Introduction. Natriuretic peptides are frequently used in diagnosing and monitoring patients with congestive heart failure

Transcription

1 ORIGINAL ARTICLE DOI / kcj Print ISSN / On-line ISSN Coyright c 2009 The Korean Society of Cardiology Oen Access N-Terminal Pro-B-Tye Natriuretic Petide in Overweight and Obese Patients With and Without Diabetes: An Analysis Based on Body Mass Index and Left Ventricular Geometry Seung Jei Park, MD, Kyoung Im Cho, MD, Sun Jae Jung, Sung Won Choi, MD, Jae Won Choi, MD, Dong Won Lee, MD, Hyeon Gook Lee, MD and Tae Ik Kim, MD Division of Cardiology, Maryknoll Medical Center, Busan, Korea ABSTRACT Background and Objectives: Several recent studies have shown that there is an inverse relationshi between lasma B-tye natriuretic etide (BNP) and body mass index (BMI) in subjects with and without heart failure. Obesity frequently coexists with diabetes, so it is imortant to consider the relationshi between diabetes and natriuretic etide levels. We evaluated the influence of diabetes on the correlation of BNP and BMI. Subjects and Methods: We examined 933 atients with chest ain and/or dysnea undergoing cardiac catheterization between Feb and Nov in the Maryknoll cardiac center who had creatinine levels <2.0 mg/dl and normal systolic heart function. BMI was checked, transthoracic echocardiograhy was erformed, and aminoterminal ro-brain natriuretic etide (NT-roBNP) was samled at the start of each case. Results: In 733 nondiabetic atients, mean lasma NT-roBNP levels of non obese individuals (BMI <23 kg/m 2 ), overweight individuals (23 BMI <25 kg/m 2 ), and obese individuals (BMI 25 kg/m 2 ) showed a significant negative correlation with increasing BMI (856.39±237.3 g/ml, ±159.6 g/ml, ±164.9 g/ml, resectively, <0.0001). However, in 200 diabetic atients, the correlation between BMI and NT-roBNP was not significant (r=-0.21, =0.19), and NT-roBNP did not correlate with mitral E/Ea in obese diabetic atients (r=0.14, =0.56). NTroBNP was significantly correlated with mitral E/Ea in the non-obese (r=0.24, =0.008) and non diabetic (r=0.32, =0.003) grous. Left ventricular (LV) mass index was significantly correlated with NT-roBNP in all BMI grous (r=0.61, <0.001), and atients with concentric cardiac hyertrohy showed the highest NT-roBNP levels. Conclusion: The resent study demonstrates that obese atients have reduced concentrations of NTroBNP comared to non obese atients desite having higher LV filling ressures. However, NT-roBNP is not suressed in obese atients with diabetes. This suggests that factors other than cardiac status affect NT-roBNP concentrations. (Korean Circ J 2009;39: ) KEY WORDS: B-tye natriuretic etide; Body mass index; Obesity. Introduction Natriuretic etides are frequently used in diagnosing and monitoring atients with congestive heart failure Received: May 2, 2009 Revision Received: June 26, 2009 Acceted: July 9, 2009 Corresondence: Kyoung Im Cho, MD, Division of Cardiology, Maryknoll Medical Center, 12 Daecheong-dong 4-ga, Jung-gu, Busan , Korea Tel: , Fax: kyoungim74@dreamwiz.com cc This is an oen-access article distributed under the terms of the Creative Commons Attribution License, which ermits unrestricted use, distribution, and reroduction in any medium, rovided the original work is roerly cited. (CHF). B-Tye natriuretic etide (BNP) and aminoterminal ro-brain natriuretic etide (NT-roBNP) are believed to correlate with the severity of heart failure symtoms and objective measures of heart function. 1-3) The NT-roBNP levels are affected by demograhic variables such as age, gender, and ethnicity, and clinical characteristics such as hyertension, atrial fibrillation, and renal function. 4-6) Elevated body mass index (BMI) and obesity have been associated with hyertension, insulin resistance and dysliidemia, and contribute to deleterious hemodynamic and morhologic cardiovascular changes. 7-9) Recent studies demonstrated that obesity is associated with decreased levels of NT-roBNP and raised concerns about the diagnostic and rognostic validity 538

