ORIGINAL ARTICLE. Abstract. Introduction

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1 ORIGINAL ARTICLE Contribution of Extracardiac Factors to the Inconsistency Between Plasma B-type Natriuretic Peptide Levels and the Severity of Pulmonary Congestion on Chest X-rays in the Diagnosis of Heart Failure Tokiko Nakane, Makoto Kawai, Kimiaki Komukai, Yosuke Kayama, Seiichiro Matsuo, Tomohisa Nagoshi, Kosuke Minai, Taro Date, Takayuki Ogawa, Hidenori Yagi and Michihiro Yoshimura Abstract Objective Chest X-rays and plasma B-type natriuretic peptide (BNP) levels are useful for diagnosing congestive heart failure. However, the relationship between plasma BNP levels and pulmonary congestion on chest X-rays often seems inconsistent. Extracardiac factors can directly alter plasma BNP levels, independent of cardiac function. In the present study, we examined the clinical factors that impact the diagnosis of heart failure by using chest X-rays and plasma BNP levels. Methods and Results This study comprised 459 consecutive patients who were admitted to the cardiovascular division of our hospital for any reason and in whom chest X-rays and plasma BNP levels were measured within 12 hours after admission. The approximate BNP value associated with pulmonary congestion that was detectable by chest X-rays was 143 pg/ml, but this value was influenced by renal function, age, and body mass index (BMI). Furthermore, we examined the effect of these three extracardiac factors on plasma BNP levels in each stage of pulmonary congestion. We found that renal dysfunction and advanced age increased the plasma BNP levels, whereas a high BMI decreased the levels, and that the effect of BMI on plasma BNP levels was greater for severe heart failure. Conclusion Extracardiac factors should be considered when the relationship between the plasma BNP levels and the severity of pulmonary congestion on chest X-rays seems inconsistent. In particular, low levels of plasma BNP in patients with a high BMI should be carefully considered to avoid underestimating the degree of heart failure. Key words: aging, body mass index, congestion grade, estimated glomerular filtration rate, obesity, renal failure (Intern Med 51: , 2012) () Introduction The plasma B-type or brain natriuretic peptide (BNP) levels are elevated in subjects with heart failure (1, 2). Although the clinical significance of plasma BNP measurement has been widely accepted, the relationship between the plasma BNP levels and pulmonary congestion findings on chest X-rays often seems to be inconsistent. It seems that the threshold of BNP levels for the severity of pulmonary congestion on chest X-rays is altered by extracardiac factors but the impact of these factors on BNP levels have not been investigated in detail or explained theoretically. We postulated that, although cardiac dysfunction exerts the most important effect on BNP production, extracardiac factors may also directly alter the plasma BNP levels, inde- Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Japan Received for publication July 18, 2011; Accepted for publication October 11, 2011 Correspondence to Dr. Makoto Kawai, cadmk@jikei.ac.jp 239

2 pendent of heart function, and change the relationship between the plasma BNP levels and pulmonary congestion on chest X-rays. The existence of such factors could explain the discrepancies between the actual severity of heart failure on chest X-ray and the plasma BNP levels. If a particular extracardiac factor directly elevates the plasma BNP levels, the amount of BNP circulating in the bloodstream would increase. Because natriuretic peptides are involved in physiological activities, they also probably mitigate the progression of heart failure (3, 4). This would result in an apparent imbalance between comparatively high plasma BNP levels and relatively mild heart failure. Conversely, if an extracardiac factor directly