metabolic syndrome ( ms ) is a group of cardiovascular ( cv ) risk factors including abdominal obesity , hypertriglyceridemia , low high - density lipoprotein cholesterol ( hdl - c ) , dysglycemia , and high blood pressure ( bp ) .
numerous studies have shown that a significant increase in systemic inflammatory markers , such as high sensitivity c - reactive protein ( hscrp ) , interleukin-6 , and tumor necrosis factor- ( tnf- ) , among others , is observed in subjects with ms .
high sensitivity c - reactive protein is a good predictor of ms and is strongly associated with abdominal obesity .
moreover , this biomarker predicts cv events in healthy people as well as in those with atherosclerotic disease [ 5 , 6 ] .
it has been reported that hscrp is elevated in an urban population of santiago , chile , with ms , and there is a clear correlation between ms , hscrp , and subclinical atherosclerosis in this population .
thus , the clustering of cv risk factors and inflammation observed in ms increase the risk of atherosclerosis .
lipoprotein - associated phospholipase a2 ( lp - pla2 ) is a recently described inflammatory marker .
it is an enzyme produced by macrophages that hydrolyzes phospholipids of oxidized low - density lipoprotein ( ldl ) , releasing oxidized fatty acids and lysophosphatidylcholine , which are potent proinflammatory and prooxidative molecules .
since oxidized ldl is mostly located in the intima of the artery , the products of lp - pla2 activity are generated mainly in the vascular wall .
given that atherosclerosis is an inflammatory disease which begins in the vascular wall , lp - pla2 may have a prominent role in its pathophysiology . both lp - pla2 and hscrp
are associated with coronary and cerebrovascular atherosclerotic disease in populations with and without a history of cv events [ 912 ] .
furthermore , lp - pla2 is related to cv risk factors , with a strong correlation with ldl , as well as various components of ms ( e.g. , abdominal obesity ) .
the vast majority of published studies do not show any association between lp - pla2 and hscrp ; hence , these inflammatory markers have been considered to be independent of each other .
the objective of this study was to analyze and compare the levels of lp - pla2 and hscrp as predictors of ms in subjects without atherosclerotic disease .
this was a descriptive cross - sectional study in 152 subjects ( 69 women ) , without history of atherosclerotic disease , who were recruited in two preventive cardiology centers of santiago between october 2011 and june 2012 : hospital clnico de la pontificia universidad catlica de chile and hospital de la previsin de carabineros de chile .
exclusion criteria were ( a ) history of coronary heart disease and/or carotid or peripheral vascular disease ; ( b ) lipid - lowering therapy ( statins , ezetimibe , fibrates , nicotinic acid , and omega 3 ) ; ( c ) use of oral contraceptives or hormone replacement therapy ; ( d ) chronic intake of anti - inflammatory medicines ( steroidal and nonsteroidal ) ; ( e ) acute and/or chronic inflammatory diseases ; and ( f ) pregnancy .
subjects were contacted by telephone and invited to participate by nurses or doctors in charge of the study .
after signing the written , informed consent , patients were subjected to clinical data collection and anthropometric and laboratory measurements , all detailed below . during the visit to the centers , subjects were interviewed about demographics , medical history , education , physical activity , family medical history , and intake of medications .
weight , height , body mass index ( bmi ) , and hip and waist circumferences were measured .
the latter was measured in the midpoint between the last rib and the iliac crest .
blood pressure was measured following the recommendations of the seventh joint national committee , with the subject sitting and after 5 minutes of rest .
venous blood samples were taken after 12-hour fasting for determining the following biochemical parameters.lp-pla2 : samples for analysis of lp - pla2 activity were frozen and stored at 70c .
levels of lp - pla2 activity were determined by enzymatic method ( diadexus , usa ) , cobas 8000 analyzer , c702 module .
prior to the analysis , precision and trueness of the enzymatic test were assessed locally , and a calibration curve was constructed , which was sent to the international center for approval . following the approval , the analysis of the subjects ' samples was performed.total cholesterol ( total - c ) : colorimetric enzymatic method , roche diagnostics cobas analyzer cobas 8000 , c702 module.hdl-c : colorimetric homogeneous enzymatic method , roche diagnostics cobas , cobas 8000 analyzer , c702 module.triglycerides : white colorimetric enzymatic method with glycerol , roche diagnostics cobas , cobas 8000 analyzer , c702 module.ldl cholesterol ( ldl - c ) : calculated by friedewald formula.blood glucose : enzymatic method ( hexokinase ) , roche diagnostics cobas , cobas 8000 analyzer , c702 module.creatinine : jaff method , roche diagnostics cobas , cobas 8000 analyzer , c70 module.hscrp : nephelometric method on bn prospec analyzer , siemens ( detection limit 0.16  mg / l).fibrinogen : clauss method in acl top 500 analyzer , instrumentation laboratory .