2 Seung Jei Park, et al. 539 of natriuretic etides in obese atients. 10)11) NT-roBNP has been shown to be increased in atients with diabetes mellitus (), even in the absence of structural heart disease, and obesity frequently coexists with diabetes. Hence, variety factors should be considered to be associated with the interindividual variability of lasma NT-roBNP levels in the diagnosis and management of heart failure atients. So, our study aimed to further exlore the association between elevated BMI and NTroBNP in diabetes and the relationshi of echocardiograhic indexes of increased left ventricular (LV) filling ressure, LV geometry and atherosclerosis as measured by common carotid intima-media thickness (CCIMT). Subjects and Methods Patients with chest ain and/or dysnea who underwent cardiac catheterization from Feb to Nov in Maryknoll cardiac center were enrolled. Subjects with atrial fibrillation or other significant cardiac arrhythmia and acute myocardial infarction at the time of clinical assessment were excluded. Other exclusion criteria included atients who did not rovide written consent and atients with regional wall motion abnormalities; symtomatic or asymtomatic LV systolic dysfunction (ejection fraction <50%); significant valvular disease (moderate or severe valvular dysfunction); and neolastic, heatic, and renal dysfunction. At the time of enrollment, data were collected on each subject, including demograhics, hysical examination, results of unblinded laboratory testing, and self-reorted medical history and active symtoms. Severity of dysnea was based on New York Heart Association criteria. Diabetes mellitus () was diagnosed if fasting lasma glucose was 126 mg/ dl or if articiants were taking insulin or oral hyoglycemic medications. Patients without were defined as non. Patients were divided into body mass index (BMI) >25 g/m 2 (obese), 23 to 25 (overweight), and <23 kg/m 2 (non obese) according to the guideline of the Korean society for the study of obesity. Significant coronary artery disease was considered if the stenosis was above 50% from the quantitative angiograhy. Echocardiograhic evaluation Measurements of left atrial (LA) dimension, left ventricular (LV) dimension, LV end diastolic and systolic volume, interventricular setal thickness (IVSd), LV osterior wall thickness (LVPWTd) and ejection fraction were erformed from 2-dimensionally targeted M-mode tracings according to the recommendations of the American Society of Echocardiograhy (ASE). LV mass was calculated by the corrected ASE cube formula and indexed for body surface area to obtain the LV mass index. The relative osterior wall thickness (RWT) was measured at end diastole as the ratio between the double of osterior wall thickness to the LV diastolic cavity diameter. LV hyertrohy (LVH) was defined as increased LV mass index >104 g/m 2 in women and >116 g/m 2 in men. 12) Concentric hyertrohy was defined as LVH with increased RWT (>0.43). Concentric LV remodeling was defined as increased RWT with normal LV mass index. Eccentric hyertrohy was defined as LVH without increased RWT. Transmitral eak early (E), atrial (A) diastolic velocities were measured in the aical 4-chamber view with the samling volume ositioned at the tis of the mitral valve. The isovolumic relaxation time (IRT), isovolumic contraction time (ICT) and total ejection time was measured at the aical 5-chamber view with the samling volume ositioned between the mitral valve and the LV outflow tract as the time taken from the closure of the aortic valve to the oening of the mitral valve. The index of combined LV systolic and diastolic function (the sum of ICT and IRT divided by ejection time) was calculated which described by Tei et al. 13) Tissue Doler measurements were obtained from the aical 4-chamber view, and the samling volume was laced at the medial (setal) and lateral corners of the mitral annulus. Early (Ea) diastolic mitral annular velocities were taken as the average of 3 measurements at each side of the mitral annulus. All echocardiograms were