AMINO-TERMINAL PRO-BRAIN NATRIURETIC PEPTID IN PREDICTION OF LEFT VENTRICULAR EJECTION FRACTION

We aimed to evaluate levels of amino-terminal pro-brain natriuretic peptid (NT-proBNP) in prediction of left ventricular ejection fraction (LVEF) in heart failure patients. Prospective study on  consecutive patients with symptoms and signs of heart failure was performed. Blood samples for NT-proBNP analysis was taken from all test subjects and echocardiography was also done in all of them. According to LVEF value, patients were divided into four groups; those with ≤,  to ,  to  and ≥. NT-proBNP values correlated with LVEF value. Regression analyis was used to evaluate how well NT-proBNP values predict LVEF. We used Receiver Operating Characteristic Curve calculation to evaluate diagnostic performance of NT-proBNP in estimation of LVEF. Average value of NT-proBNP in test group was ,±, pg/ml (p<,). Average value of NT-proBNP decreased with higher LVEF categories with signifi cant (p<,) and high negative correlation (r = -,). Stepwise multivariate linear regression analysis showed that logarithmic value of NT-proBNP was excellent predictor of LVEF value (p<,). Model equation based on regression analysis was LVEF=,–, x log (NT-proBNP). Predictive model for LVEF yielded from regression analysis had sensitivities of  and , specifi cities of  and , positive predictive values of  and  and negative predictive values of  and  for predicting patients with LVEF< and LVEF<, respectively. Th ere was negative linear correlation between NT-proBNP and LVEF. NT-proBNP was excellent predictor of LVEF value (p<,).


Introduction
Th e clinical diagnosis of chronic heart failure syndrome in absence of left ventricle dysfunction (LVEF) is often insignifi cant, especially when there are no evident clinical symptoms ().Echocardiography is routinely used method for confi rmation of left ventricle systolic dysfunction.But, it is expensive; the doctors are not trained for this method and is often unavailable for outhospital patients.So, what would be the alternative to echocardiograph diagnostics of left ventricle dysfunction?Th e answer is natriuretic peptides and their use in routine practice should reduce the other diagnostic methods in cardiology, especially in outhospital patients.This study explores the possibilities of aminoterminal pro-brain natriuretic peptid (NT-proBNP) as noninvasive indicator of left ventricle dysfunction.The aims of the study were to correlate the levels of NT-proBNP and LVEF in patients with chronic heart failure and to test the sensitivity, specifi city and accuracy of NT-proBNP as a predictor for LVEF.

Patients and Methods
Th is study was conducted on  consecutive selected patients with symptoms and signs of heart failure hospitalized at the Department for Internal Diseases in University Clinical Center Tuzla.Excluded criteria were as follows: elderly patients (over  years of age) and clinically signifi cant renal insuffi ciencies (plasma creatinin level >,mg/dl).All the patients were examined, history taken, as well as blood and urine tests, chest X-ray and electrocardiogram.Transthoracal, two-dimensional echocardiography was also done in order to calculate global systolic ventricular function through ejection fraction.Based on echocardiography maintained levels of LVEF, patients were divided into four groups: LVEF≤, LVEF -, LVEF - and LVEF≥.When the echocardiography measures were taken, there was no knowledge of serum levels of NT-proBNP.Th e blood from peripheral vein was taken to all patients  hours after the echocardiography.NT-proBNP test for all samples was done on Dimension RL MAX (Dade Behring) and the technician did not know the values of LVEF.Th e values of NT-proBNP were re-checked in our laboratory using the blood of  healthy donors (normal value  pg/ml for patients under  years of age).Plasma level of NT-proBNP was correlated with the LVEF levels in all groups of patients.