lp - pla2 : samples for analysis of lp - pla2 activity were frozen and stored at 70c .
levels of lp - pla2 activity were determined by enzymatic method ( diadexus , usa ) , cobas 8000 analyzer , c702 module .
prior to the analysis , precision and trueness of the enzymatic test were assessed locally , and a calibration curve was constructed , which was sent to the international center for approval . following the approval , the analysis of the subjects ' samples was performed . total cholesterol ( total - c ) : colorimetric enzymatic method , roche diagnostics cobas analyzer cobas 8000 , c702 module .
hdl - c : colorimetric homogeneous enzymatic method , roche diagnostics cobas , cobas 8000 analyzer , c702 module .
triglycerides : white colorimetric enzymatic method with glycerol , roche diagnostics cobas , cobas 8000 analyzer , c702 module . ldl cholesterol ( ldl - c ) : calculated by friedewald formula .
blood glucose : enzymatic method ( hexokinase ) , roche diagnostics cobas , cobas 8000 analyzer , c702 module .
creatinine : jaff method , roche diagnostics cobas , cobas 8000 analyzer , c70 module .
hypertensives were subjects who had a prior diagnosis according to the jnc 7 , with or without pharmacologic therapy , and/or those with an average blood pressure 140/90  mm hg .
dyslipidemics were subjects who had ldl - c level 130  mg / dl , hdl - c level < 40  mg / dl in men , < 50  mg / dl in women , or non - hdl - c level 160  mg / dl in the laboratory assessment .
subjects were considered diabetics if they had a prior diagnosis , with or without drug treatment , and/or if they had a fasting blood glucose 126  mg / dl during the study , according to the american diabetes association criteria .
current smokers were those subjects who smoked daily during the last month , and ex - smokers were those subjects who had at least six consecutive months without smoking .
the recent harmonized criteria were used for the diagnosis of ms , which includes a waist circumference 90  cm in men and 80  cm in women for latin american populations .
a logistic regression analysis was performed with each biomarker , adjusted for age and gender .
smooth receiver operating characteristic ( roc ) curves were constructed with cubic splines for ms ( area under the curve c value = 0.50 implies a predictive value equivalent to chance ) .
comparisons of means ( expressed as mean  standard deviation [ sd ] ) are based on the analysis of variance and linear regression models .
this study included 152 subjects ( 45% women ) with a mean age of 46  11 years .  
prevalence rate for hypertension , diabetes , dyslipidemia , and current smoking was 30% , 5% , 62% , and 31% , respectively , with no significant differences observed between genders .
prevalence of ms was 38% ( 57 subjects ) in the total sample with no significant differences between genders : 42% and 32% in men and women , respectively .  
men had significantly higher waist circumference ( p < 0.01 ) , systolic and diastolic bp ( p < 0.0001 ) , and creatinine levels ( p < 0.0001 ) than women .
mean level of hscrp was 2.1  2.2  mg / l , and there were no significant differences between men and women ( table 2 ) .
likewise , there were no significant differences in the prevalence of high levels of hscrp ( defined as > 2 
mg / l ) between genders ( 39% in men and 36% in women ) . of note , hscrp was significantly and directly correlated with bmi , waist circumference , blood glucose , systolic bp , non - hdl - c , and fibrinogen , and it was inversely and significantly correlated with hdl - c ( table 3 ) .
mean level of lp - pla2 activity was 185  48  nmol / ml / min in the total sample with significant differences between men and women : 201  nmol / ml / min and 166  nmol / ml / min ( p < 0.0001 ) , respectively ( table 2 ) .
lp - pla2 was significantly and directly correlated with bmi , waist circumference , diastolic bp , ldl - c , non - hdl - c , and plasma creatinine ; hdl - c was inversely and significantly correlated with lp - pla2 .
no significant correlations were found between lp - pla2 and blood glucose , systolic bp , hscrp , and fibrinogen ( table 3 ) .
no differences were found between lp - pla2 activity of active smokers and nonsmokers . as shown in table 4 ,
both lp - pla2 and hscrp were significantly higher in subjects with ms than in those without ms . in subjects with ms ,
lp - pla2 was 198  45  nmol / ml / min versus 180  48  nmol / ml / min in subjects without ms ( p = 0.03 ) .
mg / l in subjects with ms versus 2.2  3.2  mg / dl in those without ms ( p = 0.0001 ) .
