Plasma brain natriuretic peptide as a biochemical marker of high left ventricular end-diastolic pressure in patients with symptomatic left ventricular dysfunction

Congestive Heart Failure

Plasma brain natriuretic peptide as a biochemical marker of high left ventricular end-diastolic pressure in patients with symptomatic left ventricular dysfunction Keiko Maeda, MD, Takayoshi Tsutamoto, MD, Atsuyuki Wada, MD, Tomoko Hisanaga, MD, and Masahiko Kinoshita, MD Otsu, Japan

Background Plasma atrial natriuretic peptide (ANP), mainly from the atrium, brain natriuretic peptide (BNP), mainly from the ventricle, norepinephrine (NE), and endothelin-1 (ET-1) levels are increased with the severity of congestive heart failure (CHF). Although a close correlation between the left ventricular end-diastolic pressure (LVEDP) and plasma ANP in patients with left ventricular dysfunction has been reported, it is not yet known which cardiac natriuretic peptide is a better predictor of high LVEDP in patients with CHF.

Methods To investigate the biochemical predictors of the high LVEDP in patients with left ventricular dysfunction, we measured plasma ANP, BNP, NE, and ET-1 levels and the hemodynamic parameters in 72 patients with symptomatic left ventricular dysfunction. Stepwise multivariate regression analyses were also used to determine whether the plasma levels of ANP, BNP, NE, and ET-1 could predict high LVEDP.

Results Although significant positive correlations were found among the plasma levels of ANP, BNP, ET-1, and NE and the LVEDP, only BNP (p = 0.0001) was an independent and significant predictor of high LVEDP in patients with CHF. In all eight patients with severe CHF measured for hemodynamics before and after the treatments, the plasma BNP levels decreased in association with the decrease of LVEDP, whereas other factors increased in some patients despite the decrease of LVEDP.

Conclusions These findings suggest that plasma BNP is superior to ANP as a predictor of high LVEDP in patients with symptomatic left ventricular dysfunction. (Am Heart J 1998;135:825-32.)

Increased levels of various neurohumoral factors have been found in patients with chronic congestive heart failure (CHF),1-4 and high plasma levels of norepinephrine (NE) and endothelin-1 (ET-1) have been reported to be significant prognostic predictors of CHF,5-7 suggesting an important role for these vasoconstrictors in the pathogenesis of CHF. High levels of vasodilator neurohumoral factors have also been found in patients with CHF, and a high plasma level of atrial natriuretic peptide (ANP), mainly from the atrium, has been reported to be a significant prognostic predictor.5,8,9 Plasma brain From the First Department of Internal Medicine, Shiga University of Medical Science. Supported in part by a Grant-in-Aid for Scientific Research (C) in Japan. Submitted July 8, 1996; accepted Oct. 10, 1997. Reprint requests: Takayoshi Tsutamoto, MD, First Department of Internal Medicine, Shiga University of Medical Science, Tsukinowa, Seta, Otsu 520-2192, Japan. Copyright © 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/87272

natriuretic peptide (BNP) levels are also increased in patients with CHF and are thought to originate in ventricular myocytes.10-13 Both of these plasma cardiac natriuretic peptides (ANP and BNP) are increased with the severity of CHF because of left ventricular dysfunction, and these increases are correlated with hemodynamic parameters such as pulmonary capillary wedge pressure (PCWP) and left ventricular ejection fraction (LVEF).10,12-17 The left ventricular end-diastolic pressure (LVEDP) is thought to be an index of preload and an important hemodynamic parameter to assess cardiac function, and high LVEDP is reflected in left ventricular dysfunction. Although we reported a close correlation between the LVEDP and plasma ANP in patients with left ventricular dysfunction,17 it is not yet known which cardiac natriuretic peptide is a better predictor of high LVEDP in patients with CHF. More recently, we report-

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Figure 1

Figure 2

Plasma neurohumoral factors in patients with mild or severe CHF. *p < 0.05 versus mild CHF.

