the relationship between inflammation and hypertension has been investigated for many years.1 ) experimental studies have shown that inflammatory cytokines contribute to hypertension by increasing vascular tone and impairing endothelial function .
the relationships between hypertension and high - sensitivity crp ( hs - crp ) , tumor necrosis factor- , interleukin ( il)-6 , and il-18 are well known,2 ) but the relationship between il-18 and left ventricular hypertrophy ( lvh ) is not well studied .
inflammatory cells are activated during acute coronary syndromes , and some indexes such as the neutrophil to lymphocyte ratio3 ) and the white blood cell ( wbc ) count to mean platelet volume4 ) ratio are associated with worse prognosis . like inflammatory cells ,
il-18 was elevated in acute coronary syndromes , and high levels were correlated with worse prognosis.5 ) in addition , the role of il-18 in carotid intima media thickness ( a marker of subclinical atherosclerosis ) is well established.6 ) in experimental animal studies , there is growing evidence regarding the relationship aming il-18 , hypertension , and lvh .
il-18 knockout mice subjected to pressure overload developed less hypertrophy , but also had worse contractile function.7 ) daily administration of il-18 in healthy mice induces myocardial hypertrophy and contractile dysfunction.8 ) these results suggest that il-18 is involved in the hypertrophic response in overload cardiomyopathy . in clinical trials ,
hypertensive patients tend to have higher il-18 concentrations than normotensive groups,9)10 ) but the relationship between il-18 and lvh , which is a marker of end - organ damage , is unknown in humans . in this study , we aimed to investigate the relationship between il-18 and left ventricular mass ( lvm ) in apparently healthy subjects with or without hypertension who were free of atherosclerotic disease .
we performed an observational , cross - sectional study in order to examine the relationships between inflammation , hypertension , and lvh .
the study population was a sample of subjects admitted to the cardiology department of our institute and who were suspected to have hypertension ( n=198 ) .
subjects were eligible to participate in the study if they were 20 to 60 years of age , had no history of hypertension or cardiovascular ( cv ) disease ( coronary artery disease , stroke , peripheral vascular disease ) , were not using antihypertensive medications , were free of any other major systemic illnesses , and were not pregnant .
we performed electrocardiogram and a treadmill test to rule out clinically significant coronary artery disease . a positive or non - diagnostic test result according to the modified bruce protocol
we recruited 198 subjects ( 102 women , 96 men ) who met these criteria .
the local ethics committee assessed and approved the study , and written informed consent for participation in the study was obtained from all individuals whole blood count , total , high - density lipoprotein , and low - density cholesterol , triglycerides , glucose , and serum hs - crp and il-18 concentrations were measured using commercially available enzyme - linked immunosorbent assay ( diagnostic products corporation , los angeles , ca , usa ) .
electrocardiogram and two - dimensional echocardiography were performed in all of the subjects participating in the study .
the sokolow - lyon index ( sli ) was calculated as the sum of the amplitudes of v1s and v5r .
echocardiographic studies were performed using the acuson sequoia c256 ( siemens medical solutions usa inc .
, mountain view , ca , usa ) or the sonos 7500 ( phillips , andover , ma , usa ) . all echocardiographic measurements and the estimation of lv mass
were performed according to the recommendations of the american society of echocardiography and the european association of echocardiography.11 ) the 24 hour ambulatory blood pressure ( bp ) monitoring was performed with oscillometric equipment ( tonoport ge , berlin , germany ) .
the cuff was applied to the non - dominant arm at the end of the visit .
the device was set to obtain ambulatory bp and heart rate readings at 30 minutes intervals for 24 hours , during which the subjects were sent home and asked to perform their usual activities .
the subjects were asked to keep a diary of daily activities and the time of sleep and to return to the hospital 24 hours later .
hypertension was determined based on 24 hour systolic and diastolic bp averages ; a 130/80 mmhg cut - off value was used .
statistical calculations were performed using spss 15 for windows ( spss inc , chicago , il , usa ) .
continuous and normally distributed variables are presented as meanstandard deviation , and non - normally distributed variables are presented as median ( min - max ) .
continuous variables were compared among the groups of patients with student 's t - test for normally distributed data and the kruskal 
the pearson test for normally distributed data and the spearman test for non - normally distributed data were used for bivariate correlations .
the study population was composed of 102 women and 96 men between the ages of 20 - 60 years .
patients were divided into hypertensive ( n=76 ) and normotensive ( n=120 ) groups according to average 24 hour bp value .
the 24 hour systolic and diastolic bp averages and day and night systolic and diastolic bp averages were significantly higher in the hypertensive group .
the frequency of type 2 diabetes was very low in the study population ( 2.5% ) and was not statistically different between groups .
lvm , left ventricular mass index ( lvmi ) , sli , wbc count , hs - crp , and il-18 were higher in the hypertensive group than in the normotensive group ( table 1 ) .
day , night , and 24 hour systolic and diastolic blood pressure averages were all correlated with il-18 level in the total study population . we also found positive correlations between il-18 and body mass index ( bmi ) lvm , lvmi , triglyceride , and hs - crp and a negative correlation between il-18 and high - density lipoprotein ( table 2 ) .
the correlation between il-18 and 24 hour systolic bp are shown in fig . 1 , and the correlation between il-18 and lvmi is shown in fig .
2 . in the hypertensive group , only night systolic bp average and lvm were correlated with il-18 level ( table 3 ) . in the normotensive group , no significant correlations were found between bp averages and il-18 ; however , bmi , lvm , and hs - crp level were all positively correlated with il-18 ( table 4 ) .
in multivariate analysis , the correlations between il-18 , lvmi , and hs - crp remained statistically significant in the entire study population .
in contrast to these findings , we did not find any independent relationships in normotensive patients .
on multivariate analysis , there were no statistically significant relationships between il-18 level and bp parameters ( table 5 ) .
therefore , il-18 level was independently associated with lvmi and hs - crp level in the whole study population and in newly diagnosed hypertensive patients .
bp averages were also positively correlated with serum il-18 level in the entire study population .
il-18 level was independently associated with lvmi and hs - crp level in the whole study population and in newly diagnosed hypertensive patients .
normotensive subjects do not have clinically significant cv disease or hypertension , both of which are known to alter lvmi and il-18 level .
therefore , the absence of these diseases may explain the lack of any relationship between these parameters in this group .
we hypothesize that the independent relationships seen in the general population were mainly due to the hypertensive subjects . to our knowledge
, our study is the first to show an independent relationship between lvmi and il-18 level in humans . in most previous studies ,
hypertensive subjects had higher il-18 level than normotensive subjects , and il-18 level was positively correlated with office bp.9)10 ) these findings are consistent with our study findings . however , unlike out study , the prime study ( n=1005 ) did not find a statistically significant difference in il-18 level between hypertensive and normotensive groups.12 ) in that study , all participants were males between 50 - 59 years of age , and interleukin level was measured in plasma rather than serum .
the narrow range of age and gender might have obscured the relationship between il-18 and hypertension .
we used ambulatory blood pressure readings , which are more accurate and have different diagnostic criteria than office measurements.13 ) several studies have shown that lvh and other markers of organ damage correlate with ambulatory bp more closely than with office bp in hypertensive patients.14 ) evidence from meta - analyses of published observational studies and pooled individual data has shown that ambulatory bp is a more sensitive risk predictor of clinical cv outcomes , such as coronary morbid or fatal events and stroke , than office bp.15 ) the superiority of ambulatory bp has been shown in the general population , in hypertensive patients , in patients at high risk , and in patients with cv disease.16)17 ) these factors make our findings more valuable .
left ventricular hypertrophy , especially of the concentric type , is associated with a cv disease risk higher than 20% in 10 years.18 ) in hypertensive patients with lvh , a therapeutically - induced reduction of lvm was significantly associated with cv event reduction.19 ) antihypertensive treatment decreases the cv events associated with hypertension ; however , despite successful treatment , risk remains higher than in the general population.20 ) this finding suggests that hypertension - related cv risk is associated with factors other than high bp .
one of these factors might be inflammation ; if so , hypertension treatments targeted to inflammation may result in additional risk reduction .
increased vascular oxidative stress is one of the postulated unifying pathways that leads to hypertension .
vasoactive hormones that play an important role in the pathogenesis of hypertension ( e.g. , angiotensin ii , endothelin i ) , growth factors ( e.g. , platelet - derived growth factor , transforming growth factor- ) , and mechanical stimuli ( e.g. , shear stress and stretch ) activate nicotinamide adenine dinucleotide phospate and result in increased levels of reactive oxygen species.21 ) increased reactive oxygen species damage the vascular wall and impair vasodilation by inactivation of nitric oxide.22 ) angiotensin ii enhances the expression of il-18 receptor in vascular smooth muscle cells.23 ) angiotensin ii , along with aldosterone and endothelin-1 , increases il-18 messenger ribonucleic acid ( mrna ) and protein expression in cardiomyocytes.24 ) the sympathetic nervous system plays an important role in the pathophysiology of hypertension , and evidence supports increased release of epinephrine from the hearts of patients with essential hypertension.25 ) stimulation of the 2-adrenergic receptor activates il-18 promoter activity , upregulates il-18 mrna , and increases il-18 mrna stability and il-18 protein expression in endothelial cells.26 ) two strategies have been used to counter the effects of il-18 : il-18 binding protein ( il-18bp ) , a naturally occurring protein , and a neutralizing il-18 antibody .
recombinant human il-18bp has been investigated in clinical trials and was found to be safe in healthy and obese volunteers27 ) and in patients with psoriasis and rheumatoid arthritis.28 ) evidence from clinical and experimental data suggests that il-18 may be a therapeutic target in acute myocardial infarction,29 ) but no trials have tested this hypothesis in acute myocardial infarction or hf .
based on the scope of the accumulated data in the literature regarding il-18 blockage as a therapeutic intervention , we hypothesize that therapies directed against the inflammatory system may eventually be an option .
furthermore , the cross - sectional and observational nature of our study does not allow us to determine cause and effect relationships .
the elimination half - life of il-18 in vivo is approximately six hours.30 ) blood samples were drawn early in the morning , so our measurements did not represent the entire day and might have missed any diurnal variations .
this makes it difficult to interpret the relationship between il-18 concentration and bp variation , particularly that occurring at times other than that at which the blood samples were drawn .
for instance , variations occurring in the afternoon might have changed il-18 level significantly , but we likely did not detect this effect due to the relatively short elimination half - life . because of this study 's observational and cross sectional design , we can not make any suggestions about patient follow up or treatment strategies . further studies with more participants should be performed to clarify these matters .
our study showed that elevated level of il-18 is associated with hypertension in newly diagnosed hypertensive patients and in the general population .
we also found that lvmi was independently associated with il-18 in both hypertensive patients and in the general population .
these findings comprise a rationale for further larger scale studies that could reveal a cause and effect relationship among il-18 , hypertension , and related left ventricular hypertrophy .
however , based on our results , it is too early to suggest any therapeutic interventions targeting il-18 for treatment of hypertension and lvh .
stronger relaionships supported by future studies may lead to innovations in the treatment of hypertension and lvh in the coming decades .
our study showed that elevated level of il-18 is associated with hypertension in newly diagnosed hypertensive patients and in the general population .
we also found that lvmi was independently associated with il-18 in both hypertensive patients and in the general population .
these findings comprise a rationale for further larger scale studies that could reveal a cause and effect relationship among il-18 , hypertension , and related left ventricular hypertrophy .
however , based on our results , it is too early to suggest any therapeutic interventions targeting il-18 for treatment of hypertension and lvh .
stronger relaionships supported by future studies may lead to innovations in the treatment of hypertension and lvh in the coming decades .
 background and objectivesin clinical trials , hypertensive patients tend to have higher interleukin-18 ( il-18 ) concentrations than normotensive groups , but the relationship between il-18 and left ventricular hypertrophy ( lvh ) , which is a marker of end - organ damage , is not well studied . 
 we aimed to investigate the relationship between il-18 and lvh in apparently healthy subjects free of clinically significant atherosclerotic disease.subjects and methodswe enrolled 198 subjects ( 102 women and 96 men ) between may 2006 and march 2007 , who were free of cardiovascular or immune diseases , but were suspected to have hypertension . 
 twenty - four - hour ambulatory blood pressure monitoring and two - dimensional echocardiography were performed . 
 lipid profiles , high - sensitivity crp ( hs - crp ) , il-18 , and whole blood cell counts were measured for all subjects.resultswhite blood cell count , hs - crp , left ventricular mass , left ventricular mass index ( lvmi ) , and il-18 were higher in the hypertensive group than in the normotensive group ( p=0.045 , p=0.004 , p<0.0001 , p=0.001 , and p=0.017 respectively ) . 
 twenty - four hour day and night systolic and diastolic blood pressure averages were positively correlated with il-18 level in the entire study population . in multivariate regression analysis , left ventricular mass index and hs - crp level were independently associated with il-18 level in both the hypertensive group and the entire study population ( =0.154 , =0.149 p=0.033 , p=0.040 and =0.151 , =0.155 p=0.036 , p=0.032 respectively)conclusionwe found that il-18 level independently predicted lvmi in both the general population and in newly diagnosed hypertensive patients . 
Introduction
Subjects and Methods
Results
Discussion
Conclusion