lowers the plasma BNP levels, the decreased plasma BNP levels would not achieve enough benefits of the physiological activities of BNP, and the heart failure would worsen. Accordingly, the resultant low plasma BNP level would be associated with relatively severe heart failure. The above hypothesis was based on the previous findings of studies on BNP transgenic mice (5, 6). The liver of these transgenic mice overexpresses BNP and consequently plasma levels are always high, irrespective of heart function, and the progression of heart failure can be suppressed. The present study was undertaken to investigate the clinical characteristics of patients to identify potential extracardiac factors affecting the relationship between the plasma BNP levels and pulmonary congestion on chest X-rays. Patient population Materials and Methods This study comprised 459 consecutive patients who were admitted to the cardiovascular unit of The Jikei University Hospital for any reason between April 2008 and October Within 12 hours after admission, chest X-rays were taken and the plasma BNP levels were measured. The study protocol ( [5592]) was approved by the ethics committee of The Jikei University School of Medicine. Measurement of plasma BNP levels Whole blood (5 ml) was collected in tubes containing potassium EDTA (1 mg/ml blood). The plasma BNP level was determined within 12 hours after admission by an enzyme-linked immunosorbent assay (non-extracted) using an antibody against human BNP (Shionogi Co. Ltd., Tokyo, Japan). Grading of pulmonary congestion on chest X-rays At least three cardiologists graded the severity of pulmonary congestion based on the X-rays according to the Massachusetts General Hospital (MGH) criteria into 4 groups: 0, normal; 1, redistribution of pulmonary flow; 2, pleural effusion and/or interstitial pulmonary edema; 3, alveolar edema (7, 8). We excluded the criterion of the cardiothoracic ratio included in MGH Grade 2 criteria, because the conditions of the X-rays were not unified in the present study; chest X-rays of most patients were taken in the upright position, but some were taken in the supine position. The grade was therefore mainly based on the severity of pulmonary congestion (Fig. 1). Echocardiographic measurements Cardiologists examined patients at admission using echocardiography. The left ventricular ejection fraction (LVEF), as well as the dimensions of the LV end-diastolic, left atrial, interventricular septum, and posterior wall were measured on M-mode images. Definition of renal dysfunction Patients with renal dysfunction were defined as those having an estimated glomerular filtration rate (egfr) of <60 ml/min/1.73 m 2 at admission according to the guidelines of the Japanese Society of Nephrology (9). We calculated the egfr according to the Modification of Diet in Renal Disease equation (10) with coefficients modified for Japanese patients (11). egfr (ml/min/1.73 m 2 ) = 194 age Scr (and for females). Statistical analysis Continuous variables were expressed as the means ± standard deviation (SD) or medians. Two groups or conditions were compared using the unpaired t test or Mann-Whitney U test as necessary. More than three groups or conditions were compared using the non-repeated measures analysis of variance, Bonferroni correction, and Dunnett s test. The plasma BNP threshold for pulmonary congestion was assessed using receiver-operator characteristics (ROC) curves, and the optimal cutoff point was defined as a combination of the highest sensitivity and specificity. All tests were twotailed and p<0.05 was considered to be significant. Patient population Results The baseline characteristics of the overall population in the present study are shown in Table 1. The mean age was 65.8±13.1 years (range: years) and 74.5% (342 patients) of the patients were male. The mean values for body mass index (BMI), the plasma BNP level, LVEF on echocardiography, and egfr were 24±3.6 kg/m 2, 386.5±767.6 pg/ml, 52.8±17.3%, and 60.2±25.8 ml/min/1.73 m 2, respectively. The characteristics of each grade of pulmonary congestion are also shown in Table 1. Grades 0, 1, 2, and 3 congestion were observed in 68% (n=314), 10% (n=50), 13% (n=62), and 7% (n=33) of patients, and the mean BNP levels for each of these grades were 88.4±142.6, 660.7± 661.0, 1,055.8±1,164.7, and 1,550.6±1,313 pg/ml, respectively (Fig. 2A). 240