erformed and analyzed by one observer. Measurement of common carotid IMT Ultrasonograhy of the carotid arteries was erformed with a 10-MHz transducer (System Five, General Electronics Cor., Horten, Norway). When an otimal longitudinal image of the common carotid artery was obtained, it was frozen on the R wave of the electrocardiogram, and 5 measurements were taken from the far wall of the distal 1 cm of the common carotid artery. This was reeated on the other side, and the average measurement from the 2 sides was taken as the CCIMT (a surrogate index for atherosclerosis). Plaques or focal rotrusions were avoided. Measurements were taken at the time of examination before laboratory analysis. Measurement of lasma NT-roBNP levels The NT-roBNP level was analyzed at the time of clinical assessment. For each NT-roBNP measurement, 5 ml of whole blood was collected into tubes containing ethylene diamine tetraacetic acid (EDTA) and measured using the Elecycs 2010 latform (Roche Diagnostics, USA). Statistical analysis All data were resented as means±standard deviation and analyzed using standard statistical software {Statistical Package for Social Science (SPSS) version 13.0, Chicago, IL, USA}. Because of the large range in NTroBNP, analysis and results using a semilogarithmic

3 540 NT-ProBNP in Overweight and Obese Patients scale is also reorted. Continuous variables among the and the non grou were analyzed by one-way ANOVA and variables between the two grous were comared by t-test. Discontinuous variables were comared by Chi-square test. Correlations were obtained using Pearson s method. Multivariate stewise logistic regression analysis was erformed to assess the relationshi between the redictor variables such as age, gender, BMI, NYHA class, hyertension, diabetes mellitus, medications, hemodynamic and echocardiograhic indexes, and creatinine. A <0.05 was considered statistically significant. Results The clinical characteristics of the study oulation Baseline characteristics of the overall atient oulation are listed in Table 1. Among 933 atients, 733 were atients without {obese (n=287, 39.2%), overweight atients (n=216, 29.5%), and non obese (n=230, 31.4%)} and 200 were atients {obese (n=91, 45.5%), overweight atients (n=55, 27.5%), and non obese (n=54, 27%)}. The mean age was 60.8±10.39 years in atients and 64.6±8.75 years in non- atients. Subjects with tended to be older and had a higher body mass index than non-diabetes grous but had a similar distribution of gender. There was no significant difference between the and non- grous in cholesterol, systolic blood ressure, diastolic blood ressure, BUN, creatinine, and C-reactive rotein. However, mean lasma NT-roBNP levels were significantly higher in atients than non- atients ( ± and ±1652 g/ml, =0.006) (Table 1). Coronary artery stenosis lesion length (=0.039), Table 1. Comarisons of clinical variables between and non- grous Non- (n=733) (n=200) Age (years) 060.3± ± Male (%) Body weight (kg) 58.3± ± Body mass index (g/m 2 ) 23.78± ± Total cholesterol (mg/dl) 179.6± ± Systolic BP (mmhg) 127.2± ± Diastolic BP (mmhg) 079.2± ± NT-ro BNP (g/ml) ± ± BUN (mg/dl) 018.9± ± Creatine (mg/dl) 01.0± ± Fasting glucose (mg/dl) 101± ± ctnt (ng/ml) 0.02± ± hscrp (mg/l) 008.3± ± All values are described in mean±sd. : diabetes mellitus, BP: blood ressure, NT-ro BNP: amino-terminal ro-brain natriuretic etide, BUN: blood urea nitrogen, ctnt: cardiac secific troonin, hscrp: high sensitivity C-reactive rotein stent length (=0.024), coronary artery adventitial diameter (=0.034), and mean CCIMT (=0.016) were significant higher in atients than non- atients (Table 2). In non atients, CCIMT was significantly higher in atients with significant coronary artery disease than atients with minimal coronary artery disease (1.23±0.568 mm vs. 1.00±0.304 mm, =0.005). However, CCIMT showed no significant correlation with mean lasma NT-roBNP level (Table 3). Table 2. Comarisons of coronary angiograhic and carotid ultrasonograhic variables between and non- grous Non- (n=733) (n=200) Lesion