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* From the Departments of Cardiology (Drs. Cabanes, Heloire, and Weber), Pneumology (Drs. Richaud-Thiriez and Dusser), and Biophysics (Drs. Fulla and Vuillemard), Cochin Hospital, René Descartes University, Paris, France.
Correspondence to: Laure Cabanes, MD, PhD, Service de Cardiologie, Hôpital Cochin, 27 rue du Fg Saint-Jacques, 75014 Paris, France; e-mail: laure.cabanes{at}cch.ap-hop-paris.fr
Abstract
Study objectives: In dyspneic patients without left ventricular enlargement, it may be difficult to differentiate between obstructive lung disease and diastolic heart failure. Determination of plasma brain natriuretic peptide (BNP) levels, known to increase with ventricular stretch, may be of clinical relevance in this situation. We compared the discriminant power of BNP blood levels and of echocardiography in patients with either chronic obstructive lung disease or diastolic heart failure.
Patients: Twenty-six New York Heart Association class III dyspneic patients with normal left ventricular systolic function were enrolled: 17 patients with chronic obstructive lung disease and 9 patients with unequivocal diastolic heart failure.
Results: Echocardiographic data were unable to accurately differentiate between the two groups, whereas BNP levels were significantly and markedly higher in patients with diastolic heart failure when compared to those with obstructive lung disease (224 ± 240 pg/mL vs 14 ± 12 pg/mL, p < 0.0001).
Conclusions: These preliminary results warrant a prospective, large-scale evaluation of the value of BNP assay for determining diastolic dysfunction, a common cause of dyspnea in elderly patients, and differentiating it from other diagnoses such as obstructive lung disease.
Key Words: brain natriuretic peptide • chronic airways obstruction • congestive heart failure • diastolic failure • dyspnea
The cause of dyspnea is often difficult to determine clinically, especially in elderly patients. The prevalence of both chronic obstructive lung disease and congestive heart failure (CHF) is high, and these two conditions are often present in the same patient. This difficulty may be compounded by the occurrence of bronchospasm in elderly patients with heart failure (cardiac asthma). A chest radiograph demonstrating cardiomegaly and an echocardiogram showing depressed left ventricular function easily allow a definite diagnosis of left ventricular systolic dysfunction. In contrast, isolated diastolic heart failure, a frequent cause of CHF in the elderly, is more difficult to demonstrate because of the absence of cardiomegaly and the poor sensitivity of echocardiographic diastolic dysfunction criteria.
Plasma levels of brain natriuretic peptide (BNP) are significantly increased in patients with left ventricular dysfunction in comparison with control subjects1 2 or patients with respiratory disease3 ; preliminary data seem to indicate that BNP levels may be elevated in patients with diastolic dysfunction.4 The purpose of our study was to measure plasma levels of BNP in dyspneic patients with either documented diastolic CHF or chronic airways obstruction in order to test the discriminant power of BNP assay between these two diagnoses.
Materials and Methods
Patients
We planned to study 30 patients: 20 consecutive patients
with chronic airways obstruction and 10 consecutive patients with
isolated diastolic dysfunction. Twice as many subjects with chronic
airways obstruction were enrolled because poor echogenicity is common
in such patients. It was therefore expected that half of the
echocardiographic study findings would be considered suboptimal. Sample
size was limited to 30 patients because we postulated that BNP assays
would be of clinical interest only if marked differences were found
between both groups. Thirty patients were considered to be enough to
assess such a difference. Patients were all studied in a compensated
phase of their illness and were all in New York Heart Association class
III for dyspnea.
Of the 20 patients with chronic airways obstruction, 3 patients were subsequently withdrawn because of infectious bronchitis occurring during the study (n = 2) and paroxysmal atrial fibrillation (n = 1). The 17 remaining patients (mean ±SD age, 65 ± 6 years) had severe chronic airways obstruction, with a mean FEV1 of 1.3 ± 0.6 L/s and normal systolic left ventricular function at echocardiography or radionuclide ventriculography (mean left ventricular ejection fraction [LVEF] of 64 ± 5%). All these patients were in sinus rhythm.
Patients included in the diastolic heart failure group had a previous history of recurrent pulmonary edema based on an acute severe breathlessness, interstitial or alveolar edema on chest radiographs, and a rapid response to specific treatment of CHF. These patients were in sinus rhythm, and all had FEV1 values within the normal range. Ten patients were initially included; 1 patient was subsequently excluded because of paroxysmal atrial fibrillation. Nine patients were therefore studied (mean ± SD age, 68 ± 3 years; LVEF, 66 ± 4%; and FEV1, 2.4 ± 0.4 L/s). Patient characteristics are listed on Tables 1 2 3 .
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Cardiac Peptide Measurements
Venous blood samples were collected into
ethylenediaminetetra-acetic acid (1.5 mg/mL) and aprotinine (500
kallikrein units/mL), rapidly centrifuged at 4°C and stored at
- 20°C. BNP was assayed in a blinded fashion within 3 months of
collection with the use of two direct specific monoclonal antibodies
radioimmunoassay kit (Shionoria BNP; Shionoria; Saclay, France).
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 extraction of plasma. There was no detectable
cross-reactivity with other natriuretic peptides. This assay has an
interassay coefficient of variation near 10% and a recovery of 100%
of added peptide. The upper limit of normal BNP levels is considered,
with this assay, to be 35 pg/mL.
Statistics
Statistics were done using Statview software (Alcyd; Meylan,
France). Values for baseline characteristics are expressed as
mean and respective SDs. Cardiac peptide concentrations are given
(graphical presentation with median, 10th, 25th, 75th, and 90th
centiles) and are compared in the two groups of patients using the
nonparametric Mann-Whitney test. Statistical significance was defined
as p < 0.05.
Results
There was no significant difference between the groups regarding age (68 ± 3 years vs 65 ± 6 years, not significant [NS]), LVEF (66 ± 4% vs 64 ± 5%, NS) and sPAP (36 ± 10 mm Hg vs 36 ± 8 mm Hg, NS; Table 1 ). However, sPAP was impossible to determine in 8 of the 18 patients with chronic airways obstruction and in 2 of the 9 patients with diastolic dysfunction. A restrictive filling pattern, as previously defined, was observed in only three patients with diastolic CHF (patients 3, 6, and 9) and in one patient with chronic airways obstruction (patient 5). The median concentration of BNP was significantly and markedly higher in patients with diastolic cardiac dysfunction than in patients with chronic airways obstruction: 224 ± 240 pg/mL vs 14 ± 12 pg/mL (p < 0.001; Fig 1 ).
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The main finding of our study was a major increase of BNP levels in patients with diastolic heart failure contrasting with BNP values within normal range in those with chronic obstructive lung disease. There was nearly no overlap between the two groups.
BNP is a natriuretic peptide produced within the heart and released in response to ventricular overload and stretch. Several studies1 2 3 have demonstrated a marked elevation of BNP plasma levels in patients with systolic left ventricular failure. Furthermore, it has been shown8 9 10 that a restrictive filling pattern associated with systolic dysfunction was predictive of even higher BNP levels. A study performed by Nagaya et al11 assessed BNP levels in patients with right ventricular overload. Increased BNP levels were noted. However, the study population consisted of patients with major pulmonary hypertension due to large atrial septal defects, primary pulmonary hypertension, or pulmonary hypertension due to thromboembolism. In a more recent article,12 the same group demonstrated a correlation between BNP levels and the severity and prognosis of primary pulmonary hypertension. In this study, mean sPAP was 84 ± 1 mm Hg. In our population of patients with chronic obstructive lung disease, pulmonary hypertension was obviously less pronounced (mean sPAP, 36 ± 8 mm Hg at Doppler ultrasound); therefore, a significant increase in BNP levels did not occur. In contrast, a marked elevation of BNP levels was noted in patients with diastolic heart failure and similar sPAPs (36 ± 10 mm Hg) due to an increase of left ventricular filling pressures. The absence of BNP elevation in response to the moderate increase in pulmonary arterial pressure that can be observed in patients with isolated chronic obstructive lung disease is of important clinical value. Elevated BNP values in patients with chronic obstructive lung disease are usually not attributable to airways obstruction by itself, but most probably to an associated left ventricular dysfunction. Our study was powered to detect a clinically relevant difference in BNP levels between the two groups of patients, but was obviously unable, at this preliminary stage, to give meaningful sensitivity, specificity, and predictive values. Patients were highly selected in both groups; we included either patients with chronic obstructive lung disease and no left ventricular dysfunction or subjects with unequivocal isolated diastolic heart failure. The diagnostic value of BNP assay must therefore be prospectively studied in a larger population of less-selected patients. A bedside BNP radioimmunoassay is currently being evaluated with encouraging preliminary results. BNP levels may thus become an important determinant in the differential diagnosis of dyspnea, especially when chest radiography and transthoracic echocardiography findings are noncontributory or poorly contributory. This will be of particular interest in patients with diastolic heart failure given the current lack of standardized diagnostic criteria.13 14
Acknowledgements
We thank Luc Nonnenmacher for technical help.
Footnotes
Abbreviations: BNP = brain natriuretic peptide; CHF = congestive heart failure; DT = deceleration time; E/A = peak velocity during passive phase of diastolic filling of left ventricle/late peak of velocity following atrial contraction; LVEF = left ventricular ejection fraction; NS = not significant; sPAP = systolic pulmonary artery pressure
Received for publication September 12, 2000. Accepted for publication June 20, 2001.
References
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