B-Type Natriuretic Peptide — A Biomarker for All Seasons
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《新英格兰医药杂志》
Despite more than two decades of research that has shown the value and cost effectiveness of information from the medical history and physical examination for management decisions, physicians are increasingly reluctant to rely on these subjective data alone. The use of new biomarkers that promise to simplify clinical decision making is often adopted enthusiastically by practitioners. In the emergency department, for example, routine measurement of cardiac troponins reduces the need for busy doctors to struggle with difficult medical histories and atypical presentations of acute coronary disease when making triage decisions. When such biomarkers are used outside the context of good clinical judgment, however, new clinical challenges may result. Still, the remarkable power and versatility of the troponin biomarkers in cases of acute coronary artery disease have stimulated interest in the potential of other serum biomarkers to clarify difficult cardiovascular problems. To date, two have shown promise in clinical studies: high-sensitivity C-reactive protein and B-type natriuretic peptide.
B-type natriuretic peptide and atrial natriuretic peptide are peptide hormones released in response to myocyte stretch.1 B-type natriuretic peptide is released primarily by ventricular myocytes in the form of the active hormone and an inactive N-terminal fragment, whereas atrial natriuretic peptide and its inactive N-terminal fragment are released primarily by the atria. Both of these hormones augment urinary volume and urinary sodium excretion, relax vascular smooth muscle, and inhibit the sympathetic nervous system and the renin–angiotensin–aldosterone system. These physiologic effects result in improved loading conditions and have led to the development of recombinant B-type natriuretic peptide as a therapeutic agent for heart failure. Both hormones have also been extensively assessed as biomarkers.2
In general, biomarkers have been evaluated for four clinical purposes: screening for preclinical disease in asymptomatic persons, diagnosis of clinical disease in patients with symptoms of uncertain cause, risk stratification in patients with clinical disease, and guidance in the selection or titration of therapeutic agents in patients with known disease. The development of commercially available assays for both B-type natriuretic peptide and its inactive N-terminal fragment has led to a dramatic rise in the number of studies exploring the potential clinical use of measurement of the natriuretic peptides for all four of these purposes. In this issue of the Journal, two provocative studies provide further data on measurement of B-type natriuretic peptide for diagnosis3 and for preclinical screening.4
At present, B-type natriuretic peptide is probably best accepted as a diagnostic tool in the evaluation of acute dyspnea in the emergency department.5 In the B-Type Natriuretic Peptide for Acute Shortness of Breath Evaluation (BASEL) Study, reported by Mueller et al., patients presenting to the emergency department with acute dyspnea were randomly assigned to undergo either a single measurement of B-type natriuretic peptide or no such measurement.3 Participating clinicians were advised that a level of B-type natriuretic peptide below 100 pg per milliliter made the diagnosis of congestive heart failure unlikely, whereas a level above 500 pg per milliliter made it highly likely. For intermediate levels, use of clinical judgment and adjunctive testing were encouraged. In this single-blind trial of 452 patients, rapid measurement of B-type natriuretic peptide in the emergency department was associated with decreases in the rate of hospital admission by 10 percentage points, the median length of stay by three days, and the mean total cost of treatment by about $1,800, with no adverse effects on mortality or the rate of subsequent hospitalization.
On its face, this carefully performed trial suggests that the use of an inexpensive blood test for B-type natriuretic peptide in the emergency evaluation of acute dyspnea can significantly improve both the efficiency and the quality of care. Can the results be generalized? Theoretically, the use of an improved diagnostic test in the emergency department can reduce the use of hospital resources and associated costs in three general ways: by leading to early initiation of a highly effective therapy that reduces the risk of complications; by eliminating the need for other, more expensive tests; or by establishing an alternative diagnosis that does not require hospitalization. Approximately one third of the cost savings associated with the use of B-type natriuretic peptide measurement in the BASEL Study was achieved because the result led to an alternative diagnosis, one that did not require hospitalization. This effect is consistent with the high negative predictive value of a low level of B-type natriuretic peptide with respect to the diagnosis of heart failure.6 It is not yet fully known how the remaining two thirds of the observed cost savings in the BASEL Study resulted from the detection of an elevated level of B-type natriuretic peptide in the emergency department.
Another area of investigation in the use of novel biomarkers is prognostic screening in asymptomatic persons. In the second article in this issue of the Journal, investigators from the Framingham Offspring Study examined the long-term prognostic importance of the levels of atrial natriuretic peptide and B-type natriuretic peptide in asymptomatic middle-aged persons.4 After adjusting for traditional risk factors, Wang and colleagues found that the level of B-type natriuretic peptide was independently predictive of the risk of death, heart failure, atrial fibrillation, and stroke over a mean follow-up period of about five years. Only 2.2 percent of the participating men and 1.5 percent of the women had levels above 80 pg per milliliter, and these outlying data did not appear to explain the prognostic value of the measurement. Levels of B-type natriuretic peptide above the 80th percentile in this cohort (i.e., higher than 20 pg per milliliter) were associated with an increase by more than 60 percent in the long-term risk of death. Furthermore, there was a significant prognostic gradient with respect to the risk of heart failure, atrial fibrillation, and stroke among the three levels of B-type natriuretic peptide (low, intermediate, and high) examined.
This remarkable finding strongly suggests that there are important prognostic data even in the range of B-type natriuretic peptide levels thought, on the basis of previous studies, to rule out heart failure (i.e., levels below 100 pg per milliliter). Of note, echocardiographic measurements of left ventricular mass, left atrial diameter, and left ventricular systolic function did explain, at least statistically, much of the association between the level of B-type natriuretic peptide and the risk of death, but did not explain its association with the risk of heart failure, stroke, or atrial fibrillation. These associations persisted even after adjustment for standard risk factors and echocardiographic measurements, suggesting that slight elevations of B-type natriuretic peptide may reflect very early stages of pathologic processes that precede the development of apparent cardiac manifestations (such as measurable left ventricular hypertrophy). Alternatively, increased levels of B-type natriuretic peptide may be associated with early diastolic dysfunction,7 which was not specifically examined by Wang and colleagues. If these interesting observations are to have clinical value, at least two things need to happen. First, as the authors suggest, the findings must be replicated in other, similar cohorts. Second, therapy that can modify the adverse prognosis represented by increased B-type natriuretic peptide levels must be identified.
It is tempting to use new biomarkers to elucidate pathophysiological processes in our patients, as if we have been given a new powerful microscope to see into the body. However, to say that B-type natriuretic peptide reflects subclinical or overt hemodynamic stress does not necessarily make us any wiser about how to care for patients. We need to remember that clinical disease is the product of uncompensated perturbations in the dynamic equilibrium between risk factors and the body's defense and repair mechanisms.8 Looking at B-type natriuretic peptide in isolation may thus be akin to seeing smoke trailing out of the window of a house without having any notion of what is on fire, where that fire is, or how it can best be extinguished.
Taken together, the results of the BASEL Study and the Framingham Offspring Study suggest that B-type natriuretic peptide is both much less and much more than a blood test for heart failure: much less, in the sense that the diagnostic use of B-type natriuretic peptide augments but does not supersede careful clinical evaluation and reasoning,9 and much more, in the sense that B-type natriuretic peptide measurement may provide a very early warning signal for future cardiovascular disease in persons without symptoms.
Source Information
From the Division of Cardiology, Department of Medicine, Duke University Medical Center and Duke Clinical Research Institute, Durham, N.C.
References
de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003;362:316-322.
Cowie MR, Jourdain P, Maisel A, et al. Clinical applications of B-type natriuretic peptide (BNP) testing. Eur Heart J 2003;24:1710-1718.
Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med 2004;350:647-654.
Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004;350:655-663.
Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527-1560.
Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161-167.
Yamaguchi H, Yoshida J, Yamamoto K, et al. Elevation of plasma brain natriuretic peptide is a hallmark of diastolic heart failure independent of ventricular hypertrophy. J Am Coll Cardiol 2004;43:55-60.
Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003;348:593-600.
McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 2002;106:416-422.(Daniel B. Mark, M.D., M.P)
B-type natriuretic peptide and atrial natriuretic peptide are peptide hormones released in response to myocyte stretch.1 B-type natriuretic peptide is released primarily by ventricular myocytes in the form of the active hormone and an inactive N-terminal fragment, whereas atrial natriuretic peptide and its inactive N-terminal fragment are released primarily by the atria. Both of these hormones augment urinary volume and urinary sodium excretion, relax vascular smooth muscle, and inhibit the sympathetic nervous system and the renin–angiotensin–aldosterone system. These physiologic effects result in improved loading conditions and have led to the development of recombinant B-type natriuretic peptide as a therapeutic agent for heart failure. Both hormones have also been extensively assessed as biomarkers.2
In general, biomarkers have been evaluated for four clinical purposes: screening for preclinical disease in asymptomatic persons, diagnosis of clinical disease in patients with symptoms of uncertain cause, risk stratification in patients with clinical disease, and guidance in the selection or titration of therapeutic agents in patients with known disease. The development of commercially available assays for both B-type natriuretic peptide and its inactive N-terminal fragment has led to a dramatic rise in the number of studies exploring the potential clinical use of measurement of the natriuretic peptides for all four of these purposes. In this issue of the Journal, two provocative studies provide further data on measurement of B-type natriuretic peptide for diagnosis3 and for preclinical screening.4
At present, B-type natriuretic peptide is probably best accepted as a diagnostic tool in the evaluation of acute dyspnea in the emergency department.5 In the B-Type Natriuretic Peptide for Acute Shortness of Breath Evaluation (BASEL) Study, reported by Mueller et al., patients presenting to the emergency department with acute dyspnea were randomly assigned to undergo either a single measurement of B-type natriuretic peptide or no such measurement.3 Participating clinicians were advised that a level of B-type natriuretic peptide below 100 pg per milliliter made the diagnosis of congestive heart failure unlikely, whereas a level above 500 pg per milliliter made it highly likely. For intermediate levels, use of clinical judgment and adjunctive testing were encouraged. In this single-blind trial of 452 patients, rapid measurement of B-type natriuretic peptide in the emergency department was associated with decreases in the rate of hospital admission by 10 percentage points, the median length of stay by three days, and the mean total cost of treatment by about $1,800, with no adverse effects on mortality or the rate of subsequent hospitalization.