Results
Th e sample was consisted of  patients with mean age of ,±, years.Th ere were  of females i  of males.Average value of NT-proBNP was ,±, pg/ml (p<,) and average LVEF value was ,±, .We have found significant difference between LVEF categories in NT-proBNP levels (Table ).
Pairwise comparison between LVEF categories demonstrated that NT-proBNP levels are decreasing from lower to higher LVEF values (p<,).Spearman's rank order correlation showed signifi cant and high negative correlation of ρ s = -, between NT-proBNP and LVEF values.Graphical representation of NT-proBNP declining in categories with higher LVEF is depicted in Figure .
Total of  (,) patients had LVEF< thus having echocardiographic criteria for systolic disfunction.Patients with EF< (,±,) had signifi cantly higher NT-proBNP levels than those with with EF> (,±, pg/ml; p<,), as seen in Figure  We used stepwise linear regression analysis to evaluate impact of age, sex and NT-proBNP on LVEF value.Value of NT-proBNP due to its nonparametric nature was log-transformed.We have found that log NT-proBNP was significant predicive factor for EF value (B=-,; t=-,; df=; p<,) Age and sex were not significant predictors of EF (p>,).

Discussion
Th e values of ejection fraction are being used as absolutely valid criteria for diagnosis of left ventricle systolic dysfunction in routine practice.Th e decrease of its values can be transient usually in "stunning" myocardium with spontaneous recovery after surgical bypass ().Th e credibility of echocardiography evaluation of systolic dysfunction leaves no doubts.But, it is not always available as a screening method in general population.Th e determination of ventricle peptide substances signifi cantly increases the diagnostic accuracy of heart failure and also helps in dividing the patients according to their symptoms ().The American Cardiology Association and American Heart Association have given the instructions for use of natriuretic peptides in diff erentiation of dyspnea caused by heart failure or some other diseases ().
Our study has shown the neurohormonal activity with the signifi cant increase of NT-proBNP plasma levels in patients with heart failure.Similar results are shown in many other studies (, , , , , , ).Th is study has correlated the plasma levels of NT-proBNP with the values of LVEF and signifi cant negative linear correlation was the main result (p<,)., of examined patients had ejection fraction less than , so they had the criteria for systolic dysfunction and their values of NT-proBNP were signifi cantly higher comparing to the patients with EF> (p<,).Our results are comparable with the results of Januzi and al. (), as well as with the results of other similar studies (, , , , )

Conclusion
Th e negative linear correlation exists between the serum levels of NT-proBNP and EFLV in patients with heart failure.Th e plasma level of NT-proBNP is a good predictor of EFLV.

List of Abbreviations
Figure .Area under the ROC curve (AUROC) was , ( CI=,-,; p<,).Best sensitivity and specifi city values had threshold level of , pg/ml (Table ).Receiver Operating Characteristics (ROC) curve evaluating diagnostic and predictive power of NT-proBNP in detection of patients with EF< is displayed in Figure .Area under the ROC curve (AUROC) was , ( CI=,-,; p<,).Best sensitivity and specificity values had threshold level of , pg/ml, with sensitivity of , specifi city of  and positive and negative predicitive values of  and , respectivelly.

TABLE 1 .
.Average levels of NT-proBNP according to LVEF Receiver Operating Characteristics (ROC) curve evaluating diagnostic and predictive power of NT-proBNP in detection of patients with EF< is displayed in

TABLE 2
. Diagnostic accuracy for diff erent cutt-off values of NT-proBNP in detection of patients with EF<50% AUC value was ,.The highest sensitivity was at the result of , pg/ml, with the sensitivity ratio of .Hobbs et al. ()used the border value of  pmol/l ( pg/ml) for determining the EF< with the sensitivity ratio of  and  for specifi city and AUC value was  with credibility of .Bay et  al. ()used the increase of NT-proBNP value (> pmol/l) in identifi cation of patients with EF< with sensitivity ratio of , specifi city ratio  and AUC ,.Using the parameters based on multivariate linear regression a predictive model was build in order to predict the values of EF.Th is model correctly predict up to  of patients with EF less than  and up to  of patients with EF less than .Similar model has been used in many other studies on this topic (, , , , ).The above described model can be important in everyday practice because of its predictive power.Based on one laboratory parameter and a simple formula, it gives us the opportunity to evaluate the values of EF without echocardiography.Certainly, it is not sufficient as isolated, but it should be estimated together with the clinical findings and other tests.