CLINICAL RESEARCH: HEART FAILURE
Plasma B-type natriuretic peptide levels in systolic heart failure
importance of left ventricular diastolic function and right ventricular systolic function
Richard W. Troughton, MB, ChB, PhD*,
David L. Prior, MBBS, PhD ,
Jeremy J. Pereira, MBBS*,
Maureen Martin*,
Annette Fogarty, RDCS, RN*,
Annitta Morehead, RDCS, FASE*,
Timothy G. Yandle, PhD ,
A. Mark Richards, MD, PhD, DSc,
Randall C. Starling, MD, FACC ,
James B. Young, MD, FACC,
James D. Thomas, MD, FACC* and
Allan L. Klein, MD, FRCP(C), FACC, FASE*,*
* Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA
Kaufman Center for Heart Failure, Cleveland Clinic Foundation, Cleveland, Ohio, USA
St. Vincent's Department of Medicine, University of Melbourne, Melbourne, Australia
Christchurch Cardioendocrine Research Group, Christchurch, New Zealand
Manuscript received May 13, 2003;
revised manuscript received August 4, 2003,
accepted August 25, 2003.
* Reprint requests and correspondence: Dr. Allan L. Klein, Director of Cardiovascular Imaging Research, Department of Cardiovascular Medicine, Professor of Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F-15, Cleveland, Ohio 44195, USA.
kleina{at}ccf.org
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Abstract
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OBJECTIVES: This study was designed to characterize the importance of echocardiographic indexes, including newer indexes of diastolic function, as determinants of plasma B-type natriuretic peptide (BNP) levels in patients with systolic heart failure (SHF).
BACKGROUND: Plasma BNP levels have utility for diagnosing and managing heart failure. However, there is significant heterogeneity in BNP levels that is not explained by left ventricular size and function alone.
METHODS: In 106 patients with symptomatic SHF (left ventricular ejection fraction [LVEF] <0.35), we measured plasma BNP levels and performed comprehensive echocardiography with assessment of left ventricular diastolic function, including color M-mode (CMM) and tissue Doppler imaging (TDI), and of right ventricular (RV) function.
RESULTS: Median plasma BNP levels were elevated and increased with greater severity of diastolic dysfunction. We found significant correlations (p < 0.001 for all) between BNP and indexes of myocardial relaxation (early diastolic velocity: r = –0.26), compliance (deceleration time: r = –0.55), and filling pressure (early transmitral to early annular diastolic velocity ratio: r = 0.51; early transmitral flow to the velocity of early left ventricular flow propagation ratio: r = 0.41). In multivariate analysis, overall diastolic stage, LVEF, RV systolic dysfunction, mitral regurgitation (MR) severity, age and creatinine clearance were independent predictors of BNP levels (model fit r = 0.8, p < 0.001).
CONCLUSIONS: Plasma BNP levels are significantly related to newer diastolic indexes measured from TDI and CMM in SHF. Heterogeneity of BNP levels in patients with SHF reflects the severity of diastolic abnormality, RV dysfunction, and MR in addition to LVEF, age, and renal function. These findings may explain the powerful relationship of BNP to symptoms and prognosis in SHF.
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Abbreviations and Acronyms
| | AR | = atrial reversal | | BNP | = B-type natriuretic peptide | | CMM | = color M-mode | | DT | = deceleration time | | IQR | = interquartile range | | LVEF | = left ventricular ejection fraction | | MR | = mitral regurgitation | | NYHA | = New York Heart Association | | PV | = pulmonary vein | | RV | = right ventricle/ventricular | | SHF | = systolic heart failure | | TDI | = tissue Doppler imaging | | TR | = tricuspid regurgitation | | Vp | = velocity of early left ventricular flow propagation |
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Plasma B-type natriuretic peptide (BNP) levels are closely related to symptoms and outcome in systolic heart failure (SHF) (1–3). Recent studies indicate that plasma BNP may have a role in the diagnosis and management of heart failure (HF) (4–7). However, there is marked heterogeneity in BNP levels among subjects with SHF, which is only partially explained by differences in left ventricular (LV) dimensions or systolic function. The contribution of LV diastolic function to plasma BNP levels in SHF has not been clearly defined (8,9). In particular, there is no description of the relationship of BNP to newer indexes of diastolic function measured from color M-mode (CMM) and tissue Doppler imaging (TDI) that allow more accurate characterization of myocardial relaxation and LV filling pressures (10). We hypothesized that diastolic function measured with conventional and newer indexes would be an important determinant of plasma BNP levels. The aim of the study was to define the major echocardiographic determinants of heterogeneity in BNP levels in patients with SHF.