Correlation between LVEDP and neurohumoral factors in patients with symptomatic left ventricular dysfunction.

ed that plasma BNP is more useful than ANP for assessing the mortality in patients with chronic CHF.18 Therefore we hypothesized that plasma BNP is superior to ANP for the prediction of high LVEDP in patients with left ventricular dysfunction. Hemodynamics, ET-1, and NE can directly stimulate the cardiac natriuretic peptides.3,4,19-22 Both ET-1 and NE have been reported to be cardiotoxic factors,3,19,23-25 and these vasoconstrictors, which are increased in CHF, may have an influence on the plasma BNP as a marker of ventricular injury or damage independent of hemodynamics. In this study we evaluated whether plasma BNP is superior to ANP for the prediction of high LVEDP in patients with left ventricular dysfunction and whether endogenous NE and ET-1 directly or indirectly stimulate the secretion of cardiac natriuretic peptides in patients with CHF.

tion for more than 3 months before enrollment, 16 had dilated cardiomyopathy, and 5 had hypertensive heart disease. Patients with valvular heart disease, hypertrophic cardiomyopathy, acute myocardial infarction, and chronic renal failure were excluded. None of the patients had typical left ventricular aneurysm or severe mitral valve regurgitation. Fifty-seven of the patients were classified in New York Heart Association functional class I or II as mild CHF, and the other 15 in class III or IV were classified as severe CHF. Twenty-five patients had been treated previously with digitalis, 30 with angiotensin-converting enzyme inhibitors, seven with βblockers, 53 with vasodilators, and 31 with diuretics. All drugs were discontinued at least 24 hours before this study. To evaluate the treatment effects including those of angiotensin-converting enzyme inhibitors, eight patients in functional class III or IV underwent repeat cardiac catheterization and blood samplings after more than 4 weeks.

Methods Patients Seventy-two patients with left ventricular dysfunction (LVEF <50%) undergoing right and left heart catheterization for clinically indicated purposes were studied continually from December 1994 until March 1997 in our institution. Informed consent was obtained from all patients for participation in the study according to a protocol approved by the Committee on Human Investigation at our institution. The 53 men and 19 women ranged in age from 20 to 80 years (mean age 61 years). Fifty-one patients had had myocardial infarc-

Study protocol After 20 minutes of bedrest with the patient supine and premedicated with diazepam (5 mg orally), right heart catheterization was performed with a 7F Swan-Ganz catheter, and left heart catheterization was performed with a pigtail catheter. The heart rate was monitored by electrocardiography, and blood pressure was measured with the cuff occlusion method or femoral artery pressure. A Swan-Ganz catheter was inserted through the femoral vein into the right atrial and the main pulmonary artery, where the pressure was measured. The catheter was then inserted farther into the pulmonary artery, and PCWP was measured by occluding the balloon. Cardiac output was determined with the ther-

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Table I. Plasma neurohormonal levels and hemodynamic data in 72 patients with CHF

NYHA (functional class) Age (yr) ANP (pg/ml) BNP (pg/ml) ET-1 (pg/ml) NE (pg/ml) HR (beats/min) RAP (mm Hg) MPAP (mm Hg) PCWP (mm Hg) LVEDP (mm Hg) MBP (mm Hg) CI (L/min/m2) LVEF (%)

Mild CHF (n = 57)

Severe CHF (n = 15)

1.74 ± 0.44 60.6 ± 13.1 67.1 ± 48.3 86.8 ± 82.6 2.21 ± 0.67 260 ± 218 68 ± 17 2.9 ± 1.9 13.7 ± 5.6 6.8 ± 4.2 10.4 ± 4.7 91 ± 15 2.78 ± 0.61 39.9 ± 8.6

3.53 ± 0.52* 64.1 ± 13.1 152.7 ± 96.9* 690.6 ± 491.1* 3.56 ± 1.67* 1032 ± 1042* 91 ± 8.7* 5.6 ± 4.1* 24.7 ± 11.9* 15.1 ± 6.8* 22.7 ± 8.1* 94.3 ± 18.9 2.74 ± 0.65 28.1 ± 9.5*

NYHA, New York Heart Association. *p < 0.001 versus the value in the mild congestive heart failure group.

modilution method. A pigtail catheter was inserted through the femoral artery into the left ventricle, where the pressure was measured. LVEF was determined with left ventriculography with contrast medium or radionuclide. Blood samples were drawn from the femoral artery.