3 Grade 0 Grade 1 Grade 2 Grade 3 Figure 1. Grading of the pulmonary congestion on chest X-rays. On the basis of the severity of pulmonary congestion, chest X-rays were graded into four groups from grade 0 to 3, according to the Massachusetts General Hospital (MGH) criteria. BNP threshold for pulmonary congestion on chest X-rays The plasma BNP threshold for pulmonary congestion determined from the ROC curves generated from 459 patients was 143 pg/ml (sensitivity, 0.81 and specificity, 0.83) (Fig. 2B). The characteristics between patients with and without pulmonary congestion and the plasma BNP levels above or below 143 pg/ml are shown in Table 2. Among the various clinical characteristics, which were correlated with the plasma BNP levels by single regression analysis, age, egfr, and BMI were considered to have significant influences on the plasma BNP threshold for pulmonary congestion. However, heart rate (HR), serum albumin level, and LVEF were not significantly correlated with the plasma BNP threshold. The ROC curves of comparisons for the median age (above and below 66 years), egfr (above and below 60 ml/min/1.73 m 2 ), and median BMI (above and below 23.8) are shown in Fig. 3A-F. The plasma BNP threshold for each stage of congestion changed according to these influences. Relationship between age, egfr, BMI, and BNP The plasma BNP levels in each stage of pulmonary congestion are shown in Fig. 4A-C. The plasma BNP levels were significantly higher in patients of advanced age than in younger patients. The plasma BNP levels were significantly higher in the renal dysfunction group than that in the normal renal function group. At the same time, the plasma BNP levels were significantly lower in patients with a high BMI than in those with a low BMI. The effect of BMI on the plasma BNP levels was greater for severe heart failure, than for mild heart failure. Discussion We initially investigated the plasma BNP threshold required to induce pulmonary congestion and then searched for factors affecting these levels between grades 0 and 1 of pulmonary congestion. The results indicated a threshold 241

4 Table 1. Comparison of the Characteristics of Each Grade of Pulmonary Congestion All patients Grade 0 Grade 1 Grade 2 Grade 3 Number Age (yrs) 65.8± ± ±12.6* 71±11.8* 71±18.9* Gender (Male/Female) 342/ /68 32/18* 41/21* 23/10* BMI (kg/m 2 ) 24± ± ±3.7* 22.9±3.8* 24.9±5.3* SBP (mmhg) 135.3± ± ± ± ±35.0 DBP (mmhg) 77.8± ± ± ± ±27.8 HR (bpm) 80.3± ± ± ±23.6* 104.9±31.7* BT ( ) 36.5± ± ± ± ±1.0 SpO 2 (%) 96.3± ±1.5 97± ± ±7.3* Laboratory data BNP (pg/ml) 386.5± ± ±661.0* ±1164.7* ±1313* egfr (ml/min/1.73m 2 ) 60.2± ± ±26.4* 45.1±28.5* 37.7±25.8* WBC ( L) ± ± ±2801* ± ±5348.6* Hb (g/dl) 13.3± ± ± ±2.4* 11.9±2.8* CRP (mg/dl) 1.3± ± ± ± ±7.3* TP (g/dl) 7.0± ± ± ± ±0.74 Alb (g/dl) 4.0± ± ±0.6* 3.7±0.5* 3.7±0.6* Na (meq/l) 140± ± ± ± ±5.5 K (meq/l) 4.3± ± ± ± ±1.0 Cl (meq/l) 105.6± ± ± ± ±5.5 Echocardiography LVEF (%) 52.8± ± ±19.7* 37.4±15.1* 40.0±15.7* LVDd (mm) 52.5± ± ± ±10.9* 58±9.2* LAD (mm) 41.1± ± ± ±8.9* 44±13.7 IVS (mm) 9.2± ± ± ±1.6 10±3.2 PW (mm) 9.6± ± ± ± ±2.6 History Hypertension (n/%) 247(54) 171(54) 31(62) 28(45) 17(51)* Diabetes (n/%) 145(32) 93(29) 24(48) 17(27) 11(33)* Renal dysfunction (n/%) 72(16) 105(33) 33(66) 46(74) 25(76) Dialysis (n/%) 43(9) 9(2) 7(14) 6(9) 7(21) Underlying cardiovascular disease Ischemic cardiomyopathy (n/%) 271(59) 212(67) 20(40) 22(35) 17(51)* Valvular disease (n/%) 18(4) 4(1) 5(10) 5(8) 4(12) Arrhythmia (n/%) 111(24) 100(31) 24(48) 39(62) 14(42)* Cardiomyopathy (n/%) 31(7) 8(2) 7(14) 10(16) 6(18) Infectious heart disease (n/%) 7(2) 2(0.6) 2(4) 3(4) 0(0) Thrombosis (n/%) 7(2) 4(1) 1(2) 2(3) 0(0) Aortic disease (n/%) 2(0.4) 1(0.3) 1(2) 0(0) 0(0) Others (n/%) 12(3) 4(1) 1(2) 4(6) 3(9) BMI indicates body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; BT, body temperature; SpO 2, oxygen saturation of the blood; BNP, B-type natriuretic peptide; egfr, estimated glomerular filtration rate; WBC, white blood cells, Hb, hemoglobin; CRP, c-reactive protein; TP, serum total protein; Alb, serum albumin; Na, serum sodium; K, serum potassium; Cl, serum chloride; LVEF, left ventricular ejection fraction; LVDd, left ventricular end-diastolic dimension; LAD, left atrial dimension; IVS, interventricular septum dimension; and PW, posterior wall dimension. Statistical comparisons between each groups were performed using the non-repeated measures analysis of variance (*, vs. Grade 0 group;, vs. Grade 1 group;, vs. Grade 2 group). Differences with a p value <0.05 were considered to be statistically significant. value of 143 pg/ml, which suggested that patients with the plasma BNP levels equal to or above this value often have pulmonary congestion. This value is approximate, and of low significance in and of itself, as it would naturally vary 242

5 A B Grade 0 vs. Grade 1-3 BNP (pg/ml) n = 62 n = 33 Sensitivity n = 314 n = 50 Grade 0 Grade 1 Grade 2 Grade 3 Cut off: 143pg/mL Area under the ROC curve (AUC): Standard Error: % CI: to Sensitivity: 0.81 Specificity: 0.83 Figure 2. The relationship between the BNP level and pulmonary congestion grades. The BNP levels for each grade of pulmonary congestion on chest X-rays (A) and the ROC curve for detecting the plasma BNP threshold for pulmonary congestion (B) are shown. BNP indicates B-type natriuretic peptide, and ROC: receiver-operator characteristics among patients. We also investigated the extracardiac factors that influenced the threshold value of 143 pg/ml to identify which of the factors affected the relationship between pulmonary congestion and the plasma BNP levels. The results in Table 2 indicate that age, renal function, and BMI clearly affect the threshold. Although these three factors were previously believed to affect the plasma BNP levels to some extent (12-14), it had not been comprehensively or specifically analyzed as to how they influence the severity of heart failure. As shown in Fig. 4, the three factors significantly affected the relationship between pulmonary congestion and the plasma BNP levels at each grade of heart failure. Even when the grades of heart failure were comparable, the plasma BNP levels were higher for elderly and renal dysfunction patients. Conversely, the plasma BNP levels were decreased among the patients with a high BMI, and these levels were mostly comparable between grades 2 and 3 of pulmonary congestion, but tended to be lower for grade 3. That is, the plasma BNP levels were low in many obese patients despite the fact that they had severe pulmonary congestion. Others have documented slightly lower plasma BNP levels among obese patients (13, 14), but the present study is the first time that the effect of obesity on BNP was shown to be greater for severe heart failure, than for mild heart failure. The question arises as to how these three factors exert their effects on the relationship between pulmonary congestion and the plasma BNP levels. A schematic diagram of the likely relationship is shown in Fig. 5. Renal dysfunction, advanced age, and a high BMI are all independent risk factors for heart failure (15, 16). Previously published studies have shown that these three factors all directly lower heart function through complicated mechanisms. The heart secretes BNP in a compensatory manner. However, in the presence of renal dysfunction