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Methods
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The institutional review board of the Cleveland Clinic Foundation approved the study, and all patients gave written informed consent.
Study population.
We studied 106 consecutive patients referred to the Department of Cardiovascular Medicine at the Cleveland Clinic Foundation between May 1, 2001, and June 30, 2002, for evaluation of symptomatic (New York Heart Association [NYHA] class II to IV) SHF. Eligible patients were 18 to 75 years of age, with left ventricular ejection fraction (LVEF) <0.35. Patients were excluded by a history of mitral stenosis or mitral valve surgery, severe mitral regurgitation (>3+), or severe aortic stenosis (peak velocity >4 m/s) or aortic regurgitation. Clinical data collected from the hospital chart were verified by the investigators.
Echocardiography.
Comprehensive transthoracic echocardiography was performed using commercially available HDI 5000 (Phillips Medical Systems, N.A., Bothell, Washington) and Acuson Sequoia (Siemens Medical Solutions USA Inc., Malvern, Pennsylvania) machines. Two-dimensional and color Doppler imaging were performed in standard parasternal and apical views. Diastolic indexes (Fig. 1) were acquired over 10 consecutive beats using sweep speeds of 50 and 100 cm/s. With pulsed-wave Doppler, we acquired transmitral flow using a 1 to 2 mm sample volume placed at the mitral leaflet tips in the apical four-chamber view and pulmonary venous flow using a 4-mm sample volume placed in the right upper pulmonary vein (PV). The TDI was acquired with standard presets optimized to eliminate background noise and enhance tissue signals and using a 5 to 10 mm sample volume placed at the lateral and septal mitral annular margins and at the lateral annulus of the tricuspid valve in the four-chamber view. The CMM was acquired from the four-chamber view as previously described with the M-mode cursor aligned across the mitral valve in parallel with LV inflow and the color baseline shifted upwards to produce a clear first aliasing velocity (11).
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Figure 1 Diastolic indexes included: 1—transmitral early (E) and late (A) velocities and early deceleration time (DT); 2—pulmonary vein systolic (S), diastolic (D), and atrial reversal (AR) velocities; 3—systolic (Sa) and early (Ea) and late (Aa) diastolic mitral annular velocities measured from tissue Doppler imaging of the septal annulus; 4—the velocity of propagation (Vp) of early filling (from mitral annulus to left ventricular apex) measured from the slope of the first aliasing velocity (11).
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All images were stored onto magneto-optical disc and were measured offline later (ProSolv Software, Indianapolis, Indiana) by a single investigator (R.W.T., trained by A.L.K.) with more than four years experience, who was blind to the clinical and BNP data. Measurements were averaged over three cycles (five cycles for atrial fibrillation, n = 4) and from pulsed-wave Doppler included transmitral peak E and A velocities and early deceleration time (DT) and PV systolic (S), diastolic (D), and atrial reversal (AR) flows (11). From CMM, the velocity of propagation (Vp) of early filling (from mitral annulus to LV apex) was measured from the slope of the first aliasing velocity (10). The peak systolic (Sa), early (Ea), and late diastolic (Aa) velocities were measured from tissue Doppler of the septal and lateral mitral annular margins and the lateral tricuspid annular margin (10). Overall diastolic stage, determined from the pattern of transmitral and PV flows, was defined as abnormal relaxation (stage I: transmitral E:A ratio <1, DT >220 ms, PV S:D ratio >1, AR < 35 cm/s), pseudonormal (stage II: E:A ratio 1 to 2, DT 150 to 220 ms, S:D ratio <1, AR >35 cm/s), or restrictive (stage III: E:A ratio >2, DT <150 ms, S:D ratio <1, AR >35 cm/s). The LVEF was measured using Simpson's biplane method. The LV mass was estimated from the formula by Devereux et al. (12). The maximal left atrial area was measured in the apical four-chamber view. The RV systolic function was graded on a scale from 0 to 5 based on a semiquantitative visual estimate of normal, mild, mild-moderate, moderate, moderately severe, or severe dysfunction. The severity of mitral regurgitation was quantified on a semicontinuous scale from none (0) to moderately severe (3+) based on an integrated assessment of jet area and length, regurgitant orifice area (from the proximal isovelocity surface area method), and vena contracta measurements in multiple views (13). Intraobserver variability in measurement ranged from 5% for TDI indexes to 7% for transmitral indexes and 10% for Vp from CMM.
BNP assays.
Blood samples taken at the time of echocardiography were collected into ethylenediamine-tetraacetic acid tubes on ice; plasma was immediately separated and stored at –80°C. Samples were transported on dry ice to the Christchurch Cardioendocrine Research Group for analysis. Plasma BNP levels were assayed using a validated radioimmunoassay described previously (14). Interassay coefficients of variation were 8% to 15%; intra-assay coefficients of variation were 6% to 8%. Plasma electrolytes and creatinine were also analyzed.
Statistics.
Continuous variables are summarized as mean ± SD. The BNP levels are summarized as median and interquartile range (IQR). The natural log of BNP levels was used for correlation with echocardiographic indexes and in regression analyses. Associations of logn BNP with echocardiographic and clinical indexes were assessed by Spearman's correlation coefficient. Independent predictors of BNP were determined by multiple regression analysis with candidate variables added to a model containing log BNP as the dependent variable and patient age, and LVEF and calculated creatinine clearance (Cockcroft-Gault formula) as covariates. Standardized beta regression coefficients and their significance from multiple linear regression analysis are reported. Related diastolic indexes were added interchangeably with overall diastolic stage to avoid colinearity. The Kruskal-Wallis test was used to compare differences in BNP levels between subjects grouped according to pattern of diastolic function, RV systolic function, MR severity, and NYHA functional class.
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Results
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Demographic and clinical data for the 106 patients are shown in Table 1. Subjects were predominantly in NYHA functional class II or III.
Diastolic function.
Diastolic indexes are summarized in Table 2. The pattern of diastolic filling was restrictive in 47 subjects, pseudonormal in 25 subjects, and showed abnormal relaxation in 34 subjects. Mitral annular velocities from TDI were lower than seen in previous studies of normal subjects. Systolic and early and late diastolic velocities were significantly lower at the septal than the lateral annulus (p < 0.05 for each). The index of filling pressure (E/Ea) was higher at the septal margin compared with the lateral annular margin (p < 0.05). The mean Vp derived from CMM was 30 ± 8 cm/s, suggesting delayed early flow propagation and the increased mean E/Vp ratio was consistent with elevated filling pressures.
Plasma BNP levels.
The median plasma BNP level for the group was 76.5 pg/ml (IQR 39 to 146). Plasma BNP levels were lower than the upper limit for the normal population with this assay (40 pg/ml) in 30 patients (28%) and below 100 pg/ml in 67 patients (65%). Plasma BNP levels were significantly related to symptomatic status, increasing with higher NYHA functional class from II (61 pg/ml; IQR 29 to 117) to III (101 pg/ml; IQR 54 to 218) and IV (224 pg/ml; IQR 139 to 406; p < 0.001).
Plasma BNP levels and diastolic function.
Plasma BNP levels increased significantly (p < 0.001) according to severity of overall diastolic dysfunction from abnormal relaxation (37 pg/ml, IQR 16 to 65) to pseudonormal filling (69 pg/ml, IQR 33 to 138) and restrictive filling (137 pg/ml, IQR 73 to 224) (Fig. 2). Additionally, logn BNP correlated significantly with newer indexes of diastolic function (Table 3), including septal Ea (r = –0.26, p < 0.001), Aa (r = –0.55, p < 0.001), and E/Ea ratio (r = 0.51, p < 0.001) derived from TDI (Fig. 3), as well as the E/Vp ratio (r = 0.41, p < 0.001) derived from CMM. Significant relationships were noted for logn BNP (Figs. 3 and 4) with indexes of LV relaxation (septal Ea), compliance (DT), and filling pressure (E/Ea and E/Vp) as well as with indexes of left atrial function (left atrial area, A and Aa).