Measurements of plasma ANP, BNP, ET-1, and NE Samples for the assay of plasma ANP, BNP, and ET-1 levels were transferred to chilled disposable tubes containing aprotinin (500 kallikrein inactivator U/ml) and ethylenediaminetetraacetic acid (1 mg/ml). Samples for the assay of plasma NE levels were transferred to chilled disposable tubes containing ethylenediaminetetraacetic acid (1 mg/ml). The blood samples were immediately placed on ice and centrifuged at 40° C, and aliquots of plasma were immediately stored at –30° C until assay was performed. Plasma ANP levels were measured with a specific immunoradiometric assay for human α-ANP (Shionoria ANP kit, Osaka, Japan) as reported previously.10,18 The minimal detectable quantity of human ANP is 5 pg/ml. The intraassay and interassay coefficients of variation were 5.1% and 5.8%, respectively. The cross-reactivity with human BNP was <0.001% on a molar basis. Plasma BNP levels were measured with a specific immunoradiometric assay for human BNP (Shionoria BNP kit, Osaka, Japan) as reported previously.10,18 This assay system uses two monoclonal antibodies against human BNP, one recognizing a carboxyterminal sequence and the other the ring structure of human BNP, and measures human BNP by sandwiching it between the two antibodies without the extraction of plasma.10,18 The intraassay and

Figure 3

Relation between plasma ANP and BNP levels and LVEDP in eight patients with severe CHF before (solid circles) and after (open circles) treatment for heart failure. Dashed line represents linear regression line between plasma BNP and LVEDP in Fig. 2. Patients’ plasma BNP levels decreased in association with decrease of LVEDP, parallel to linear regression line in Fig. 2, but plasma ANP levels of one of patients increased and that of another one patient did not change despite decrease in LVEDP.

interassay coefficients of variation were 5.2% and 6.1%, respectively. The minimal detectable quantity of human BNP is 2 pg/ml. The cross-reactivity with human α-ANP was <0.001% on a molar basis. In 25 age-matched normal subjects, the mean plasma ANP level was 12.7 ± 6.4 pg/ml, and the mean plasma BNP level was 15.2 ± 14.2 pg/ml. Plasma ET-1 levels were measured by radioimmunoassay as described.4 This antibody showed 100% cross-reactivity with ET-1, 7% with ET-2, 7% with ET-3, and 17% with big ET-1. However, it did not cross-react with angiotensin I or II, vasopressin, or human cardiac natriuretic peptides. The mean plasma ET-1 level was 1.5 ± 0.9 pg/ml in 20 age-matched normal control subjects, as we previously reported.4 Plasma NE levels were measured by high-performance liquid chromatography.

Statistical analysis Data are expressed as the mean ± SD. Statistical comparisons were made with Student’s unpaired t test. Univariate and stepwise multivariate regression analyses were used to detect independent predictors of plasma ANP and BNP among the 10 variables, as listed in the following text. In addition, univariate and stepwise multivariate regression analyses were used to detect independent predictors of high LVEDP in patients with symptomatic left ventricular dysfunction among the four biochemical factors such as cardiac natriuretic peptides. Linear regression analysis was used to determine the relations between continuous variables. A value of p < 0.05 was considered significant.

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Table II. Univariate and multivariate linear model of plasma neurohumoral factors and hemodynamic parameters in patients with symptomatic left ventricular dysfunction ANP Univariate Variable

Correlation coefficient

p Value

ET-1 NE HR RAP MPAP PCWP LVEDP MBP CI LVEF

0.52 0.47 0.31 0.34 0.50 0.55 0.56 –0.03 –0.21 –0.47

<0.001 <0.001 <0.01 <0.01 <0.001 <0.001 <0.001 NS NS <0.001

BNP Multivariate β-coefficient 0.294

0.32

Univariate

p Value

Correlation coefficient

p Value

0.0063 NS NS NS NS NS 0.0054 NS NS NS

0.61 0.69 0.37 0.56 0.68 0.71 0.79 0.01 –0.14 –0.46

<0.001 <0.001 <0.01 <0.001 <0.001 <0.001 <0.001 NS NS <0.001

Multivariate β-coefficient 0.245 0.319

0.499

p Value 0.0006 0.0001 NS NS NS NS 0.0001 NS NS NS

NS, Not significant.

Results Hemodynamic data Cardiac catheterization data are shown in Table I. Heart rate (HR), right atrial pressure (RAP), mean pulmonary artery pressure (MPAP), PCWP, and LVEDP were significantly increased and LVEF was significantly decreased in the patients with severe CHF compared with the patients with mild CHF.