or advanced age, the plasma BNP levels can be much higher than those that would be expected based on the actual severity of heart failure. That is, renal dysfunction and advanced age are believed to directly increase the plasma BNP levels, independent of cardiac dysfunction. On the other hand, a high BMI significantly decreases the plasma BNP levels, apparently independent of cardiac function. In this manner, extracardiac factors directly affect the plasma BNP levels independent of their effect on cardiac function, but BNP in the bloodstream eventually affects the severity of heart failure due to its innate physiological activities. The extracardiac factors therefore create considerable variations in the relationship between pulmonary congestion and the plasma BNP levels, and ultimately, affect the amelioration of heart failure by BNP. We next briefly considered the mechanisms involved in the effects of renal dysfunction, advanced age, and a high BMI on the plasma BNP levels. In general, the plasma BNP levels are regulated by the amount of BNP secreted from the heart, and the amount of clearance from the periphery. Clearance is determined by the number of clearance receptors and the neutral endopeptidase activity (17, 18). The plasma BNP levels were elevated under renal dysfunction because the clearance of BNP at the kidney may be decreased and the amount of BNP secreted from the heart was increased in renal dysfunction due to volume overload and some inflammatory factors. Regarding aging, the plasma BNP levels may be elevated because of low grade systemic inflammation, renal dysfunction and increased cardiac stiffness, all of which would be associated with aging. Reduced levels of BNP in the obese subjects with and without heart failure have been shown in this study and also in several previous reports (13, 14). A possible reason for the reduction in the BNP levels may be related to the increased clear- 243

6 Table 2. A Comparison of the Characteristics between Patients with and without Pulmonary Congestion Grade 0 Grade 1~3 BNP<143pg/mL BNP 143pg/mL BNP<143pg/mL BNP 143pg/mL Number Age (yrs) 62.6± ±13.4* 64.5± ±14.3* Gender (Male/Female) 223/47 23/21 16/9 80/40 BMI (kg/m 2 ) 24.3± ±3.5* 25.7± ±4.0* SBP (mmhg) 135.2± ± ± ±32.9 DBP (mmhg) 77.1± ± ± ±22.9 HR (bpm) 73.6± ± ± ±31.1* BT ( ) 36.4± ± ± ±0.8 SpO 2 (%) 98.4± ± ± ±5.7 Laboratory data BNP (pg/ml) 42.3± ±212.5* 56.0± ±1108.8* egfr (ml/min/1.73m 2 ) 70.6± ±21.5* 64.5± ±25.9* WBC ( L) ± ± ± ± Hb (g/dl) 13.9± ±1.9 13± ±2.6 CRP (mg/dl) 0.40± ± ± ±5.1 TP (g/dl) 7.2± ± ± ±0.9 Alb (g/dl) 4.2± ± ± ±0.6* Na (meq/l) 140± ±5.5* 140± ±4.7 K (meq/l) 4.2± ±0.6* 4.3± ±0.8 Cl (meq/l) 106.1± ± ± ±4.9* Echocardiography LVEF (%) 61.8± ± ± ±16.7* LVDd (mm) 49.3± ± ±5.1 58±12.7* LAD (mm) 38.0± ±13.3* 36.2± ±8.4 IVS (mm) 9.0± ± ± ±2.6 PW (mm) 9.1± ± ± ±2.3 History Hypertension (n/%) 141(52) 27(61) 15(60) 64(53) Diabetes (n/%) 80(29) 16(36) 11(44) 38(31) Dialysis (n/%) 4(1) 7(15)* 1(4) 31(25)* Underlying cardiovascular disease Ischemic cardiomyopathy (n/%) 188(69) 24(54)* 14(56) 45(37) Valvular disease (n/%) 1(0.3) 3(6)* 1(4) 13(20) Arrhythmia (n/%) 89(32) 10(22) 3(12) 64(53)* Cardiomyopathy (n/%) 4(1) 4(9) 0(0) 23(19)* Infectious heart disease (n/%) 1(0.3) 1(2) 1(4) 4(3) Thrombosis (n/%) 3(1) 1(2) 3(12) 0(0)* Aortic disease (n/%) 1(0.3) 0(0) 1(4) 0(0)* Others (n/%) 3(1) 1(2) 2(8) 6(5) BMI indicates body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; BT, body temperature; SpO 2, oxygen saturation of the blood; BNP, B-type natriuretic peptide; egfr, estimated glomerular filtration rate; WBC, white blood cells, Hb, hemoglobin; CRP, c-reactive protein; TP, serum total protein; Alb, serum albumin; Na, serum sodium; K, serum potassium; Cl, serum chloride; LVEF, left ventricular ejection fraction; LVDd, left ventricular end-diastolic dimension; LAD, left atrial dimension; IVS, interventricular septum dimension; and PW, posterior wall dimension. Statistical comparisons between each groups were performed using the non-repeated measures analysis of variance (*, vs. BNP <143 pg/ml group among the same Grade 0 to Grade 3 groups;, vs. Grade 0 group among the same plasma BNP level groups). Differences with a p value <0.05 were considered to be statistically significant. 244