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Figure 2 Box-plot depiction of plasma B-type natriuretic peptide (BNP) levels according to overall diastolic stage (upper panel; p < 0.001 for trend), right ventricular (RV) function (middle panel; p < 0.001 for trend), and mitral regurgitation (MR) severity (lower panel). The box defines the interquartile range with the median indicated by the crossbar. The error bars indicate the 5th and 95th percentiles.
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Table 3 Univariate and Multivariate Relationships of Clinical and Echocardiographic Indexes to Logn B-Type Natriuretic Peptide
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Figure 3 Scatter plots depicting the relationship of Logn B-type natriuretic peptide (BNP) to early diastolic (Ea) (upper panel) and late diastolic (Aa) (middle panel) mitral annular velocities from tissue Doppler imaging. The lower panel depicts the relationship of Log BNP to the ratio of early transmitral to early mitral annular velocities (E/Ea).
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Figure 4 Scatter plots depicting the relationship of Logn B-type natriuretic peptide (BNP) to the combined indexes of filling pressure derived from the ratio of early transmitral velocity to the velocity of propagation of early left ventricular flow (E/Vp) (upper panel), early transmitral deceleration time (DT) (middle panel), left atrial (LA) area (lower panel).
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Determinants of plasma BNP levels.
The BNP levels increased with greater severity of RV systolic dysfunction with median values of 31 pg/ml (IQR 18 to 59), 72 pg/ml (IQR 38 to 129), 85 pg/ml (IQR 60 to 165), 167 pg/ml (IQR 83 to 256) and 281 pg/ml (IQR 119 to 467) with normal, mild, moderate, moderately severe, and severe dysfunction respectively (p < 0.001) (Fig. 2). Similarly, BNP levels were significantly higher (p < 0.001) with increasing grades of MR from none to moderately severe. Statistically significant correlations were found for logn BNP with LV diastolic and systolic volumes and LVEF (Table 3), but not LV mass (r = 0.1; p = 0.9). Patients with moderately severe (3+) tricuspid regurgitation (TR) had higher BNP levels (269 pg/ml [IQR 219 to 426], n = 7) than those with less severe TR (59 pg/ml [IQR 17 to 101], n = 99; p = 0.001). The BNP levels were not significantly different among patients with trivial, mild (1+), moderate (2+), or no TR.
In multiple linear regression analysis (Table 3), LVEF, plasma creatinine, age, severity of RV dysfunction (using either semiquantitative assessment or from tricuspid annular Sa velocity), and severity of MR were independent predictors of logn BNP (overall model fit, r = 0.8, p < 0.001). Early DT, but not any other diastolic variable, was an independent predictor in this model. When overall diastolic stage was added to the model, it was a powerful independent predictor of BNP levels. Addition of LV volumes or mass, or of specific medications including beta-blockers, angiotensin-converting enzyme inhibitors, and digoxin did not significantly alter the fit of the model.
Compared with those with elevated BNP levels, patients with BNP levels <40 pg/ml were younger (50 ± 12 vs. 59 ± 15; p = 0.005), had a greater likelihood of milder (stage I) diastolic function (61% vs. 18%; p < 0.001), less RV dysfunction (70% vs. 35% with mild dysfunction, p < 0.001), less severe MR (70% vs. 51% with mild MR; p = 0.003), and were less symptomatic (80% vs. 54% in NYHA functional class II; p = 0.002).
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Discussion
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Increasingly, plasma BNP levels are being incorporated into the clinical assessment and management of SHF (4,5,15). Heterogeneity in BNP levels among individuals with SHF can cause some confusion in interpreting results. It is unclear why some patients with LVEF <35% have BNP levels in the normal range whereas others exhibit extremely elevated levels. To better understand the determinants of BNP levels in patients with SHF, we performed careful assessment of cardiac function and noninvasive hemodynamics with comprehensive echocardiography. This is the largest study to compare BNP levels to diastolic function in patients with SHF and the first to incorporate newer indexes of diastolic function assessed from TDI and CMM.
The results of our study show that: 1) there are significant relationships between BNP levels and LV diastolic function measured by conventional and newer echocardiographic modalities, including indexes of LV relaxation measured by early annular velocities (Ea) as well as markers of compliance (DT) and filling pressure (E/Ea, E/Vp); 2) BNP levels are related to the severity of RV dysfunction and mitral regurgitation; and 3) patients with BNP levels in the normal range have less impairment of LV systolic and diastolic function and exhibit only mild degrees of RV systolic dysfunction and MR.
Elevated BNP levels have previously been demonstrated in patients with abnormal relaxation and normal LV systolic function (16), but this is the first study to demonstrate such a relationship, albeit weak, with this index in SHF. Values for Ea and Vp were depressed with a narrower range compared to normal (10), and correlation coefficients for BNP with these relatively preload independent markers of myocardial relaxation were less strong. In contrast, stronger relationships were seen for BNP levels with noninvasive measures of LV filling pressure, such as E/Ea, E/Vp, and DT, which is consistent with the understanding that LV wall stress is an important stimulus to BNP secretion (9,17).
In multivariate analysis, severity of overall diastolic dysfunction was independently related to BNP levels. Early transmitral DT, a measure of LV compliance and filling pressure, was the strongest diastolic index that independently predicted BNP levels. In previous studies, DT was a strong independent predictor of mortality (18). The relationship of BNP to DT has been noted before (19) and may explain the independent prognostic power of BNP in other series (2,20). Synthesis of BNP by cardiac fibroblasts has been documented in an animal model of myocardial infarction (21). Whether this mechanism contributes to BNP secretion from ventricles with reduced compliance and increased fibrosis is unclear.
The severity of RV systolic dysfunction added independent information about BNP levels in addition to patient age, renal function, and LV systolic and diastolic function. This relationship was present when RV function was assessed semiquantitatively by visual estimates or by quantitation of tricuspid annular systolic velocities. Elevated BNP levels have been demonstrated in the setting of isolated RV dysfunction (22). Secretion of BNP from RV myocytes may become important in advanced SHF with increasing RV wall stress and dysfunction. We also noted significant relationships of BNP with measures of left atrial area and function, and it is possible that secretion of BNP from atrial myocytes may increase with more severe diastolic dysfunction or MR.
The strong relationship of BNP level to symptoms has been clearly documented (23) and was evident in our study population. The importance of echocardiographically determined indexes of diastolic function, RV function, and MR as determinants of BNP levels in our study may explain why BNP is so closely related to symptomatic status in SHF, as each of these factors is known to influence symptoms in heart failure. It is possible that BNP levels act as a global index of cardiac function and symptoms reflecting the combined effects of LV systolic and diastolic function as well as MR severity and RV dysfunction. The relationship of BNP levels to these factors may also explain why BNP is such a powerful independent predictor of mortality in both SHF and in HF with preserved LVEF, as previous studies have shown each factor to predict mortality (24–26). The effect of these factors on BNP levels may also explain the lack of specificity of BNP in predicting LV function (27), and why the addition of Doppler data may improve the utility of BNP in diagnosing HF (15).
The secretion and clearance of BNP is complex and incompletely characterized (17), but is clearly influenced by patient age, gender, and renal function (28). In our study, age and renal function were important determinants of BNP, but gender was not, possibly because of the small number of women in the study population. The relationship of BNP to LV volumes and EF was weaker than seen in other studies (29), likely reflecting the narrower range for LVEF in this study.
One important point to note from our study is that nearly two-thirds of patients had BNP levels <100 pg/ml, which was the level with greatest sensitivity and specificity for diagnosing decompensated HF in the recently published BNP study (7). In one-third of our patients, BNP levels were below the upper limit for the normal population by this assay (40 pg/ml). This may reflect the fact that we studied outpatients who in most cases were clinically stable and already receiving trial-based doses of proven therapies. Our study demonstrates that patients with lower levels of BNP were more likely to have a higher LVEF; less advanced LV diastolic function, normal or mildly impaired RV function, and only trivial or mild MR.
These results provide a framework for interpreting BNP levels in patients with SHF. Our findings suggest that BNP levels performed in the clinic may allow the clinician to rapidly identify patients with SHF who may have more significant cardiac abnormalities. This in turn may facilitate the identification of patients who may benefit from more intensive investigation or therapy (6). Plasma BNP-guided therapy has been tested in pilot studies with some success (6). Our findings suggest that the ideal target BNP level may vary for individual patients and that the baseline BNP level and echocardiographic findings may be important in determining this target level.
Study limitations.
The study population was relatively small and included only clinically stable outpatients. Echocardiography and BNP assays were performed at only a single time point. The relationship of BNP to echocardiography indexes at serial time points following changes in therapy or in clinically decompensated patients cannot be deduced from our study, although it is possible that heterogeneity of BNP levels seen in acute HF(7) may be explained by our findings. Indexes of filling pressure were derived from echo and not measured invasively. There were few patients (n = 4) with atrial fibrillation, which is known to influence BNP levels.
Conclusions.
Our findings indicate that BNP levels are significantly related to newer diastolic indexes measured from TDI and CMM in SHF. Plasma BNP levels in patients with SHF reflect the severity of diastolic abnormality, RV systolic dysfunction, and MR in addition to LVEF, age, and renal function. These findings may explain the powerful relationship of BNP to symptoms and prognosis in SHF.
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Acknowledgments
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The authors thank Marie Campbell for assistance in preparing the manuscript.
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Footnotes
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The study was supported by grants from the American Society of Echocardiography, the National Aeronautics and Space Administration, Houston, Texas (Grant NCC9-58), the Cleveland Clinic Foundation, and Glaxo SmithKline (BNP assays). Dr. Richards is the National Heart Foundation of New Zealand Chair of Cardiovascular Studies. Gottlieb C. Freisinger II, MD, acted as the Guest Editor for this paper.
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G. A. Whalley, S. P. Wright, A. Pearl, G. D. Gamble, H. J. Walsh, M. Richards, and R. N. Doughty
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C. Mueller
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Eur. Heart J.,
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W.H. Wilson Tang, G. S. Francis, D. A. Morrow, L. K. Newby, C. P. Cannon, R. L. Jesse, A. B. Storrow, R. H. Christenson, COMMITTEE MEMBERS, R. H. Christenson, et al.
National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Utilization of Cardiac Biomarker Testing in Heart Failure
Circulation,
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W.H. W. Tang, W. Tong, R. W. Troughton, M. G. Martin, K. Shrestha, A. Borowski, S. Jasper, S. L. Hazen, and A. L. Klein
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C.-M. Yu, J. E. Sanderson, T. H. Marwick, and J. K. Oh
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A. B. Scardovi, C. Coletta, N. Aspromonte, S. Perna, M. Greggi, P. D'Errigo, A. Sestili, and V. Ceci
Brain natriuretic peptide plasma level is a reliable indicator of advanced diastolic dysfunction in patients with chronic heart failure
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B Norager, M Husic, J E Moller, A Bo Hansen, P A Pellikka, and K Egstrup
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J. E. Moller, P. A. Pellikka, G. S. Hillis, and J. K. Oh
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Circulation,
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A. A. Chen, M. J. Wood, D. G. Krauser, A. L. Baggish, R. Tung, S. Anwaruddin, M. H. Picard, and J. L. Januzzi
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Y. Iwanaga, I. Nishi, S. Furuichi, T. Noguchi, K. Sase, Y. Kihara, Y. Goto, and H. Nonogi
B-Type Natriuretic Peptide Strongly Reflects Diastolic Wall Stress in Patients With Chronic Heart Failure: Comparison Between Systolic and Diastolic Heart Failure
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S. Ichihara, A. Noda, K. Nagata, K. Obata, J. Xu, G. Ichihara, S. Oikawa, S. Kawanishi, Y. Yamada, and M. Yokota
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R. Valle, E. Bagolin, C. Canali, P. Giovinazzo, S. Barro, N. Aspromonte, E. Carbonieri, and L. Milani
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F. H Rutten, K. G M Moons, M.-J. M Cramer, D. E Grobbee, N. P A Zuithoff, J.-W. J Lammers, and A. W Hoes
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C. Tschope, M. Kasner, D. Westermann, R. Gaub, W. C. Poller, and H.-P. Schultheiss
The role of NT-proBNP in the diagnostics of isolated diastolic dysfunction: correlation with echocardiographic and invasive measurements
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C. Kistorp, I. Raymond, F. Pedersen, F. Gustafsson, J. Faber, and P. Hildebrandt
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T. Nishikimi, H. Matsuoka, W.H. W. Tang, R. C. Starling, J. B. Young, G. S. Francis, J. P. Girod, M. J. Lee, and F. Van Lente
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A. Sharp and J. Mayet
Review: The utility of BNP in clinical practice
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Abstract
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