length (mm) 4.96± ± Stent length (mm) 05.64± ± Adventitial diameter (mm) 7.95± ± CCIMT (mm) 01.15± ± All values are described in mean±sd. : diabetes mellitus, CC- IMT: common carotid intima-media thickness Table 3. Correlation analysis of variables with lasma NT-roBNP between the and the non- grou Variable Patients with non r Univariate Table 4. Comarisons of echocardiograhic variables between the and the non- grou Non- (n=733) (n=200) LV EF (%) 063.3± ± RWT 04.37± ± LV mass index (g/cm 2 ) ± ± LA diameter (cm) 04.07± ± E (cm/sec) ± ± A (cm/sec) ± ± E/Ea 07.35± ± Tei index 00.30± ± All values are described in mean±sd. LV: left atrium, : diabetes mellitus, EF: ejection fraction, RWT: relative wall thickness, LAD: left atrial dimension, E: eak early velocity, A: eak atrial velocity, Ea: Early diastolic mitral annular velocity Multivariate Age Body mass index LV mass index CC-IMT E/Ea Patients with Age Body mass index LV mass index CC-IMT E/Ea : diabetes mellitus, NT-roBNP: aminoterminal ro-brain natriuretic etide, E: eak early velocity, CC-IMT: common carotid intima-media thickness, Ea: early diastolic mitral annular velocity

4 Seung Jei Park, et al. 541 The correlation between lasma BNP level and echocardiograhic findings There was no significant difference between the and non- grous in LV ejection fraction, relative wall thickness, mitral E and A velocity. However, LV mass index, LA diameter, E/Ea and Tei index were (g/ml) 1,400 1,200 1, Normal 0 non Fig. 1. Comarisons of NT-roBNP level according to the left ventricular geometry in the and non- grou. : diabetes mellitus, NT-ro BNP: aminoterminal ro-brain natriuretic etide, CR: concentric remodeling, EH: eccentric hyertrohy, CH: concentric hyertrohy. CR EH CH significantly higher in atients than non- atients (Table 4). Plasma NT-roBNP values did not correlate with LV filling ressure reresented by mitral E/Ea in obese diabetic atients (r=0.14, =0.56). However, NT-roBNP was significantly correlated with this variable in the non obese (r=0.24, =0.008) and non- atients (r=0.32, =0.005). The significant correlation of NT-roBNP and LV mass index was observed in univariate linear regression analysis (r=0.65, = 0.001) and atients with concentric hyertrohy showed the highest NT-roBNP levels (Fig. 1). Even after adjusting for age, gender, diabetes, creatinine, ejection fraction and E/Ea in multivariate linear regression analysis, LV mass index was significantly associated with NTroBNP (r=0.57, =0.03) (Table 3). The correlation between lasma BNP level and BMI In 733 non- atients, lasma NT-roBNP levels were significantly lower in obese (289.62±164.9 g/ml) and overweight atients (601.69±159.6 g/ml) com- Table 5. Comarisons of variables in the non- grou according to the body mass index Non- Non-obese (n=230) Overweight (n=216) Obese (n=287) NT-roBNP (g/ml) ± ±159.6* ±164.9* Log NT-roBNP (g/ml) 05.03± ±1.71* ±1.58* Significant CAD (%) 41% (n=94) 47% (n=101) 43% (n=122) NYHA class >II 33% (n=75) 38% (n=82)1 32% (n=93) LV mass index (g/cm 2 ) ± ±27.58* ±27.93* RWT 00.43± ± ± E (cm/sec) ± ± ± A (cm/sec) ± ± ± E/Ea 05.38± ±3.24* ±2.38* Tei index ± ± ± All values are described in mean±sd. : diabetes mellitus, NT-roBNP: amino-terminal ro-brain natriuretic etide, CAD: coronary artery disease, NYHA: New York Heart Association, LV: left ventricle, RWT: relative wall thickness, E: eak early velocity, A: eak atrial velocity, Ea: early diastolic mitral annular velocity. *<0.05 vs. non obese, <0.05 vs. overweight Table 6. Comarisons of variables in the grou according to the body mass index Non obese (n=54) Overweight (n=55) Obese (n=91) NT-roBNP (g/ml) ± ± ± Log NT-roBNP (g/ml) 05.52± ± ± Significant CAD (%) 63% (n=34) 53% (n=29) 54% (n=49) NYHA class >II 54% (n=29) 47% (n=26) 44% (n=40) LV mass index (g/cm 3 ) ± ± ± RWT 00.43± ± ± E velocity ± ± ± A velocity ± ± ± E/Ea 07.48± ± ± Tei index 00.28± ±0.15* 0.38±0.22* All values are described in mean±sd. : diabetes mellitus, NT-roBNP: amino-terminal ro-brain natriuretic etide, CAD: coronary artery disease, NYHA: New York Heart Association, LV: left ventricle, RWT: relative wall thickness, E: eak early velocity, A: eak atrial velocity, Ea: early diastolic mitral annular velocity. *<0.05 vs. non obese, <0.05 vs. overweight