both biomarkers significantly increased with the number of ms components : lp - pla2 levels increased from 163  nmol / ml / min to 198  nmol / ml / min ( p < 0.01 ) and hscrp increased from 1.5  mg / l to 4.1  mg / l ( p = 0.04 ) when subjects with 0 and 3 components of ms were compared ( figures 1 and 2 ) .
the results of the logistic regression analysis for determining ms , which included both biomarkers adjusted for age and gender , were as follows : odds ratio ( or ) for lppla2 : 1.02 ( confidence interval [ ci ] : 1.001.02 , p = 0.03 ) and or for hscrp : 2.5 ( ci : 1.653.80 , p < 0.0001 ) .   figure 3 shows the roc curves for both biomarkers adjusted for age and gender : lp - pla2 , c value = 0.66 [ 0.570.74 ] and hscrp , c value = 0.73 [ 0.650.81 ] . according to this analysis , although hscrp shows a better area under the curve , from a statistical point of view , it can not be shown that it is better than lp - pla2 , as the cis of both biomarkers overlap .
in this study , we have demonstrated in a population without atherosclerotic disease that levels of lp - pla2 activity and hscrp are elevated in subjects with ms .
both biomarkers significantly increased with the number of metabolic risk factors , and both were shown to be independent and statistically significant predictors of ms .
the ms corresponds to a clustering of cv and metabolic risk factors and inflammation . in our country ,
ms prevalence is approximately 30% , and it is occurring at younger ages , probably due to the overweight , obesity , and insulin resistance epidemic .
although , the pathophysiologic mechanism involved in ms is not entirely clear , it has been shown that it confers an increased risk for diabetes and atherosclerotic cv disease [ 9 , 15 ] .
recent studies have reported that the presence of ms and inflammation ( determined by hscrp ) confers more cv risk than the presence of ms alone [ 16 , 17 ] .
high sensitivity c - reactive protein is also a predictor for the development of ms and diabetes . in our country , we have previously reported that subjects with ms and elevated hscrp have more subclinical atherosclerosis and carotid atherosclerotic plaques .
therefore , many inflammatory markers related to ms have been investigated in the search of a possible explanation for the elevated cv risk associated with it .
the most studied biomarker is hscrp ; however , there are new biomarkers associated with atherosclerotic disease that may be more specific to vascular inflammation . among them
is lp - pla2 , an enzyme that acts on oxidized ldl and produces strong inflammatory and oxidative mediators of the intima .
epidemiologic and clinical studies have shown an association between atherosclerotic disease and lp - pla2 concentration , in a similar way as reported with hscrp [ 911 , 13 ] . in this study , we have demonstrated that both biomarkers , lp - pla2 and hscrp , predicted ms with a similar power . regarding the association of hscrp with ms
, this study confirms the available evidence showing that levels of hscrp are increased in subjects with ms [ 16 , 17 , 20 ] .
our results also support the association between hscrp and overall / visceral obesity , hdl - c , non - hdl - c , and glycemia .
similar to the findings of ballantyne and colleagues , we demonstrated that hscrp is not associated with lp - pla2 , suggesting that their inflammation pathways are different from a physiologic point of view .
conversely , hscrp was related to fibrinogen , also an acute phase protein that has a similar mechanism of production by the liver .
hscrp is produced by the liver , primarily by the action of interleukin-6 , a cytokine that increases in the conditions of visceral obesity and insulin resistance .
based on this evidence , although hscrp is an important inflammatory marker , it is unspecific .
activity levels of lp - pla2 were also significantly higher in subjects with ms in our study .
these findings are similar to those from the bruneck study in 2009 . in that study ,
tsimikas et al . found significant associations between lp - pla2 and ldl - c , non - hdl - c , hdl - c , and homeostasis model assessment insulin resistance ( homa - ir ) , whereas correlations with bmi and waist circumference were weaker .
our results are identical to those reported by these authors regarding lipid factors and obesity .
however , we did not find any direct correlation with blood glucose , and we did not measure insulin resistance .
furthermore , lp - pla2 was not correlated to bp and smoking in our study , which was seen in the bruneck study .
lastly , we found no association between lp - pla2 and fibrinogen , which confirms that lp - pla2 inflammatory pathway is not through acute phase reaction .
it is important to analyze the relationship between lp - pla2 and ldl - c and non - hdl - c ( atherogenic cholesterol ) . after adjusting for gender and age ,
our population had an average ldl - c level of 128  mg / dl , which suggests that , even at moderate levels of ldl - c , subjects with ms had elevated activity of this enzyme .
this result could be because many subjects with ms have primarily small and dense ldl molecules , which are prone to oxidation and therefore they are substrate for lp - pla2 .
the inflammation produced by lp - pla2 is primarily in the vascular level , because lysophosphatidylcholine and oxidized fatty acids , generated after lp - pla2 action over oxidized ldl , induce adhesion molecules and other cytokines in the same vascular wall .
