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European Journal of Heart Failure 2008 10(1):70-77; doi:10.1016/j.ejheart.2007.10.009
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© 2008 European Society of Cardiology

Ultrasound lung comets for the differential diagnosis of acute cardiogenic dyspnoea: A comparison with natriuretic peptides

L. Gargania,*, F. Frassia, G. Soldatib, P. Tesorioc, M. Gheorghiaded and E. Picanoa

a Institute of Clinical Physiology, National Research Council Pisa, Italy
b Hospital "Valle del Serchio", Castelnuovo Garfagnana Lucca, Italy
c Clinica "Montevergine" Mercogliano, Avellino, Italy
d Division of Cardiology, Feinberg School of Medicine, Northwestern University Chicago, IL, USA

* Corresponding author. CNR, Institute of Clinical Physiology, Via G. Moruzzi, 1, 56124, Pisa, Italy. Tel.: +39 050 3152399; fax: +39 050 3152216. E-mail address: gargani{at}ifc.cnr.it (L. Gargani).


   Abstract
Top
 Abstract
1. Materials and methods
 2. Results
 3. Discussion
 Acknowledgments
 References
 
Background: Acute dyspnoea as a presenting symptom is a frequent diagnostic challenge for physicians. The main differential diagnosis is between dyspnoea of cardiac and non-cardiac origin. Natriuretic peptides have been shown to be useful in this setting. Ultrasound lung comets (ULCs) are a simple, echographic method which can be used to assess pulmonary congestion.

Aim: To evaluate the accuracy of ULCs for predicting dyspnoea of cardiac origin compared to natriuretic peptides.

Methods: We evaluated 149 patients admitted with acute dyspnoea. Chest sonography and NT-proBNP assessments were performed a maximum of 4 h apart and independently analyzed. ULCs were evaluated via cardiac probes placed on the anterior and lateral chest. Two independent physicians, blinded to ULCs and NT-proBNP findings, reviewed all the medical records to establish the aetiologic diagnosis of dyspnoea.

Results: Cardiogenic dyspnoea was confirmed in 122 patients and ruled-out in 27 patients. The number of ULCs was significantly correlated to NT-proBNP values (r=.69, p<.0001). Receiver operating characteristic analysis, showed an area under the curve of .893 for ULCs and .978 (p=.001) for NT-proBNP, in predicting the cardiac origin of dyspnoea.

Conclusions: In patients admitted with acute dyspnoea, pulmonary congestion, sonographically imaged as ULCs, is significantly correlated to NT-proBNP values. The accuracy of ULCs in predicting the cardiac origin of dyspnoea is high.

Key Words: Ultrasound lung comets • NT-proBNP • Differential diagnosis of dyspnoea

Received March 26, 2007; Revised August 14, 2007; Accepted October 18, 2007

Acute dyspnoea is a common cause of hospitalisation; it may occur due to acute decompensated heart failure, exacerbation of chronic obstructive pulmonary disease (COPD), anxiety state, and many other conditions. Acute dyspnoea is extremely important from an epidemiological, prognostic and economic point of view [1-3]. Differentiating cardiac from non-cardiac causes of dyspnoea in patients admitted to the hospital with acute shortness of breath remains a clinical challenge. Difficulties in making an appropriate diagnosis can lead to delays in the institution of appropriate medical therapy [4-6]. Plasma levels of B-type natriuretic peptide (BNP) and its amino-terminal fragment N-terminal proBNP (NT-proBNP) have been shown to be useful, in addition to clinical judgement, for aetiological diagnosis in patients with acute onset of dyspnoea, and are now considered a part of the standard work-up of these patients in the Emergency Room, according to latest guidelines [7-9]. More recently, ultrasound lung comets (ULCs) have been proposed as a simple, echographic method for semi-quantitative assessment of pulmonary congestion in heart failure patients [10]. The number of ULCs has been shown to increase with worsening New York Heart Association (NYHA) functional class [11]. ULCs are also related to Kerley B-lines and lung water score on chest X-ray [12], to extravascular lung water measured invasively by thermodilution method [13], and to the severity of diastolic dysfunction, for any given level of systolic dysfunction [11]. ULCs are detectable with hand-held echocardiography systems and do not require the expertise necessary for echocardiographic examination and interpretation [14]. The present study hypothesis is that cardiogenic dyspnoea, unlike non-cardiogenic dyspnoea, is associated with some degree of pulmonary congestion and therefore with the presence of ULCs.

The aim of this study was to evaluate the accuracy of ULCs to predict the cardiac origin of dyspnoea, compared to natriuretic peptides.


   1. Materials and methods
Top
 Abstract
 1. Materials and methods
2. Results
 3. Discussion
 Acknowledgments
 References
 
1.1. Study population
In this prospective study we evaluated 149 consecutive patients (51 females; mean age 71±11 years) admitted to the Cardiology and Pneumology Division of the Institute of Clinical Physiology in Pisa between November 2004 and March 2006. The inclusion criteria were: 1) presence of dyspnoea at admission (NYHA class II, III or IV), as reported on the case history; 2) a venous blood sample taken for NT-proBNP analysis on the day of admission; 3) assessment of ULCs performed within 4 h of the NT-proBNP assay; 4) no diuretic therapy between the two measurements. Despite the prospective study design, more than one hundred patients were excluded from the analysis due to: an excessive time lag between the two measurements, missing laboratory values (most frequently BNP instead of NT-proBNP assay) or temporary unavailability of sonography or, most frequently, because the emergency physician in charge did not notify the sonographer on call in time.

The review board of the Institute approved the study protocol, and all participants provided informed consent.

1.2. Natriuretic peptide analysis
Peripheral venous blood samples were obtained from each patient at admission. Blood samples were collected by venipuncture into ice-chilled disposable polypropylene tubes containing aprotinin (500 kIU/ml of plasma) and ethylene diamine tetra acetic acid (EDTA, 1 g/l of plasma), and then analyzed by an electrochemiluminescence sandwich immunoassay (ECLIA) method for NT-proBNP using an Elecsys® 2010 analyzer (Roche Diagnostics, Mannheim, Germany). Plasma samples were centrifuged for 15 min at 4 °C, and then stored at –20 °C in polypropylene tubes until assay. The coefficient of variation for inter- and intra-assay precision is <4%. The analytical performance has been previously described [15].

1.3. Chest echography and echocardiography
Patients underwent an echographic evaluation of ULCs within 4 h of the NT-proBNP blood sampling at admission. A lung comet was defined, as previously described [10], as an echogenic, coherent, wedge-shaped signal with a narrow origin from the hyperechoic pleural line. A typical normal (without ULCs) and abnormal (with ULCs) chest echographic pattern is shown in Fig. 1 (upper panel). We analyzed the anterior and lateral hemithoraxes, scanning along the parasternal, midclavear, anterior axillary and medium axillary line, from the second to the fifth intercostal space on the right hemithorax, and from the second to the fourth intercostal space on the left hemithorax. We scanned a total of 28 chest sites (Fig. 1, lower panel) and recorded the number of ULCs found at each site. The total number of ULCs was the "comet score". A score of ≤5 ULCs was defined as a normal echographic chest pattern, as it has been reported that healthy patients may have a small number of ULCs, especially confined laterally to the last intercostal spaces above the diaphragm [16]. All patients were analyzed in the supine or near-supine position; however, if the patient was orthopnoic the sitting position was used. We used the cardiac probes (2.5-3.5 MHz) available for the ultrasound systems in our Institute (Philips Sonos 7500, Siemens Acuson Sequoia, Esaote MyLab50). Intra- and inter-observer variability of ULCs assessments are 5.1% and 7.4% in our laboratory [12].


Figure 01
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  		Fig. 1 Upper panel: normal (left) and abnormal (right) chest sonography findings with ULCs. Lower panel: echographic chest scanning for ULCs.

 
All patients underwent comprehensive transthoracic echocardiography examination at rest. Left ventricular volumes and ejection fraction (EF) were measured according to the modified biplane Simpson's method according to the American Society of Echocardiography and adjusted for body surface area [17]. Diastolic function was determined from the pattern of mitral and pulmonary venous flow velocity by pulsed Doppler echocardiography, complemented by mitral annular velocity by tissue Doppler imaging, when needed. Diastolic dysfunction was staged as being ‘‘absent’’ (grade 0), ‘‘mild’’ (grade 1, impaired relaxation), ‘‘moderate’’ (grade 2, pseudonormalized filling pattern), and ‘‘severe’’ (grade 3, restrictive filling pattern) [18].

1.4. Reference standard definition of cardiogenic dyspnoea
To determine the patient's clinical diagnosis, two cardiologists who were blinded to the number of ULCs and NT-proBNP values, reviewed all of the medical records pertaining to the patient, and made an independent initial assessment of the probability of the patient having congestive heart failure (CHF). Although blinded to the treating physicians' diagnosis, the two cardiologists had access to all hospital data sheets and to any additional information that later became available. Confirmation of a high-probability CHF was based on the Framingham criteria, with corroborative information including clinical diary, information on hospital course (response to diuretics, vasodilators inotropes or haemodynamic monitoring), electrocardiograms, chest X-ray, echocardiography and results of subsequent cardiac testing, including nuclear medicine or magnetic resonance ejection fractions, or left ventriculography done at cardiac catheterization. For patients with a diagnosis other than CHF, confirmation was attempted using the following variables: normal chest X-ray (lack of heart enlargement and signs of pulmonary congestion), X-ray signs of COPD, pneumonia or lung cancer, normal heart function by echocardiography, abnormal pulmonary function tests or follow-up in pulmonary clinic, response to treatment with nebulizers, steroids or antibiotics. After reviewing all information, if agreement was achieved, then the case was categorized as one of following: 1) dyspnoea due to CHF (cardiogenic dyspnoea), 2) history of CHF but dyspnoea due to a non-cardiac cause (non-cardiogenic dyspnoea), or 3) dyspnoea due to a non-cardiac cause (non-cardiogenic dyspnoea). In cases where the two cardiologists failed to agree on a diagnosis (n=3, .02%), a consensus was reached with a third expert.

1.5. Statistical analysis
Continuous variables are expressed as mean±standard deviation or as median (25th, 75th percentiles) as appropriate. Categorical variables are presented as counts and percentages.

Univariate comparisons were made with {chi}2 or two-sample t tests as appropriate. Differences in median NT-proBNP concentrations and the median number of ULCs were tested by the Mann-Whitney non-parametric test. The diagnostic utility of NT-proBNP and ULCs in separating cardiogenic dyspnoea from other causes of dyspnoea was determined using receiver operating characteristic (ROC) curves. The results are expressed in terms of area under the curve (AUC) and the 95% confidence interval for this area. The best threshold was obtained by selecting the point on the ROC curve that maximized both sensitivity and specificity. The areas under the ROC curves were compared by using Hanley's method [19]. Correlation between NT-proBNP values and the number of ULCs was assessed with non-parametric Spearman correlation coefficient analysis. A p value of <.05 was considered statistically significant. All statistical analysis were performed using the SPSS/PC software package version 13 (SPSS Inc, Chicago, Illinois) and MedCalc for Windows version 7.6.0.0. (MedCalc Software, Mariakerke, Belgium).


   2. Results
Top
 Abstract
 1. Materials and methods
 2. Results
3. Discussion
 Acknowledgments
 References
 
2.1. Clinical findings
The main characteristics of the patients are listed in Table 1. Cardiogenic dyspnoea was diagnosed in 122 of the 149 patients and ruled-out in 27. Main causes of cardiogenic dyspnoea were: systolic dysfunction (n=93, mean EF 31±10%, in 41 of these patients diastolic dysfunction was also present), isolated diastolic dysfunction (n=5, moderate in 1 and severe in 4), severe valvulopathy (n=11), arrhythmias (n=13, 10 chronic atrial fibrillation, 1 atrial flutter, 1 junctional tachycardia, 1 ventricular tachycardia).


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  		Table 1 Patients' main characteristics

 
In the 27 patients with non-cardiogenic dyspnoea the diagnoses were: COPD (n=3 severe, n=1 moderate), exacerbation of COPD (n=7), pulmonary restrictive disorder (n=1), bronchiectasis (n=1), asthma (n=1), fibrothorax (n=1), obesity (Body Mass Index≥35, n=3), pulmonary embolism (n=1), panic attack (n=1), dyspnoea of non determined origin in which a cardiogenic origin was excluded (n=7). Among these 7 patients, 1 had HCV-related hepatic insufficiency, 1 had gastroesophagitis consequent to hiatal hernia, 1 had hypothyroidism due to autoimmune thyroid disease, 1 had metabolic acidosis subsequent to renal insufficiency, 1 had anomalous venous return, 2 had idiopathic orthostatic hypotension. The patient with fibrothorax was the only one categorised as "history of CHF but dyspnoea due to a non-cardiac cause", as she was diagnosed with respiratory insufficiency due to post-radiotherapy fibrothorax and metastatic pleural effusion.