5 542 NT-ProBNP in Overweight and Obese Patients ared with non obese atients (856.39±237.3 g/ml) (<0001) desite similar significant coronary artery disease and severity of dysnea (Table 5). However, in 200 atients, lasma NT-roBNP levels was ± g/ml, ±457.3 g/ml, ±147.1 g/ml, resectively, which showed no significant negative correlation between BMI and NT-roBNP (r= -0.21, =0.19) (Table 3 and 6) Dro-line charts of logtransformed mean lasma NT-roBNP levels (deendent variable) against BMI (indeendent) according to resence of significant coronary disease are shown in Fig. 2. Mean log NT-roBNP levels among atients with significant coronary artery disease decrease with increasing obesity, which is statistically significant in non- atients (5.29±1.62, 4.77±1.65, 4.53±1.43, =0.002). Discussion In recent years, natriuretic etides have been gaining widesread oularity as sensitive and secific markers for the LV failure. BNP is rincially roduced in the ventricles as rohormone re-robnp, which is then enzymatically cleaved into the biologically active BNP (32 amino acids in length) and the biologically inactive NT-roBNP (76 amino acids in length). 14) It is found mainly in the cardiac ventricles, and its release aears to be directly roortional to ventricular volume exansion and ressure overload. 15) BNP is an indeendent redictor of high LV end-diastolic ressure and the NTroBNP levels were ositively correlated with the NYHA functional class of dysnea and the systolic dysfunction. 16)17) The measurement of NT-roBNP has been reorted to be a non-invasive, simle, and accurate test for older atients, obese atients, atients with chronic ulmonary diseases, and even for those atients having difficulty being tested by echocardiogram. Thus, its clinical usefulness for the differential diagnosis of heart failure is imortant. 18)19) Elevated body mass index (BMI) and obesity have been associated with hyertension, insulin resistance and recent studies demonstrated that obesity is associated with decreased levels of NT-roBNP and raised concerns about the diagnostic and rognostic validity of natriuretic etides in obese atients. 11)20) Several otential mechanistic exlanations deserve consideration. First, it is ossible that the low natriuretic etide levels in overweight and obese atients reflect less advanced stages of HF comared with lean atients. 21) Cardiac cachexia, a state characterized by weight loss and neurohumoral/cytokine activation, is another otential exlanation for a low BMI-high BNP association. 22) Recent evidence suggests that there may be increased clearance of circulating BNP in obesity because natriuretic etide clearance recetors are abundant on human adiocytes. 23) High levels of BNP could, through their liolytic effect, be exected to exaggerate the wasting rocess, which imlies that a reduced BNP level in obese HF atients may be related to a decreased level of wasting. Conversely, it is also ossible that overweight and obesity are associated with less robust synthesis and/or release of BNP from the myocardium. 5) In the resent study, NT-roBNP concentrations were lower in obese non atients desite higher E/Ea which has been shown to correlate with invasive measures of LV filling ressure 24) and this occurs with resence of myocardial ischemia confirmed by coronary angiograhy. These findings have several imlications. Not only do they bring 5.40 CAD Presence Absence 5.80 CAD 5.20 Presence Absence Mean log NT-roBNP Mean log NT-roBNP Non obese Overweight Obese Non obese Overweight Obese Non- Fig. 2. Dro-line charts of mean log NT-roBNP showing differences in the resence of significant coronary artery disease (CAD). Concentrations decrease with increasing obesity, which is statistically significant in non- atients (=0.002). NT-ro BNP: amino-terminal ro-brain natriuretic etide, : diabetes mellitus.