thus , it can be hypothesized that , unlike hscrp ( which occurs as a result of inflammation caused by other cytokines from the visceral fat ) , lp - pla2 is directly involved in the inflammatory process , and , subsequently , the atherogenic process of the plaque .
thus , lp - pla2 could be a more specific marker of atherosclerotic events in patients with ms .
confirmation of this hypothesis must be demonstrated by studies of cv events in patients with ms , who have these biomarkers measured , and with findings adjusted for all the risk factors associated with hscrp and lp - pla2 . in this regard , it should be noted that a meta - analysis evaluating the clinical use of hscrp has shown that this biomarker adds little in the prognosis of cv risk , when adjusting by the risk factors involved in ms .
conversely , the fact that lp - pla2 was weakly related to these metabolic factors should preserve its power as a biomarker .
the reasons for not having completely cleared lp - pla2 prognosis utility are based primarily on the different techniques used for its measurement , which makes it impossible to compare the results of different studies . in this study
, we did not expect to find the same power for hscrp and lp - pla2 as predictors of ms .
we expected hscrp to be a better predictor , given its close association with metabolic risk factors included in ms .
however , from a statistical point of view ( as demonstrated by the roc curves ) , both had a similar level of prediction .
these results suggest that lp - pla2 is related to ms through other pathways that are not fully known and most likely not associated with the metabolic risk factors . we know that lp - pla2 is linked through oxidized ldl , which is elevated in subjects with ms ,
although it can not be perceived due to the moderate levels of ldl - c observed in the subjects of our study .
oxidized  ldl , and , for measuring  oxidized  ldl in the clinic , it required more expensive and sophisticated methods not frequently used in clinical practice .
since ms is highly prevalent in our population , our results could provide knowledge about nontraditional risk factors that could help to identify which patients with ms must be treated earlier and more aggressively .
this is important , because currently there is a pharmacologic inhibitor of lp - pla2 activity , darapladib , which is being investigated in subjects with atherosclerotic disease .
in addition , another study is currently investigating the use of a monoclonal antibody against interleukin-1 for the intervention against high hscrp .
if these studies have positive results , the measurement and targeting of these biomarkers might become important components of clinical management of patients .
finally , it must be noted that we found no studies in literature that compare lp - pla2 and hscrp as predictors of ms in the general population .
our study has some limitations : ( 1 ) it is a cross - sectional study , and hence causality inferences can not be made ; ( 2 ) it was done in a small , nonrandom sample of subjects ; ( 3 ) we did not include homa - ir , which could explain the relationship of insulin resistance with ms and inflammatory markers ; ( 4 ) finally , we only determined lp - pla2 activity instead of mass .
this decision was subject to the availability of the laboratory determination in our country . however , currently , it is the most used technique , and it has shown the best correlation with ms .
the strengths of the study include the following : ( 1 ) the recruitment of subjects was performed prospectively ; ( 2 ) subjects with lipid - lowering therapy and women with hormone replacement therapy were excluded , among others ; ( 3 ) this study has validated the measurement of lp - pla2 in our country . in conclusion ,
prospective studies must confirm which of the markers or if both markers are causally related to the atherosclerotic consequences observed in subjects with ms .
 high sensitivity c - reactive protein ( hscrp ) is a marker of metabolic syndrome ( ms ) and cardiovascular ( cv ) disease . 
 lipoprotein - associated phospholipase a2 ( lp - pla2 ) also predicts cv disease . 
 there are no reports comparing these markers as predictors of ms 
 . methods . 
 cross - sectional study comparing lp - pla2 and hscrp as predictors of ms in asymptomatic subjects was carried out ; 152 subjects without known atherosclerosis participated . 
 data were collected on demographics , cardiovascular risk factors , anthropometric and biochemical measurements , and hscrp and lp - pla2 activity levels . 
 a logistic regression analysis was performed with each biomarker and receiver operating characteristic ( roc ) curves were constructed for ms . results . 
 mean age was 46  11 years , and 38% of the subjects had ms . 
 mean lp - pla2 activity was 185  48  nmol / ml / min , and mean hscrp was 2.1  2.2  
 mg / l . 
 subjects with ms had significantly higher levels of lp - pla2 ( p = 0.03 ) and hscrp ( p < 0.0001 ) than those without ms . 
 roc curves showed that both markers predicted ms . 
 conclusion . 
 lp - pla2 and hscrp are elevated in subjects with ms . 
 both biomarkers were independent and significant predictors for ms , emphasizing the role of inflammation in ms . 
 further research is necessary to determine if inflammation predicts a higher risk for cv events in ms subjects . 