explored various mechanistic events involved in crp - mediated endothelial nitric oxide synthase ( enos ) inhibition and documented that increased nadph oxidase activation and gtpch1 downregulation are associated with crp - mediated enos uncoupling in human airway epithelial cells in vitro [ 57 ] . in vivo studies have shown that crp impairs endothelial vasoreactivity and decreases enos activity [ 48 , 49 , 5154 ] .
guan et al . [ 58 ] showed that a single intravenous injection of adeno - associated virus ( aav ) vector with hscrp to male rats resulted in efficient and sustained expression of crp in the liver and other tissues and an increase in serum crp to 15  g / ml at 2 and 4  months .
the authors went on to show impaired endothelium - dependent vasoreactivity in the aav - hscrp rats versus the control rats administered aav - green fluorescent protein .
previously , we have shown that crp inhibits prostacyclin synthase , resulting in decreased prostacyclin , which is a potent vasodilator .
thus , crp , by inducing ed , could put individuals with mets at further risk for hypertension and cvd .
individuals with mets are in a procoagulant state , as evidenced by increased circulating plasminogen activator inhibitor-1 ( pai-1 ) .
we have shown that crp induces pai-1 and decreases tissue plasminogen activator in endothelial cells [ 59 , 60 ] .
crp appears to induce pai-1 antigen and activity via upregulation of nuclear factor-b ( nf-b ) and rho kinase activities .
individuals with mets have increased circulating levels of cell adhesion molecules ( cams ) . in 943 70-old participants ( 50% women ) of the prospective investigation of the vasculature in uppsala seniors ( pivus ) study ,
ingelsson et al .   reported that vascular cell adhesion molecule-1 ( vcam-1 ) , e - selectin , and crp demonstrated the strongest associations with mets and insulin resistance . also , in the women s health study , women with mets had significantly higher crp and soluble intercellular adhesion molecule-1 ( icam-1 ) levels that correlated significantly with increased vascular risk
. furthermore , kressel et al .   showed that individuals with mets had significantly higher values of crp , soluble icam , and soluble vcam compared with those without mets .
rosso et al .   demonstrated increased vcam in individuals with mets , and this correlated significantly with the quantitative insulin - sensitivity check index ( quicki ) .
we have previously shown in shear stress and static conditions that crp upregulates icam , vcam , nf-b , and monocyte - endothelial cell adhesion in a dose - dependent manner .
the proinflammatory effects of crp that have been documented in monocyte - macrophages include induction of tissue factor , proinflammatory cytokines , reactive oxygen species , chemokine receptor ccr2 , release of matrix metalloproteinase ( mmp ) , cd11b expression , and oxidized ldl uptake as well as inhibition of cholesterol efflux and lipopolysaccharide ( lps)-induced il-10 release [ 6773 , 74 ] .
another important in vivo demonstration made recently is from our group on the induction of myeloperoxidase activity in macrophages by crp administration .
several lines of experimental evidence support the role of monocyte chemotactic protein-1 ( mcp-1 ) in atherogenesis , insulin resistance , and adipose tissue - mediated inflammation . also , crp has been reported to induce mcp-1 in endothelial cells   and its receptor ccr2 on monocytes .
furthermore , esposito et al .   have reported that in both obese and non - obese women , il-10 levels were significantly lower in women with mets . in this regard , we have reported that crp inhibits lps - induced il-10 release from human monocyte - derived macrophages .
recently , bisoendial et al .   examined whole - blood expression for 95 inflammatory markers before and after infusion of 1.25  mg / kg of recombinant human crp in five male volunteers using quantitative real - time polymerase chain reaction analysis .
relevant transcript levels were measured at baseline and 4 and 8  h after recombinant human crp infusion .
crp caused significant upregulation of mmp-9 , mcp-1 , plasminogen activator urokinase , macrophage inflammatory protein 1  , and nf-b mrnas in peripheral leukocytes .
the corresponding increase in plasma protein levels of mmp-9 ( 78    32  ng / ml to 109    41  ng / ml ; p  =  0.014 ) and mcp-1 ( 312    92  pg / ml to 2,590    898  pg / ml ; p  =  0.007 ) closely mirrored mrna findings .