6 Seung Jei Park, et al. 543 into question the roer use of NT-roBNP as diagnostic tests for obese atients with volume overload, but they also raise the ossibility that the decreased concentrations of natriuretic etides may lay a role in the develoment of heart failure in obese atients. However, the resent study demonstrates that NT-roBNP is not suressed in obese atients with and also shows a oor correlation with E/Ea. The mechanisms of NTro BNP is not suressed in obese atients with diabetes can be exlained by several ossibilities. The natriuretic system and adiosity are closely linked bidirectionally. 25) Liolysis is mediated by catecholamines (stimulation of liolysis) and insulin (inhibition of liolysis), and natriuretic etides have recently been shown to be imortant stimuli for liolysis in humans and are similar in otency to catecholamines, and their effect is indeendent of both catecholamines and an insulin athway. 26) So, obese diabetic atients may have higher concentrations of natriuretic etides comared with those without diabetes. Moreover, atients may be more likely to excrete NT-roBNP (and BNP) in resonse to a similar degree of ischemic insult, 27) and then the higher NT-roBNP concentrations that we observed in atients with in the absence of overt HF, a finding considered to reresent a summation effect of risk factors for structural heart disease, may still indicate an increased risk for cardiovascular morbidity and mortality. Our resent study is meaningful as we obtained the basic clinical data on the NT-roBNP test from a large study oulation. However, as our study was a cross-section study and the study oulation was not homogenous, further rosective study will be required. In addition, although the accuracy of the test was high, in some atients, their clinical results did not correlate to the NT-roBNP value. In the interretation of the NTroBNP test, therefore, clinical results and echocardiograhy must also be taken into consideration. Third, the atients with renal insufficiency were also excluded in the resent study. Because, in the setting of HF, imaired renal function is common and strongly related with adverse outcomes, further study is warranted that will investigate the relationshi between obesity and lasma BNP under the condition of renal insufficiency. Further studies will be required on atients showing a discreancy between clinical features and symtoms and the NTroBNP values. REFERENCES 1) Maisel AS, Krishnaswami P, Nowak RM, et al. Raid measurement of B-tye natriuretic etide in the emergency diagnosis of heart failure. N Engl J Med 2002;347: ) Maeda K, Tsutamoto T, Wada A, et al. Plasma brain natriuretic etide as a biochemical marker of high left ventricular end diastolic ressure in atients with symtomatic left ventricular dysfunction. Am Heart J 1998;135: ) Friedl W, Mair J, Thomas S, Pichler M, Puschendorf B. Natriuretic etides and cyclic guanosine 3, 5 -monohoshate in asymtomatic and symtomatic left ventricular dysfunction. Heart 1996; 76: ) Maisel AS, Cloton P, Krishnaswamy P, et al. Imact of age, race, and sex on the ability of B-tye natriuretic etide to aid in the emergency diagnosis of heart failure: results from the Breathing Not Proerly (BNP) multinational study. Am Heart J 2004; 147: ) Wang TJ, Larson MG, Levy D, et al. Imact of obesity on lasma natriuretic etide levels. Circulation 2004;109: ) Tang WH, Girod JP, Lee MJ, et al. Plasma B-tye natriuretic etide levels in ambulatory