Plasma levels of ANP, BNP, NE and ET-1 in patients with left ventricular dysfunction The plasma ANP and BNP levels were significantly increased in the patients with severe CHF compared with the patients with mild CHF (67.1 ± 48.3 pg/ml vs 152.7 ± 96.9 pg/ml, p < 0.001; 86.8 ± 82.6 vs 690.6 ± 491.1 pg/ml, p < 0.001). The plasma ET-1 and NE levels were significantly increased in the patients with severe CHF compared with those in the patients with mild CHF (2.21 ± 0.67 vs 3.56 ± 1.67 pg/ml, p < 0.001; 260 ± 218 vs 1031 ± 1042 pg/ml, p < 0.001), as shown in Fig. 1.

Correlation of plasma levels of ANP and BNP with hemodynamic parameters and plasma NE and ET-1 levels The correlations between hemodynamic data and plasma ET-1 and NE levels with plasma ANP and BNP levels are shown in Table II. The plasma ANP levels had a significant positive correlation with the plasma ET-1 levels, plasma NE levels, HR, RAP, MPAP, PCWP, and LVEDP and a significant negative correlation with

LVEF but no correlation with mean blood pressure (MBP) or cardiac index (CI). The plasma BNP levels had also a significant positive correlation with the plasma ET-1 levels, plasma NE levels, HR, RAP, MPAP, PCWP, and LVEDP and a significant negative correlation with LVEF but no correlation with MBP and CI. To investigate the independent predictors of ANP and BNP, stepwise multivariate regression analysis was used with 10 variables such as ET-1, NE, HR, RAP, MPAP, PCWP, LVEDP, LVEF, MBP, and CI. Among these 10 variables LVEDP (p = 0.0054) and ET-1 (p = 0.0063) were independent and significant predictors of ANP, and among these parameters LVEDP (p = 0.0001), NE (p = 0.0003), and ET-1 (p = 0.0006) were independent and significant predictors of BNP.

Correlation between neurohumoral factors and LVEDP in patients with CHF Significant positive correlations were seen between LVEDP and plasma ANP, BNP, ET-1, and NE levels as shown in Fig. 2. However, only plasma BNP level (p = 0.0001) was an independent and significant predictor of LVEDP among the four biochemical factors of plasma ANP, BNP, ET-1, and NE in patients with symptomatic left ventricular dysfunction by stepwise multivariate analysis. In all eight patients who underwent repeat cardiac catheterization before and after the treatments with angiotensin-converting enzyme inhibitors (Table III), the plasma BNP levels decreased in association with the decrease of LVEDP parallel to the linear regression line

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Table III. Hemodynamic and neurohumoral parameters in eight patients before and after treatment for severe CHF Patient age (yr) Sex Diagnosis 66

M

71

F

65

F

73

F

70

M

43

F

75

F

62

M

OMI After OMI After DCM After OMI After DCM After HHD After DCM After HHD After

LVEF RAP MPAP PCWP Before 50 Before 35 Before 38 Before 40 Before 17 Before 50 Before 34 Before 50

39 3 35 0 30 5 26 1 17 3 37 2 14 0 41 2

4 13 6 13 7 18 12 17 15 33 3 18 2 12 2 20

18 8 29 4 10 3 30 10 50 19 34 6 17 6 26 9

11 16 15 8 9 12 22 13 30 25 15 6 13 16 16 22

LVEDP

MBP

CI

ANP

BNP

NE

ET-1

22 87 26 78 20 126 30 86 35 110 30 88 23 105 27 105

116 2.17 91 3.10 107 4.17 113 3.00 103 2.62 127 2.86 92 3.58 117 4.19

2.052 79 3.03 59 3.16 47 2.53 160 2.74 370 4.20 92 2.82 22 3.48 76

110 220 120 170 70 11 160 100 230 830 140 210 42 31 120 92

970 147 840 376 290 247 1200 317 1300 642 410 739 430 328 900 355

558 2.95 693 2.17 449 3.19 992 1.62 1008 5.65 277 2.70 1626 2.35 729 1.16

4.92 2.14 2.73 6.65 4.76 2.17 3.93 4.88

OMI, Old myocardial infarction; DCM, dilated cardiomyopathy; HHD, hypertensive heart disease.

shown in Fig. 2 and accompanied by an improvement of symptoms (New York Heart Association functional class 3.9 ± 0.4 vs 2.0 ± 0.5, p < 0.001) (Fig. 3). The decrease of plasma ANP levels also paralleled the decrease of LVEDP in all but two patients. In one patient the plasma ANP level did not change despite the decrease of LVEDP (from 30 to 10 mm Hg), and in the other patient the plasma ANP level increased despite the decrease of LVEDP (from 35 to 25 mm Hg) (Fig. 3). The plasma NE level increased in one patient and the plasma ET-1 level increased in three patients despite the decrease of LVEDP (Table III).

Discussion Previous studies reported the correlation between hemodynamics and neurohumoral factors such as plasma cardiac natriuretic peptides, and plasma levels of ANP were thought to be a hemodynamic predictor in patients with CHF.10,13 In fact, we previously reported a close correlation between the LVEDP and plasma ANP in patients with left ventricular dysfunction.17 However, it remained unknown as to which cardiac natriuretic peptide, ANP, mainly from the atrium, or BNP, mainly from the ventricle, is a better predictor of high LVEDP (an index of preload) in patients with left ventricular dysfunction. Moreover, there have been no reports on serial changes in the relation between LVEDP and neurohumoral factors such as cardiac natriuretic peptides before and after the treatment of CHF. In this study we

demonstrated that the plasma level of BNP is superior to that of ANP for predicting high LVEDP in patients with CHF and left ventricular dysfunction not only in a single measurement but in serial measurements after treatment with angiotensin-converting enzyme inhibitors. These findings are consistent with the report that BNP is superior to ANP for predicting the effect of angiotensin-converting enzyme inhibitors12 and also support our recent finding that plasma BNP is more useful than ANP for assessing mortality in patients with symptomatic left ventricular dysfunction.18 ET-1, NE, and a hemodynamic abnormality can directly stimulate the cardiac natriuretic peptides.20-22 Both plasma ET-1 and NE have been reported to be cardiotoxic factors,3,19,23-25 and these vasoconstrictors, which are increased in CHF, may have an influence on the plasma BNP as a marker of ventricular injury or damage independent of hemodynamics. In this study high plasma ET1 was found to be an independent predictor of plasma ANP and BNP among the hemodynamic parameters obtained by cardiac catheterization, suggesting that ET-1 directly stimulates the secretion of cardiac natriuretic peptides in patients with CHF. Moreover, high plasma NE was found to be an independent predictor of plasma BNP among the various hemodynamic parameters including LVEDP, suggesting that NE directly increases the secretion of BNP from the ventricle in patients with CHF. Because both ET-1 and NE were reported to have cardiotoxicity,3,19,23-25 our findings are consistent with the

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idea that plasma BNP, secreted mainly from the ventricle, is a sensitive biochemical marker of left ventricular injury or damage. ANP is secreted mainly from the atria, and the secretion of ANP is regulated by the stretching of the atria.26 In this study the plasma ANP level showed significant correlations with RAP, MPAP, PCWP, LVEDP, and LVEF, but only LVEDP was an independent and significant predictor of ANP among the hemodynamic parameters. There have been a number of reports of a relationship between plasma ANP levels and PCWP,14,16,26 but few studies have reported a relationship between plasma ANP levels and LVEDP.15,17 The present finding is consistent with our previous report that only LVEDP was found to be an independent and significant predictor of ANP among various hemodynamic parameters and plasma catecholamine levels in patients with left-sided heart failure.17 Although the factors associated with ANP secretion are well known, the regulation of BNP, secreted mainly from the ventricle,10 is not fully elucidated. Previous studies reported that the secretion of BNP is regulated by blood pressure and fluid volume.10 The mechanism of the secretion of BNP is not sufficiently clear; however, Nakagawa et al.27 reported that BNP mRNA increased as rapidly as immediate induction of the c-fos gene expression and reached a maximal level within 1 hour in rat ventricular cardiocytes stimulated by ET-1 in vitro. Moreover, previous studies showed that BNP concentration and BNP mRNA in the ventricle were increased in rats with hypertension or acute myocardial infarction.28,29 These findings suggest that BNP plays a role as a cardiac hormone against ventricular overload such as myocardial ischemia, necrosis, damage, and local mechanical stress on ventricular myocytes. In patients with CHF previous studies showed that plasma BNP levels correlated with PCWP, LVEDP, LVEF, and CI.10,11,13 Yoshimura et al.10 demonstrated that the plasma BNP had significant correlations with PCWP, LVEDP, and LVEF in the dilated cardiomyopathy group but not in the mitral stenosis group; consequently, the plasma BNP levels reflect the degree of left ventricular overload. However, to our knowledge there have been no reports concerning which cardiac natriuretic peptide is a better predictor of high LVEDP in patients with CHF, especially by repeat measurements of LVEDP in the same patients. Our finding of a relatively close correlation between plasma BNP and LVEDP suggests that the secretion of BNP from the ventricle is regulated by end-diastolic

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left ventricular wall stretch, as shown in ANP in the atrium. Further studies including the measurements of ventricular volume and wall stress are required to clarify this hypothesis. In this study plasma NE was not an independent predictor of ANP, suggesting the ANP secretion is mainly regulated by the increase of preload, partly caused by the vasoconstriction by sympathetic nervous activation. In contrast, plasma NE was an independent predictor of BNP, suggesting that BNP secretion from the ventricle is regulated by NE independent of LVEDP or the ejection fraction in patients with CHF. Because catecholamines are well known to induce myocardial injury or damage,23,24 in patients with a high plasma NE level endogenous catecholamines may cause myocardial injury or damage. Moreover, previous studies suggest that plasma BNP is a sensitive biochemical marker of left ventricular injury and damage in patients with CHF,11-13 indicating that high plasma BNP may be a marker of catecholamine-induced cardiotoxicity independent of hemodynamics. Although ET-1, a potent vasoconstrictor, stimulates the secretion of both ANP and BNP in atrial and ventricular cardiocytes from neonatal rats, 20,21 whether ET-1 directly or indirectly stimulates the secretion of cardiac natriuretic peptides in patients with CHF remains unknown. In this study plasma ET-1 was an independent significant predictor of ANP and BNP, suggesting that ET-1 directly stimulates the secretion of cardiac natriuretic peptides independent of hemodynamics in patients with CHF. ET-1 is thought to act not only as a humoral but also as a local factor such as an autocrine and paracrine factor in various tissues. A recent study reported that both ET-1 mRNA and the ET-1 content are increased in rats with CHF and myocardial infarction and that an ET receptor antagonist improved the mortality of CHF rats, suggesting that the sustained increase of ET-1 in this model causes left ventricular remodeling and cardiotoxicity including ventricular arrhythmia.25 These results indicate that in patients with left ventricular dysfunction and a high plasma BNP level, the increase of ET-1 in the ventricle may stimulate the secretion of the cardiac natriuretic peptides in the heart. Because high plasma BNP is a marker of left ventricular damage and perhaps is a marker of left ventricular remodeling11 and of the prognosis of patients with myocardial infarction,30 plasma BNP may be a marker of ET-1-induced cardiotoxicity independent of hemodynamics.

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Limitations In this study we performed left-sided catheterization and right-sided catheterization for the clinical purposes in patients with CHF. Therefore we evaluated a relatively small number of patients with severe CHF and high LVEDP. Moreover, we refrained from conducting left ventriculography in patients with high LVEDP and severe symptoms. Therefore the parameters of left ventricular volume, which may be an important regulator of plasma BNP,13 were not included in the analysis. In conclusion, the plasma levels of BNP were superior to those of ANP for the prediction of high LVEDP in patients with left ventricular dysfunction, suggesting that high plasma BNP is a useful noninvasive index of high LVEDP in patients with left ventricular dysfunction. Although BNP appears to be regulated mainly by LVEDP, NE and ET-1, which are increased in CHF, may directly stimulate the secretion of BNP in patients with left ventricular dysfunction. These findings are consistent with the hypothesis that the plasma BNP, secreted mainly from the ventricle, is a biochemical marker of left ventricular dysfunction or damage.

10.

11.

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13.

14.

15.

16.

We thank Ms. Ikuko Sakaguchi for excellent technical assistance.

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al. Rapid ventricular induction of brain natriuretic peptide gene expression in experimental acute myocardial infarction. Circulation 1995;92:1558-64. 30. Omland T, Askvaag A, Bonarjee V, Cadahl K, Lie RT, Nilsen D, et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction: comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide. Circulation 1996;93:1963-9.