2.2. Natriuretic peptide findings
Abnormal values of NT-proBNP (≥157 ng/l, our laboratory cut-off) were found in all of the 122 patients with cardiogenic dyspnoea, and in 10 of the 27 patients with non-cardiogenic dyspnoea. Patients with cardiogenic dyspnoea had significantly higher values of NT-proBNP (median value 2899 ng/l, 25th and 75th percentiles 1024 ng/l and 7139 ng/l), compared to patients with non-cardiogenic dyspnoea (median value 78 ng/l, 25th and 75th percentiles 54 ng/l and 245 ng/l, p<.0001).

2.3. Chest echography findings
Assessment of ULCs was always performed in less than 5 min, with a feasibility of 100%. ULCs were found in 93 of the 122 patients with cardiogenic dyspnoea, and in 3 of the 27 patients with non-cardiogenic dyspnoea. Patients with cardiogenic dyspnoea had significantly higher values of ULCs (median value 23, 25th and 75th percentiles 7 and 56), compared to patients with non-cardiogenic dyspnoea (median value 0, 25th and 75th percentiles 0 and 3, p<.0001).

2.4. Correlation between clinical, biochemistry and chest echography findings
NT-proBNP values were correlated with the number of ULCs (r=.69, p<.0001). ROC curve analysis was used to evaluate the analytical relationship between NT-proBNP, the number of ULCs and the diagnosis of cardiogenic dyspnoea (Fig. 2). An NT-proBNP plasma concentration of 298 ng/l was found to maximize the overall diagnostic accuracy with a sensitivity of 97% and a specificity of 92.6%. The presence of 4 ULCs was found to maximize the overall diagnostic accuracy with a sensitivity of 81% and a specificity of 85%. The presence of 9 ULCs had a sensitivity of 73% and a specificity of 100%. The negative predictive value was higher for NT-proBNP than ULCs (100% vs 45%), whereas the positive predictive value was slightly higher for ULCs than NT-proBNP (97% vs 92%). Both tests showed an excellent AUC, which was slightly better for NT-proBNP (Fig. 2).


Figure 02
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  		Fig. 2 ROC curve for NT-proBNP and ULCs for differentiating dyspnoea of cardiac origin from non-cardiac origin in a Cardiology-Pneumology Department.

 
A concordance table for the two tests is shown in Fig. 3. The dominant source of discordance was due to abnormal NT-proBNP values (≥157 ng/l according to pre-determined cut-off) with normal ULCs (≤5 according to pre-determined cut-off, corresponding with the best cut-off by ROC analysis). Of these 37 patients, 29 were eventually classified as cardiogenic dyspnoea (true positive with NT-proBNP, false negative with ULCs). In 3 of these 29 false negative ULCs, diuretics were given just a few seconds or minutes prior to the NT-proBNP sampling, but 2-4 h before chest sonography. This time lag may well explain the partial dissolution of watery ULCs at the time of ultrasound scanning. The only discordant result due to positive ULCs and negative NT-proBNP was eventually classified as non-cardiogenic dyspnoea due to bronchiectasis: in this case ULCs were of mild severity (n=9), localized at one region, and probably due to interstitial subpleural fibrosis, as shown by chest CT.


Figure 03
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  		Fig. 3 Concordance Table for the two tests.

 

   3. Discussion
Top
 Abstract
 1. Materials and methods
 2. Results
 3. Discussion
Acknowledgments
 References
 
This study shows that ULCs are a simple and useful method for the differential diagnosis of cardiogenic versus non-cardiogenic acute dyspnoea.

The reliability of ULCs makes this method appealing for use in the emergency care setting. ULCs provide a direct, morphological, readily apparent imaging of abnormal increases in lung water. The abnormal signal can be quantified on the basis of the number of comets on the chest [10]. However, natriuretic peptides remain the more powerful tool for the differential diagnosis of acute dyspnoea.

3.1. Pathophysiological correlates of natriuretic peptides and ULCs
Increased left ventricular filling pressure is the common haemodynamic trigger for both natriuretic peptides and ULCs. Wall distension is generally considered the main mechanical stimulus for natriuretic peptide production by ventricular tissue from stretched cardiomyocytes [20]. The presence of ULCs as a sign of pulmonary interstitial oedema is linked to augmented left ventricular filling pressures, this unbalances Starling forces at the alveolar-capillary barrier, with resulting pulmonary congestion [10]. Thus, the overall good concordance and the significant correlation between ULCs and NT-proBNP found in this study are not surprising.

There are other echographic methods to assess left ventricular filling pressures, such as the ratio of early diastolic mitral inflow velocity to early diastolic velocity of the mitral annulus (E/Ea) [21]. ULCs have shown significant correlations to E/Ea both at rest and at peak stress [11,22] Compared to E/Ea, ULCs do not require the expertise necessary for echocardiographic examination and interpretation, and can also be assessed using hand-held echocardiography systems without Doppler imaging [14].

3.2. Comparison with previous studies
To the best of our knowledge, this is the first study to evaluate the relative diagnostic ability of ULCs vs cardiac peptides in patients with acute dyspnoea. Our findings are certainly consistent with the literature, showing the usefulness of cardiac peptides in this setting, and especially their excellent negative predictive value for ruling out cardiac aetiology of dyspnoea [9,23,24]. Our study also demonstrates, once more, the feasibility and usefulness of ULCs in evaluating lung water in heart failure patients [10]. In particular, the present findings are consistent with those of Lichtenstein et al., who studied 66 Intensive Care patients; of these 40 had acute cardiogenic pulmonary oedema and 26 had exacerbation of COPD. ULCs were present in all the patients with cardiogenic pulmonary oedema, while 24 of the 26 patients with exacerbation of COPD had no ULCs, with a sensitivity of 100% and a specificity of 92% [25]. Our study confirms these data, as we found a significantly higher number of ULCs in cardiogenic dyspnoea, compared to non-cardiogenic dyspnoea, including exacerbation of COPD. However, some peculiarities of our study should be noted: 1) the patient selection criteria was acute dyspnoea, i.e. a frequent and challenging clinical problem; 2) the study was performed in the Cardio-Pulmonary Department rather than the Intensive Care Unit where possibly sicker patients with more obvious, advanced degrees of disease would be recruited; 3) we analyzed ULCs in a more quantitative way and directly compared the chest sonography results with cardiac peptides.

3.3. Clinical implications
This study shows that ULCs have good accuracy for predicting dyspnoea of cardiac origin, which is comparable to natriuretic peptides. If these data can be confirmed in a larger number of patients, assessment of ULCs could become a valuable test for use in situations where natriuretic peptide measurement is not available.

Pulmonary congestion is one of the most important diagnostic and therapeutic targets in CHF [26,27]. ULCs directly image extravascular lung water, and may represent an extension of the physical examination of the chest, enabling the detection of lung congestion transparent to chest auscultation. The technique requires very basic technology (2D imaging, possible even using a hand-held device), is easy to learn, fast to perform, quantitative, and can be added to cardiac natriuretic peptides and/or standard, comprehensive cardiac echo Doppler evaluation. In clinical situations when time is limited, the chest scan can even be restricted to a "hot spot", at the right third anterior axillary intercostal space, which has been shown to have a good correlation with radiologically assessed extravascular lung water [10]. Measurement of ULCs also has potential limitations. The ULC score is likely to be of limited value (i.e., lack of sensitivity) in patients presenting with isolated dyspnoea on exertion, since in these patients ULCs may only appear at peak exercise [22]. In addition, at a first evaluation it can be impossible to distinguish watery cardiogenic ULCs from fibrotic pneumogenic ULCs in patients with interstitial lung fibrosis [10], although only watery ULCs are quickly lysed by diuretics [28]. One can also assume that ULC score is not able to discriminate cardiac from non-cardiac pulmonary oedema in Coronary Care Unit patients with acute respiratory distress syndrome (ARDS) (i.e., lack of specificity). In fact, ULCs are a sensitive marker of ARDS both in the experimental [29] and clinical setting [30]. In ARDS patients, chest sonography focused on ULCs should be combined with a comprehensive echocardiography study to evaluate systolic and diastolic cardiac function [31]. In fact, patients with cardiogenic oedema are more likely to have a lower ejection fraction, higher degree of diastolic dysfunction and higher E/Ea value when compared to ARDS patients [32]. In clinical practice, chest X-ray is the most extensively used test to assess extravascular lung water. In 2004, our group described a good correlation between the amount of extravascular lung water assessed by chest X-ray and the number of ULCs detected by chest sonography [12]. Chest X-ray however has limitations [33,34]: it requires radiologic apparatus and -albeit minimal- radiation exposure [35], is based on a subjective, operator-dependent reader with substantial inter-observer variability [7], and detects only the most extreme variations in extravascular lung water [8]. As a consequence, the most recent (2005) ESC guidelines state that "radiographic findings alone do not allow a reliable estimation of the pulmonary capillary pressure, and are therefore not suitable as the only basis for therapeutic decisions" [7]. The AHA-ACC guidelines (2005) go even further stating that "Serial chest radiographs are not recommended in the management of chronic heart failure (HF). Although the cardiothoracic ratio is commonly believed to reflect the cardiac dilatation that is characteristic of HF, enlargement of the cardiac silhouette primarily reflects changes in right ventricular volume rather than LV function, because the right ventricle forms most of the border of dilated hearts on radiographs. Similarly, changes in the radiographic assessment of pulmonary vascular congestion are too insensitive to detect any but the most extreme changes in fluid status" [8].

Natriuretic peptides have a very high negative predictive value that allows us to rule out dyspnoea of cardiogenic origin when values are normal. However, there are several circumstances in which natriuretic peptides may be elevated for other reasons, and data may be confounded. Patients with renal failure have elevated natriuretic peptide levels; therefore diagnosing CHF in this population should rely on more standard criteria. It has recently been demonstrated that NT-proBNP is useful for both diagnosing and excluding acute CHF across a wide spectrum of renal function, but at higher cut-off points, such as 1200 ng/l [36]. Thus, especially in cases where NT-proBNP levels are only slightly abnormal, the "grey zone", echographic assessment of pulmonary congestion could help in the management of patients with dyspnoea.

Moreover, natriuretic peptide analysis is not always available, especially in peripheral emergency departments, as it requires specialised laboratory equipment. If the assay is not available, ULCs may offer a plausible alternative.

3.4. Study limitations
A limitation of this study is the small number of patients with non-cardiogenic dyspnoea compared to the number of patients with cardiogenic dyspnoea. This difference may influence the accuracy of ULCs, overestimating its specificity. Ideally this study should be repeated in an Emergency Department, where the proportion of patients with cardiogenic and non-cardiogenic dyspnoea would be more representative of reality.

In this study we have not compared ULCs to clinical and radiographic signs of heart failure; we have focused instead on the correlation with natriuretic peptides. A further evaluation of the accuracy of ULC measurement compared with clinical and radiographic signs of acute heart failure would be of great interest.

Patients were evaluated upon admission to our Cardio-thoracic (Cardiology and Pneumology) Department; therefore some initial referral bias was unavoidable.

In this study, the time delay between the venipuncture and assessment of ULCs was always less than 4 h. Nevertheless, as both signs are so dynamic [22,37], a better correlation would have been obtained with a simultaneous evaluation of the two variables. In particular, lung water can change very rapidly, sometimes in a matter of minutes, either spontaneously or following therapeutic interventions. This may explain the significant rate of false negative ULCs when chest sonography was performed even a few hours after admission. Diuretic therapy initiated upon admission can rapidly change the amount of extravascular lung water and when the "light is switched on" (i.e. when chest sonography is started) the ultrasonic fingerprints of pulmonary congestion may have already been cleared by therapy. On the basis of our findings, we now believe that evaluation of ULCs should be performed simultaneously with assessment of cardiac peptides, in order to optimize its diagnostic potential.

The two cardiologists who were responsible for defining CHF and non-CHF were blinded to the results of the ultrasound and NT-proBNP tests. However, the clinical management of the patients was not blinded to the results of NT-proBNP. At least in theory, this might have erroneously increased the number of patients with dyspnoea of cardiac origin.


   Acknowledgments
Top
 Abstract
 1. Materials and methods
 2. Results
 3. Discussion
 Acknowledgments
References
 
The authors would like to thank Dr. Concetta Prontera and her co-workers, for performing all the NT-proBNP analyses, and Dr. Giuseppe Rossi for his valuable help with the statistical analysis.


   References
Top
 Abstract
 1. Materials and methods
 2. Results
 3. Discussion
 Acknowledgments
 References
 

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