atients with established chronic symtomatic systolic heart failure. Circulation 2003;108: ) Krauss RM, Winston M, Fletcher BJ, Grundy SM. Obesity: imact on cardiovascular disease. Circulation 1998;98: ) de Divitiis O, Fazio S, Petitto M, Maddalena G, Contaldo F, Mancini M. Obesity and cardiac function. Circulation 1981;64: ) Alert MA, Lambert CR, Terry BE, et al. Influence of left ventricular mass on left ventricular diastolic filling in normotensive morbid obesity. Am Heart J 1995;130: ) Rivera, Cortés, Salvador, et al. Obese subjects with heart failure have lower N-terminal ro-brain natriuretic etide lasma levels irresective of etiology. Eur J Heart Fail 2005;7: ) Taylor JA, Christenson RH, Rao K, Jorge M, Gottlieb SS. B-tye natriuretic etide and N-terminal ro B-tye natriuretic etide are deressed in obesity desite higher left ventricular end diastolic ressures. Am Heart J 2006;152: ) Ganau A, Devereux RB, Roman MJ, et al. Patterns of left ventricular hyertrohy and geometric remodeling in essential hyertension. J Am Coll Cardiol 1992;19: ) Tei C, Nishimura RA, Seward JB, Tajik AJ. Noninvasive Dolerderived myocardial erformance index: correlation with simultaneous measurements of cardiac catheterization measurements. J Am Soc Echocardiogr 1997;10: ) Hall C. Essential biochemistry and hysiology of (NT-ro) BNP. Eur J Heart Fail 2004;6: ) Maeda K, Tsutamoto T, Wada A, Hisanaga T, Kinoshita M. Plasma brain natriuretic etide as a biochemical marker of high left ventricular end-diastolic ressure in atients with symtomatic left ventricular dysfunction. Am Heart J 1998;135: ) Kang DH, Kim MJ, Kang SJ, et al. Role of B-tye natriuretic etide in diagnosis and follow-u of diastolic heart failure. Korean Circ J 2006;36: ) Kim SH, Kim JS, Baek KK, et al. Role of NT-roPNP in evaluation of functional status in congestive heart failure. Korean Circ J 2004;34: ) Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-tye natriuretic etide in the diagnosis of congestive heart failure in an urgentcare setting. J Am Coll Cardiol 2001;37: ) Choi JY. The role of Brain natriuretic etide in the atients with acute dysnea in the emergency deartment. Korean Circ J 2007; 37: ) McCord J, Mundy BJ, Hudson MP, et al. Relationshi between obesity and B-tye natriuretic etide levels. Arch Intern Med 2004;164: ) Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Woo MA, Tillisch JH. The relationshi between obesity and mortality in atients with heart failure. J Am Coll Cardiol 2001;38: ) Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990;323: ) Sarzani R, Dessi-Fulgheri P, Paci VM, Esinosa E, Raelli A. Exression of natriuretic etide recetors in human adiose

7 544 NT-ProBNP in Overweight and Obese Patients and other tissues. J Endocrinol Invest 1996;19: ) Ommen SR, Nishimura RA, Aleton CP, et al. Clinical utility of Doler echocardiograhy and tissue Doler imaging in the estimation of left ventricular filling ressures: a comarative simultaneous Doler-catheterisation study. Circulation 2000; 102: ) Sengenes C. Increased liolysis in adiose tissue and liid mobilization to natriuretic etides during low-calorie diet in obes women. Int J Obes Relat Metab Disord 2002;26: ) Kalra PR, Tigas S. Regulation of liolysis: natriuretic etides and the develoment of cachexia. Int J Cardiol 2002;85: ) Bhalla MA, Chiang A, Eshteyn VA, et al. Prognostic role of B- tye natriuretic etide levels in atients with tye 2 diabetes mellitus. J Am Coll Cardiol 2004;44: