diastolic heart failure ( dhf ) is a clinical syndrome characterized by the symptoms and signs of heart failure , a preserved ejection fraction and abnormal diastolic function .
the percentage of patients with dhf in epidemiological studies ranges from 4071% ( mean 56% ) , but in hospital - based cohort studies it is slightly lower , ranging from 2455% ( mean 41% ) .
elderliness , hypertension with left ventricular ( lv ) hypertrophy , pathologies such as diabetes , obesity , coronary artery disease , new onset atrial fibrillation , and others are commonly associated with dhf [ 24 ] .
cardiotrophin-1 ( ct-1 ) is a member of the interleukin ( il)-6 cytokine family that shares the transmembrane signaling protein , glycoprotein ( gp ) 130 , as a receptor .
ct-1 mrna is expressed in adult human heart , skeletal muscle , ovary , colon , prostate and testis and in fetal kidney and lung .
ct-1 has hypertrophic and cytoprotective actions on the cardiac myocytes and may play an important role in other organ systems .
the plasma concentration of ct-1 is increased in various cardiovascular diseases such as congestive heart failure , hypertension , valvular heart disease , acute coronary syndrome , and cardiomyopathies [ 818 ] . although , the prognostic importance of ct-1 in various cardiovascular diseases , including congestive heart failure , is well - known , there is limited data about ct-1 in patients with dhf .
the purpose of the present study was to determine if ct-1 levels are significantly different in dhf patients compared to controls and to investigate the relationship between ct-1 and echocardiographic parameters .
fifty - seven consecutive patients ( mean age 578 years , 24 ( 42% ) males ) diagnosed with dhf in our clinic and 33 controls ( mean age 557 years , 12 ( 36% ) males ) were included in the study .
dhf was diagnosed when symptoms ( dyspnea not associated with any other cause ) and signs ( rale or peripheral edema ) of heart failure were observed along with a preserved lv ejection fraction ( lvef ) ( 50% ) and evidence of diastolic dysfunction .
the control group was formed from volunteer subjects admitted to our clinic who did not have heart failure symptoms and signs and who had a preserved lvef . in order to exclude other causes of dyspnea
, all patients underwent physical and laboratory examinations , including serum hemoglobin and thyroid hormones , chest radiogram and spirometry .
patients with systolic heart failure , moderate or severe valvular stenosis or regurgitation , congenital heart disease , atrial fibrillation , chronic obstructive pulmonary disease , malignancy , and other extracellular fluid - increasing diseases , such as hypothyroidism and liver cirrhosis , were excluded from the study .
all of the study participants underwent echocardiographic evaluation ( 2.5 mhz transducer , philips envisor c , bothell , washington , usa ) .
standardized projections and measurements were performed for the evaluation of cardiac anatomy , ventricular function and valve competence .
lv mass index was obtained by dividing the lv mass by the body surface area .
the following conventional mitral inflow pulse wave doppler parameters were measured : peak velocity of early diastolic filling ( e ) , late filling ( a ) , and deceleration time ( dt ) of the e - wave velocity and isovolumetric relaxation time ( ivrt ) .
these parameters were obtained from the apical four - chamber view with a 1 to 3 mm sample volume placed between the mitral leaflet tips during diastole .
pulmonary venous flow parameters were also measured : peak systolic velocity ( ps ) , peak anterograde diastolic velocity ( pd ) and the ps / pd ratio .
these parameters were obtained from the apical four - chamber view with a 2 to 3 mm sample volume placed 1 cm into the pulmonary vein .
tissue doppler parameters were measured : peak systolic mitral annular velocity ( sm ) and early diastolic mitral annular velocity ( em ) and late diastolic mitral velocity ( am ) .
these parameters were obtained from the apical four - chamber view with a 2 to 5 mm sample volume placed 1 cm within the septal and lateral insertions of the mitral leaflets .
the mean of 3 or more measurements was used for analysis of the doppler data .
the ratio of mitral peak velocity of early diastolic filling to early diastolic mitral annular velocity ( e / em ) was calculated for the lateral and septal annulus and the mean of the lateral and septal e / em were also determined .
as previously described , the formula ( 1.24(e / em)+1.9 ) was used to estimate pulmonary capillary wedge pressure ( pcwp ) .
patients with mean e / em 8 or a change in e / a ratio with the valsalva maneuver of < 0.5 were excluded from the study .
diastolic dysfunction was defined as em < am if em was less than 10 cm / sec in lateral mitral annulus or less than 8 cm / sec in septal mitral annulus .
blood samples were obtained during admission for routine chemistry , including ct-1 and n - terminal pro - b - type natriuretic peptide ( nt - probnp ) following an overnight fast .