7 A Under 66 years C egfr over 60 E BMI under 23.8 Cut off: 127pg/mL AUC: Sensitivity: 0.79 Specificity: 0.91 Cut off: 127pg/mL AUC: Sensitivity: 0.69 Specificity: 0.93 Cut off: 145pg/mL AUC: Sensitivity: 0.88 Specificity: 0.83 B Over 66 years D egfr under 60 F BMI over 23.8 Cut off: 165pg/mL AUC: Sensitivity: 0.86 Specificity: 0.80 Cut off: 192pg/mL AUC: Sensitivity: 0.87 Specificity: 0.75 Cut off: 127pg/mL AUC: Sensitivity: 0.80 Specificity: 0.90 Figure 3. ROC curves for detecting the plasma BNP threshold for pulmonary congestion based on chest X-rays and the influences of extracardiac factors. ROC curves for the patient groups; (A), age younger than 66 years; (B), age older than 66 years; (C), egfr over 60 ml/min/1.73 m 2 ; (D), egfr under 60 ml/min/1.73 m 2 ; (E), BMI under 23.8; (F), BMI over egfr indicates the estimated glomerular filtration rate, BMI: body mass index, BNP: B-type natriuretic peptide, and ROC: receiver-operator characteristics ance of circulating BNP due to the alteration of clearance receptors or peptide degradation (19, 20). This may be because natriuretic peptide clearance receptors are abundant on human adipocytes (19), and the vascularity of adipose tissue may permit increased degradation of BNP by neutral endopeptidase (21). It has not been clarified whether or not obesity directly reduces the synthesis of BNP in the heart. The results of the present study can be applied to various clinical situations. It is well known that the plasma BNP levels are increased when pulmonary congestion is severe. However, if these levels are much higher than indicated by the chest X-ray findings, hidden renal dysfunction should be suspected; even when the creatinine level is not so increased, we should never overlook the possibility of renal dysfunction in such a case. Conversely, the lower plasma BNP levels relative to the grade of pulmonary congestion in obese patients do not necessarily imply a mild degree of heart failure. Furthermore, although the differentiation of heart failure from pneumonia on chest X-rays is difficult, heart failure should not be ruled out simply based on the low plasma BNP levels. Caution must be exercised particularly for obese patients, because their plasma BNP levels can be low even in the presence of severe heart failure. Figure 6 shows an example of a clinical scenario using chest X-rays and the rapid BNP assay for the diagnosis of heart failure and other conditions (2, 12-14, 22). Limitations 1) This cross-sectional study comprised consecutive patients who had been admitted to the cardiovascular unit in The Jikei University Hospital for any reason. Therefore, the threshold level of plasma BNP for pulmonary congestion evaluated in our study may be slightly different compared to other studies. 2) The conditions of the X-rays were not unified, as they were taken in the upright position or supine position. Therefore, the grading of the severity of pulmonary congestion was possibly difficult, and particularly indistinguishable between grades 2 and 3. However, the expert cardiologists consistently evaluated the severity of pulmonary congestion of all X-rays based on the fixed criteria in this study. 3) This study was done with consecutive patients with cardiovascular diseases who were admitted to our hospital. Thus, a substantial number of patients might have been suffering from so-called acute heart failure to a varying degree. The conclusion of this study may be somewhat limited in acute heart failure. 4) As far as renal dysfunction, HD may affect the present results. However, our additional study using non-hd patients showed a similar result (data not shown). 245

8 A under 66 years over 66 years n = 44 n = 249 BNP (pg/ml) n = 18 n = 18 n = 12 n = 21 n = 219 n = n = 143 n = 171 B Grade 0 Grade 1 Grade 2 Grade 3 ALL egfr over 60 egfr under 60 n = 46 n = 208 BNP (pg/ml) n = 208 n = 104 n = 17 n = 33 n = 16 n= 8 n = 25 n = 249 C Grade 0 Grade 1 Grade 2 Grade 3 ALL BMI under 23.8 BMI over 23.8 n = 22 n = 192 BNP (pg/ml) n = 16 n = 10 n = n = 141 n = 19 n = 17 n= n = Grade 0 Grade 1 Grade 2 Grade 3 ALL Figure 4. The relationship between the plasma BNP levels and other patient characteristics in each stage of pulmonary congestion. The plasma BNP levels (mean, closed circles) according to the congestion grade 0-3 on chest X-rays were compared between each group according to the following factors: (A), by age (<66 years or 66 years); (B), by egfr (<60 ml/min/1.73 m 2 or 60 ml/min/1.73 m 2 ); (C), by BMI (<23.8 or 23.8). The bars indicate the SD. Differences with a p value <0.05 (*) were considered to be statistically significant. egfr indicates the estimated glomerular filtration rate, BMI: body mass index, and BNP: B-type natriuretic peptide 246

9 Grade 0 BNP Grade 1 Extracardiac Factors Renal Dysfunction Advanced Age etc. Grade 1 BNP Grade 2 Extracardiac Factors High BMI etc. Grade 3 BNP BNP BNP Pulmonary congestion improved by increased endogenous BNP Grade 3 Pulmonary congestion worsened by decreased endogenous BNP BNP Figure 5. Changes in the balance between the degree of heart failure and the plasma BNP levels. Renal dysfunction, advanced age, and a high BMI all directly decrease the heart function. At the same time, the heart secretes BNP in a compensatory manner, but in the presence of renal dysfunction or advanced age, the plasma BNP levels can be much higher than would be expected based on the actual extent of heart failure. That is, renal dysfunction and advanced age may directly increase the plasma BNP levels, independent of cardiac dysfunction. In contrast, a high BMI significantly decreases the plasma BNP levels independent of cardiac function, so the plasma BNP levels can be much lower in subjects with a high BMI than would be expected based on the actual extent of heart failure. The extracardiac factors are therefore responsible for considerable variations in the relationship between pulmonary congestion and the plasma BNP levels. BMI indicates body mass index, and BNP: B-type natriuretic peptide Predict plasma BNP level by this chest X-ray. >>> About 400~600 pg/ml?? For instance Obtain blood sample simultaneously. Real plasma BNP level: 200pg/mL or Real plasma BNP level: 2,000 pg/ml Relatively-low plasma BNP level compared to the predicted value may be explained by - youth - obesity - atrial overload (e.g. mitral stenosis) - other than heart diseases such as pneumonia, lung cancer, lung tuberculosis, etc. Relatively-high plasma BNP level compared to the predicted value may be explained by - renal insufficiency - advanced age - inflammation such as infectious heart diseases, systemic inflammatory response syndrome, etc. Figure 6. A clinical scenario for using chest X-rays and the rapid BNP assay for the diagnosis of heart failure and other diseases. From the findings of chest X-rays of a patient with heart failure, we could estimate the plasma BNP value, but a decreased BNP may be explained by youth, obesity or atrial overload, and adversely, an increased BNP may be explained by renal dysfunction, advanced age or the presence of systemic inflammatory response syndrome. BNP: B-type natriuretic peptide 247