thus , mets individuals , who have persistently high crp levels , may demonstrate increased leukocyte activation compared with those with low crp levels , and this may contribute to increased cardiovascular risk in these individuals .
oxidative stress , mainly superoxide , plays a critical role in the pathogenesis of mets parameters .
they also demonstrate increased superoxide , nitrotyrosine , and oxidized ldl in mets patients compared with controls , although mets patients studied in this report were on various medications , including statins ( 39% ) and oral hyperglycemics ( 21% ) .
thus , there is an emergent need to study monocyte biology in drug - nave mets patients with low and high crp levels , a subject that has not yet been explored .
furthermore , crp has been shown by numerous investigators , including our group , to result in increased superoxide production as a result of enhanced nadph oxidase activity in endothelial cells as well as in human peripheral blood monocytes [ 55 , 57 , 68 , 73 , 81 , 82 ] .
also , in situ hybridization revealed the presence of crp mrna that co - localized with p22phox , an essential component of nadph oxidase .
we also demonstrated in wistar rats that crp stimulates superoxide production in macrophages via upregulation of nadph oxidase .
increased oxidized ldl in the vessel wall and circulation has been shown in patients with acute coronary syndrome and is associated with ed and predicted cardiovascular events .
furthermore , patients with mets exhibit increased plasma oxidized ldl levels . in addition , we recently showed that crp promotes oxidized ldl uptake and cholesterol ester accumulation in wistar rats [ 74 ] .
tissue factor is increased in morbidly obese persons with abnormal glucose tolerance compared with those with normal glucose tolerance .
diamant et al .   also demonstrated increased tissue factor  containing microparticles in type 2 diabetes mellitus that correlated significantly with features of mets in this population . in vivo ,
we have shown that crp promotes tissue factor activity in vitro and in vivo in the rat model and shown that it occurs via activation of reactive oxygen species and nf-b .
mmps and their tissue inhibitors of metalloproteinase ( timp ) may play a role in cardiovascular complications associated with mets .
studies have shown increased levels of pro - mmp-9 , mmp-8 , and timp-1 in mets patients compared with controls .
furthermore , we have confirmed in vitro and in vivo that crp augments mmp-9 release and activity when injected into wistar rats .
studies in animal models have demonstrated the importance of ikk in the pathogenesis of insulin resistance in obese and diabetic rodents .
recently , it has also been shown in humans that obesity is associated with an increase in nf-b binding in the nucleus and a decrease in the inhibitory b in the mononuclear cells , with increased mrna for tnf , il-6 , macrophage inhibitory factor , and mmp-9 , consistent with the proinflammatory state .
recently , we have shown that crp induces nf-b activity in rat macrophages in vivo [ 68 , 74 ] .
also , we have previously shown that in mets patients , simvastatin therapy decreased hscrp levels and mononuclear nf-b activity .
emerging laboratory and clinical evidence has shown a strong relationship between crp and various features of mets .
the addition of crp to the present definition of the mets may help identify patients at high risk for future diabetes and cvd .
further investigation is clearly needed not only to clarify the molecular role of crp in the pathogenesis of mets , but also to shed new light on the role of crp , specifically in mediating vascular effects and conferring increased risk of cardiovascular events in mets patients with high crp levels . in this regard
, it should be emphasized that the justification for the use of statins in prevention : an intervention trial evaluating rosuvastatin ( jupiter ) [ 90 ] study showed a clear benefit of statin therapy in patients with crp greater than 2  mg / l , and the published evidence base supports a role for statin therapy in mets .
 metabolic syndrome is associated with increased propensity for diabetes and cardiovascular disease . 
 low - grade inflammation is characteristic of metabolic syndrome . 
 c - reactive protein , the best characterized biomarker of inflammation , is also an independent predictor of future cardiovascular events . 
 this review outlines the role of high - sensitivity c - reactive protein in contributing to increased cardiovascular risk in metabolic syndrome by inducing endothelial cell dysfunction and activating monocytes . 