On its face, this carefully performed trial suggests that the use of an inexpensive blood test for B-type natriuretic peptide in the emergency evaluation of acute dyspnea can significantly improve both the efficiency and the quality of care. Can the results be generalized? Theoretically, the use of an improved diagnostic test in the emergency department can reduce the use of hospital resources and associated costs in three general ways: by leading to early initiation of a highly effective therapy that reduces the risk of complications; by eliminating the need for other, more expensive tests; or by establishing an alternative diagnosis that does not require hospitalization. Approximately one third of the cost savings associated with the use of B-type natriuretic peptide measurement in the BASEL Study was achieved because the result led to an alternative diagnosis, one that did not require hospitalization. This effect is consistent with the high negative predictive value of a low level of B-type natriuretic peptide with respect to the diagnosis of heart failure.6 It is not yet fully known how the remaining two thirds of the observed cost savings in the BASEL Study resulted from the detection of an elevated level of B-type natriuretic peptide in the emergency department.
Another area of investigation in the use of novel biomarkers is prognostic screening in asymptomatic persons. In the second article in this issue of the Journal, investigators from the Framingham Offspring Study examined the long-term prognostic importance of the levels of atrial natriuretic peptide and B-type natriuretic peptide in asymptomatic middle-aged persons.4 After adjusting for traditional risk factors, Wang and colleagues found that the level of B-type natriuretic peptide was independently predictive of the risk of death, heart failure, atrial fibrillation, and stroke over a mean follow-up period of about five years. Only 2.2 percent of the participating men and 1.5 percent of the women had levels above 80 pg per milliliter, and these outlying data did not appear to explain the prognostic value of the measurement. Levels of B-type natriuretic peptide above the 80th percentile in this cohort (i.e., higher than 20 pg per milliliter) were associated with an increase by more than 60 percent in the long-term risk of death. Furthermore, there was a significant prognostic gradient with respect to the risk of heart failure, atrial fibrillation, and stroke among the three levels of B-type natriuretic peptide (low, intermediate, and high) examined.
This remarkable finding strongly suggests that there are important prognostic data even in the range of B-type natriuretic peptide levels thought, on the basis of previous studies, to rule out heart failure (i.e., levels below 100 pg per milliliter). Of note, echocardiographic measurements of left ventricular mass, left atrial diameter, and left ventricular systolic function did explain, at least statistically, much of the association between the level of B-type natriuretic peptide and the risk of death, but did not explain its association with the risk of heart failure, stroke, or atrial fibrillation. These associations persisted even after adjustment for standard risk factors and echocardiographic measurements, suggesting that slight elevations of B-type natriuretic peptide may reflect very early stages of pathologic processes that precede the development of apparent cardiac manifestations (such as measurable left ventricular hypertrophy). Alternatively, increased levels of B-type natriuretic peptide may be associated with early diastolic dysfunction,7 which was not specifically examined by Wang and colleagues. If these interesting observations are to have clinical value, at least two things need to happen. First, as the authors suggest, the findings must be replicated in other, similar cohorts. Second, therapy that can modify the adverse prognosis represented by increased B-type natriuretic peptide levels must be identified.
It is tempting to use new biomarkers to elucidate pathophysiological processes in our patients, as if we have been given a new powerful microscope to see into the body. However, to say that B-type natriuretic peptide reflects subclinical or overt hemodynamic stress does not necessarily make us any wiser about how to care for patients. We need to remember that clinical disease is the product of uncompensated perturbations in the dynamic equilibrium between risk factors and the body's defense and repair mechanisms.8 Looking at B-type natriuretic peptide in isolation may thus be akin to seeing smoke trailing out of the window of a house without having any notion of what is on fire, where that fire is, or how it can best be extinguished.
Taken together, the results of the BASEL Study and the Framingham Offspring Study suggest that B-type natriuretic peptide is both much less and much more than a blood test for heart failure: much less, in the sense that the diagnostic use of B-type natriuretic peptide augments but does not supersede careful clinical evaluation and reasoning,9 and much more, in the sense that B-type natriuretic peptide measurement may provide a very early warning signal for future cardiovascular disease in persons without symptoms.
Source Information
From the Division of Cardiology, Department of Medicine, Duke University Medical Center and Duke Clinical Research Institute, Durham, N.C.
References
de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003;362:316-322.
Cowie MR, Jourdain P, Maisel A, et al. Clinical applications of B-type natriuretic peptide (BNP) testing. Eur Heart J 2003;24:1710-1718.
Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med 2004;350:647-654.
Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004;350:655-663.
Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527-1560.
Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161-167.
Yamaguchi H, Yoshida J, Yamamoto K, et al. Elevation of plasma brain natriuretic peptide is a hallmark of diastolic heart failure independent of ventricular hypertrophy. J Am Coll Cardiol 2004;43:55-60.
Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003;348:593-600.
McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 2002;106:416-422.(Daniel B. Mark, M.D., M.P)