© 2004 American Thoracic Society
Brain Natriuretic PeptideIs It Helpful in Detecting Pulmonary Hypertension in Fibrotic Lung Disease?Division of Pulmonary, Critical Care, and Sleep Medicine Tufts-New England Medical Center Boston, Massachusetts Pulmonary hypertension occurs commonly in advanced interstitial lung disease and is associated with a worse functional capacity as well as prognosis (1). Because the cardinal symptom of both conditions is exertional dyspnea, it may be difficult on clinical grounds alone to detect underlying pulmonary hypertension. A diffusing capacity of less than 42% of predicted is a risk factor (2), but it lacks specificity. Echocardiography is used for screening but is expensive and may be unreliable in identifying patients with mild disease. Often, right heart catheterization is the only way to obtain definitive information. To date, no simple, inexpensive and reliable screening test has been developed to identify patients with interstitial lung disease who have concomitant pulmonary hypertension. In the current issue of the Journal (pp. 360–365), Leuchte and coworkers (3) report that measurement of circulating brain natriuretic peptide (BNP) might be just such a test. First isolated from porcine brain, BNP is found mainly in the cardiac ventricles (4). By virtue of its natriuretic, vasodilator, and antiproliferative actions, BNP, along with atrial natriuretic peptide, serves a physiologic regulatory role in the cardiovascular system (5). In both left and right ventricles, BNP gene expression and release into the circulation are enhanced by stretching or hypertrophy, ameliorating the severity of left-sided heart failure and/or pulmonary hypertension (5, 6). BNP has also found a therapeutic role in treating left heart failure, with preliminary reports suggesting possible efficacy in patients with right heart failure as well (7). The greatest clinical utility of BNP thus far identified is to serve as a marker of ventricular dysfunction. Based on the work of Maisel and others (8), BNP has proven to be a highly sensitive and specific marker of left ventricular failure, particularly when circulating levels exceed 500 pg/ml. Recent studies also demonstrate that BNP levels correlate well with the severity of pulmonary hemodynamic and functional impairment in patients with idiopathic (primary) pulmonary arterial hypertension (9).
Leuchte and coworkers (3) found elevated BNP levels in 20 of 39 patients with severe lung fibrosis. Patients with increased BNP levels had greater elevations in mean pulmonary artery pressure and pulmonary vascular resistance than those with normal BNP levels, as well as lower cardiac outputs and mixed venous oxygen saturations. Those with high BNP levels also had shorter 6-minute walk distances, indicating functional incapacity, but pulmonary function variables including total lung capacity and diffusing capacity bore no relation to elevations in BNP. Based on the sensitivity and specificity of BNP in detecting moderate to severe pulmonary hypertension ( The performance of a test like BNP, however, to detect a physiologic abnormality like pulmonary hypertension depends heavily on the patient population selected and the prevalence of the abnormality in that population. The prevalence of moderate/severe pulmonary hypertension in the cohort of Leuchte and coworkers was greater than 25%—a proportion that is likely to enhance the performance of the test in comparison with a lower prevalence. Also, patients with left-ventricular failure, renal dysfunction, or chronic obstructive pulmonary disease, all conditions that are associated with increases in BNP levels (10), were carefully screened out. Further, patients had severe restriction on average and thus represented a narrow spectrum of those with interstitial fibrosis. BNP would probably not have performed so well as a screening test if used on a population of interstitial fibrosis patients with a wider range of severities and comorbidities, particularly if used to detect those with mild pulmonary hypertension, not just moderate to severe. A remarkable finding in the current study was the lack of correlation between measures of lung function and BNP levels or even the severity of pulmonary hypertension. On the surface, this would seem to be counterintuitive. As the authors point out, however, the narrow spectrum of lung restriction represented by the patient cohort is likely responsible. Had the authors examined patients with a wider range of lung dysfunction, such a correlation probably would have been found. On the other hand, the lack of an association suggests that for patients with severe lung restriction, factors other than lung dysfunction alone contribute to the severity of pulmonary hypertension. Such factors might include genetic differences, differences in oxygenation during sleep, and different medical regimens, to name just a few. BNP clearly performed better in this study than the diffusing capacity for carbon monoxide, which did not correlate with the presence of pulmonary hypertension at all. An important omission, however, was that the reliability of BNP was not compared with that of echocardiography, currently the most commonly used screening technique. Although cardiac echocardiographs have limitations in patients with underlying lung disease (11), BNP is unlikely to replace them as a screening tool, because they provide not only an estimate of pulmonary artery systolic pressure, but also information about biventricular function that can be very valuable in patients with suspected pulmonary hypertension. In this context, it would be of interest to know not only how the sensitivities and specificities of the two techniques compare, but also whether BNP complements echocardiography. Despite a number of shortcomings, Leuchte and coworkers (3) have made a very important observation. Because of its simplicity, wide availability, and relatively low expense, BNP measurement is almost certain to assume a role in the evaluation of patients with fibrotic lung disease. The more important questions remain to be answered. Will BNP add to the current screening tools, particularly echocardiography, in a cost-effective manner? Will BNP serve not only as a marker of pulmonary hypertension but also as a way to identify those patients who are more apt to respond to specific antipulmonary hypertension therapy as well as a way to assess the response to therapy? These questions can only be answered by properly designed prospective studies that are yet to be performed. FOOTNOTES Conflict of Interest Statement: N.S.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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35 mm Hg), Leuchte and coworkers (