10 Conclusion In patients with cardiovascular disease who were admitted to our unit, the approximate plasma BNP threshold associated with pulmonary congestion that was detectable by chest X-rays was 143 pg/ml, but this value was largely influenced by both cardiac function and extracardiac factors. Renal dysfunction and advanced age increase the levels, whereas a high BMI decreases the plasma BNP level. Therefore, extracardiac factors should be considered when the relationship between the plasma BNP level and the severity of pulmonary congestion on chest X-rays seems inconsistent. Among the various extracardiac factors, the low levels of plasma BNP in patients with a high BMI should be carefully considered in order to avoid underestimating the degree of heart failure. The authors state that they have no Conflict of Interest (COI). Acknowledgement We thank the trial physicians and nurses in all of the participating hospitals for their important contribution to the study. References 1. Mukoyama M, Nakao K, Obata K, et al. Augmented secretion of brain natriuretic peptide in acute myocardial infarction. Biochem Biophys Res Commun 180: , Yasue H, Yoshimura M, Sumida H, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 90: , Saito Y, Nakao K, Nishimura K, et al. Clinical application of atrial natriuretic polypeptide in patients with congestive heart failure: beneficial effects on left ventricular function. Circulation 76: , Yoshimura M, Yasue H, Okumura K, et al. Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation 87: , Ogawa Y, Itoh H, Tamura N, et al. Molecular cloning of the complementary DNA and gene that encode mouse brain natriuretic peptide and generation of transgenic mice that overexpress the brain natriuretic peptide gene. J Clin Invest 93: , Yamahara K, Itoh H, Chun TH, et al. Significance and therapeutic potential of the natriuretic peptides/cgmp/cgmp-dependent protein kinase pathway in vascular regeneration. Proc Natl Acad Sci USA 100: , Knudsen CW, Omland T, Clopton P, et al. Diagnostic value of B- Type natriuretic peptide and chest radiographic findings in patients with acute dyspnea. Am J Med 116: , Carlson KJ, Lee DC, Goroll AH, Leahy M, Johnson RA. An analysis of physicians reasons for prescribing long-term digitalis therapy in outpatients. J Chronic Dis 38: , Japanese Society of Nephrology. Clinical practice guidebook for diagnosis and treatment of chronic kidney disease Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130: , Matsuo S, Imai E, Horio M, et al. Collaborators developing the Japanese equation for estimated GFR. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53: , McCullough PA, Duc P, Omland T, et al. Breathing Not Properly Multinational Study Investigators. B-type natriuretic peptide and renal function in the diagnosis of heart failure: an analysis from the Breathing Not Properly Multinational Study. Am J Kidney Dis 41: , Wang TJ, Larson MG, Levy D, et al. Impact of obesity on plasma natriuretic peptide levels. Circulation 109: , Mehra MR, Uber PA, Park MH, et al. Obesity and suppressed B- Type natriuretic peptide levels in heart failure. J Am Coll Cardiol 43: , McCullough PA, Soman SS, Shah SS, et al. Risks associated with renal dysfunction in patients in the coronary care unit. J Am Coll Cardiol 36: , Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med 347: , Suga S, Nakao K, Hosoda K, et al. Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Endocrinology 130: , Hashimoto Y, Nakao K, Hama N, et al. Clearance mechanisms of atrial and brain natriuretic peptides in rats. Pharm Res 11: 60-64, Sarzani R, Dessi-Fulgheri P, Paci VM, Espinosa E, Rappelli A. Expression of natriuretic peptide receptors in human adipose and other tissues. J Endocrinol Invest 19: , Sengenès C, Berlan M, De Glisezinski I, Lafontan M, Galitzky J. Natriuretic peptides: a new lipolytic pathway in human adipocytes. FASEB J 14: , McCullough PA, Sandberg KR. Sorting out the evidence on natriuretic peptides. Rev Cardiovasc Med 4 Suppl 4: S13-S19, Inoue T, Kawai M, Nakane T, et al. Influence of low grade inflammation on plasma B-type natriuretic peptide levels. Intern Med 49: , The Japanese Society of Internal Medicine 248