ct-1 values were measured with a sandwich enzyme immunoassay method ( organon teknika microwell system reader 230 s , germany ) in our hospital laboratory .
nt - probnp analyses were made by the electrochemiluminescence immunoassay method ( cobas 6000 analyzer , roche diagnostics gmbh , mannheim , germany ) .
the cockcroft - gault formula was used to calculate creatinine clearance . according to kolmogorov - smirnov normality test
, 2 independent sample t tests were used to compare the normally distributed independent variables between the 2 groups , and mann - whitney u test was used to compare the non - normally distributed independent variables between the 2 groups . normally distributed continuous data were expressed as mean  standard deviation ( sd ) ; non - normally distributed continuous variables were presented as median and interquartile range ( iqr ) [ quartile l to quartile 3 ] .
linear regression analyses were used to determine the effect of age , creatinine clearance , systolic blood pressure , left atrium diameter , and lv mass index on log ct-1 and log nt - probnp .
statistical analysis was performed by using commercial software ( ibm spss statistics 19 , spss inc .
fifty - seven consecutive patients ( mean age 578 years , 24 ( 42% ) males ) diagnosed with dhf in our clinic and 33 controls ( mean age 557 years , 12 ( 36% ) males ) were included in the study .
dhf was diagnosed when symptoms ( dyspnea not associated with any other cause ) and signs ( rale or peripheral edema ) of heart failure were observed along with a preserved lv ejection fraction ( lvef ) ( 50% ) and evidence of diastolic dysfunction .
the control group was formed from volunteer subjects admitted to our clinic who did not have heart failure symptoms and signs and who had a preserved lvef . in order to exclude other causes of dyspnea
, all patients underwent physical and laboratory examinations , including serum hemoglobin and thyroid hormones , chest radiogram and spirometry .
patients with systolic heart failure , moderate or severe valvular stenosis or regurgitation , congenital heart disease , atrial fibrillation , chronic obstructive pulmonary disease , malignancy , and other extracellular fluid - increasing diseases , such as hypothyroidism and liver cirrhosis , were excluded from the study .
all of the study participants underwent echocardiographic evaluation ( 2.5 mhz transducer , philips envisor c , bothell , washington , usa ) .
standardized projections and measurements were performed for the evaluation of cardiac anatomy , ventricular function and valve competence .
lv mass index was obtained by dividing the lv mass by the body surface area .
the following conventional mitral inflow pulse wave doppler parameters were measured : peak velocity of early diastolic filling ( e ) , late filling ( a ) , and deceleration time ( dt ) of the e - wave velocity and isovolumetric relaxation time ( ivrt ) .
these parameters were obtained from the apical four - chamber view with a 1 to 3 mm sample volume placed between the mitral leaflet tips during diastole .
pulmonary venous flow parameters were also measured : peak systolic velocity ( ps ) , peak anterograde diastolic velocity ( pd ) and the ps / pd ratio .
these parameters were obtained from the apical four - chamber view with a 2 to 3 mm sample volume placed 1 cm into the pulmonary vein .
tissue doppler parameters were measured : peak systolic mitral annular velocity ( sm ) and early diastolic mitral annular velocity ( em ) and late diastolic mitral velocity ( am ) .
these parameters were obtained from the apical four - chamber view with a 2 to 5 mm sample volume placed 1 cm within the septal and lateral insertions of the mitral leaflets .
the mean of 3 or more measurements was used for analysis of the doppler data .
the ratio of mitral peak velocity of early diastolic filling to early diastolic mitral annular velocity ( e / em ) was calculated for the lateral and septal annulus and the mean of the lateral and septal e / em were also determined .
as previously described , the formula ( 1.24(e / em)+1.9 ) was used to estimate pulmonary capillary wedge pressure ( pcwp ) .
patients with mean e / em 8 or a change in e / a ratio with the valsalva maneuver of < 0.5 were excluded from the study .
diastolic dysfunction was defined as em < am if em was less than 10 cm / sec in lateral mitral annulus or less than 8 cm / sec in septal mitral annulus .
blood samples were obtained during admission for routine chemistry , including ct-1 and n - terminal pro - b - type natriuretic peptide ( nt - probnp ) following an overnight fast .
ct-1 values were measured with a sandwich enzyme immunoassay method ( organon teknika microwell system reader 230 s , germany ) in our hospital laboratory .
nt - probnp analyses were made by the electrochemiluminescence immunoassay method ( cobas 6000 analyzer , roche diagnostics gmbh , mannheim , germany ) .
according to kolmogorov - smirnov normality test , 2 independent sample t tests were used to compare the normally distributed independent variables between the 2 groups , and mann - whitney u test was used to compare the non - normally distributed independent variables between the 2 groups .
normally distributed continuous data were expressed as mean  standard deviation ( sd ) ; non - normally distributed continuous variables were presented as median and interquartile range ( iqr ) [ quartile l to quartile 3 ] .
linear regression analyses were used to determine the effect of age , creatinine clearance , systolic blood pressure , left atrium diameter , and lv mass index on log ct-1 and log nt - probnp .
statistical analysis was performed by using commercial software ( ibm spss statistics 19 , spss inc .
there were no significant differences between the patient and control groups with regard to age , sex , hypertension , diabetes , cad , smoking , medications , body mass index , fasting blood glucose , thyroid status , lipid profile , creatinine clearance , serum creatinine and hemoglobin levels ( table 1 ) .
the patient group had a higher lv posterior wall thickness and a larger left atrial size , but differences in lvef , chamber sizes , and mass index remained insignificant ( tables 1 and 2 ) .
arterial blood pressures were also not different between the 2 groups . ct-1 and nt - probnp were significantly higher in the patient group ( ct-1 : 11.30 [ 8.0916.51 ] fmol / ml vs. 17.5 [ 8.9528.74 ] fmol / ml , p=0.017 ; nt - probnp : 64 [ 27.595 ] pg / ml vs. 82 [ 55.5241 ] pg / ml , p=0.009 ) ( table 1 ) .
the mitral e , lateral , septal and mean e / em and the pcwp estimated from each of the e / em measurements were all significantly higher , whereas ps / pd , lateral and septal em and lateral and septal em / am were significantly lower in the patient group ( table 2 ) .
ct-1 positively correlated with nt - probnp ( p=0.001 , r=0.349 ) , mean e / em ( p=0.003 , r=0.307 ) , and estimated mean pcwp ( p=0.001 , r=0.308 ) ( figure 1 ) . according to bivariate linear regression analyses , log ct-1 was predicted by left atrium diameter and log nt - probnp was predicted by age , creatinine clearance , and left atrium diameter ( table 3 ) . in multiple linear regression analysis ,
log ct-1 and log nt - probnp were predicted only by left atrium diameter ( table 4 ) .
the data of this study shows that the ct-1 is elevated in dhf patients and is associated with nt - probnp and estimated lv filling pressures in dhf patients .
the ct-1 protein expression is constitutive not only in the heart , but also in the pulmonary , renal , gastrointestinal , cerebral , and muscular tissues .
cardiac myocytes and cardiac fibroblasts may produce ct-1 in situations of biomechanical stress and under exposure to humoral factors such as angiotensin ii and norepineprine [ 2325 ] .
ventricular stretch caused by pressure or volume overload is thought to be the major stimulus of myocardial ct-1 release .
previous studies have found that ct-1 promotes myocardial structural changes , later participating in the progression of lv remodeling , which results in lv failure in various diseases such as hypertensive heart disease , coronary artery disease , aortic stenosis , and dilated cardiomyopathy .
both bnp and ct-1 have a beneficial effect not only on the myocardium but also on hemodynamic variables .
therefore , ongoing stimulation of bnp and ct-1 caused by ventricular stretch and circulating cytokines , promote structural remodeling and may become maladaptive with the progression of heart failure .
ct-1 levels correlate with the severity of the heart failure and has been shown to be an independent predictor of mortality in chronic heart failure .
plasma ct-1 has high diagnostic efficacy for heart failure ( at concentration of 68 fmol / ml , sensitivity and specificity were 95% and 82.5% , respectively ) .
talwar et al found that plasma ct-1 levels measured shortly after an acute myocardial infarction serve as a strong independent predictor of lv systolic dysfunction . in another study , talwar et al .
found that changes in ct-1 levels may reflect early changes in ventricular physiology that occur in the early part of the heart failure process before they can be detected echocardiographically .
it was also found that ct-1 is significantly increased in patients with moderate to severe mitral regurgitation despite having normal lv systolic function and no hypertrophy .
they were unable to demonstrate a similar increase in subjects with tricuspid or aortic regurgitation .
in our study , we showed ct-1 elevation in a group of dhf patients with normal lv systolic function and no significant hypertrophy , but having more dilated left atrium than controls . considering these results
, it may be speculated that left atrial wall stretch is a more important and earlier stimulation for ct-1 secretion rather than ventricular wall stretch .
it has already been shown that ct-1 mrna was detected in both atria and ventricles . in a series of studies performed by lopez et al
, they concluded that ct-1 is a more sensitive and specific biomarker than nt - pro bnp for detection of the inappropriateness of lv mass and lv dysfunction in hypertension , and nt - pro bnp remains a useful diagnostic tool for hypertensive heart disease only when lv systolic dysfunction is present .
it was also shown that elevated ct-1 levels represent an earlier stage of the same neurohumoral cascade that results in elevated plasma bnp .
, both ct-1 and nt - pro bnp were found to be more elevated in dhf patients than in control subjects , and there was a positive correlation between ct-1 and nt - pro bnp .
previous studies show that elevated nt - probnp values is diagnostic for dhf and associated with elevated lv filling pressures .
it has been found that there is a strong correlation between nt - probnp and e / em , and a threshold of 269.1 pg / ml of nt - probnp predicted an e / em > 15 with 90% sensitivity and 73% specificity in dhf .
the positive correlation between elevated ct-1 and nt - probnp , e / em and pcwp in our study implies that pressure overload represented as increases in lv filling pressures could be the main underlying mechanism for ct-1 secretion in patients with dhf .
a series of studies performed by lopez et al concluded that ct-1 is associated with systolic and diastolic dysfunction in hypertensive patients . in the other study they found that the ratio of peak velocity of early diastolic filling to peak velocity of late filling of mitral inflow ( e / a ) is the only parameter that differed in the hypertensive group , while dt and ivrt remained unchanged .
significant association was found between normalization of ct-1 and regression of lv hypertrophy and increment of e / a . in their studies
they only used conventional doppler parameters in order to evaluate diastolic function , and e / a was the only parameter found to be different from the control group . in our study
chronic ct-1 treatment resulted in the development of insulin resistance as judged by a decrease in insulin - stimulated glucose uptake .
we found high glucose levels in dhf patients , but this difference was insignificant , probably due to small sample size .
second , despite the evidences that e / em is an effective noninvasive predictor of lv filling pressures , we did not measure lv pressures directly .
it was already known that adipose tissue can be recognized as a source of ct-1 , which could account for the high circulating levels of ct-1 in patients with metabolic syndrome .
finally , ct-1 mrna is expressed in other organs , and potential additional sources of circulating ct-1 can not be excluded in patients with dhf .
this increase was associated with nt - probnp and estimated lv filling pressures in dhf patients .
our results suggest that diastolic dysfunction and subsequent pressure increase at the left side of the heart may be responsible for ct-1 increase in dhf patients
. however , further studies are required to elucidate the underlying mechanism for the ct-1 increase in these patients .
 summarybackgroundcardiotrophin-1 ( ct-1 ) is a member of the interleukin ( il-6 ) family of cytokines and is increased in various cardiovascular diseases , including chronic heart failure . 
 the aim of the study was to determine if plasma ct-1 is associated with diastolic heart failure ( dhf ) and to investigate the relationship between ct-1 and echocardiographic parameters.material/methodsfifty-seven consecutive patients ( mean age 578 years , 24 males ) diagnosed with dhf in our clinic and 33 controls ( mean age 557 years , 12 males ) were included in the study . 
 all study participants underwent echocardiographic evaluation and blood samples were obtained.resultsct-1 and nt - probnp values were significantly higher in dhf subjects than in controls ( 11.30 [ 8.0916.51 ] vs. 17.5 [ 8.9528.74 ] fmol / ml , p=0.017 and 64 [ 27.595 ] vs. 82 [ 55.5241 ] pg / ml , p=0.009 , respectively ) 
 . the mitral peak velocity of early diastolic filling ( e ) , mean ratio of e to early diastolic mitral annular velocity ( e / em ) , and the pulmonary capillary wedge pressure ( pcwp ) estimated from e / em measurements were all significantly higher in the patient group ( 62.2714.69 vs. 75.6718.85 cm / sec , 6.401.48 vs. 10.303.48 , and 10 [ 911]vs . 
 14[1216 ] mmhg , p0.001 for all ) . 
 lateral and septal em were significantly lower in the patient group ( 10.691.87 vs. 8.692.00 cm / sec and 8.911.22 vs. 6.651.58 cm / sec , p<0.001 for both ) . 
 ct-1 positively correlated with nt - probnp ( p=0.001 , r=0.349 ) , mean e / em ( p=0.003 , r=0.307 ) , and estimated mean pcwp ( p=0.001 , r=0.308).conclusionsct-1 is elevated in patients with dhf and is associated with nt - probnp and estimated left ventricular filling pressures . 
Background
Material and Methods
Study population
Echocardiographic measurements
Biochemical measurements
Statistical analysis
Results
Discussion
Conclusions