REVIEW ARTICLE
The value of (NT-pro)
BNP
in the diagnosis,
prognosis and treatment of congestive heart failure R.R.J. van Kimmenade, J.A. Bakker, H.J.G.M. Crijns, M.P. van Dieijen-Visser, Y.M. Pinto
Congestive heart failure constitutes one of the major causes of morbidity and mortality in Western countries. However, it is often misdiagnosed and the validity of the diagnosis is often difficult to establish. The clinical signs are not very sensitive and symptoms are nonspecific. Secretion of natriuretic peptides is increased in situations of cardiac overload. Testing the levels of these peptides, especially BNP and NT-proBNP, appears to offer a significant advance in the diagnosis and treatment of heart failure. In this artide we would like to discuss the value of natriuretic peptides in congestive heart failure and give a short review of the literature. (Neth HeartJ2004;12:61-3.) Key words: natriuretic peptides, congestive heart failure, review A s early as 1981, De Bold et al. reported that atrial tissue extracts induced severe natriuresis in rats. This observation started further studies of a new class of natriuretic peptides derived from atria. Contributions from several investigators over the past two decades have demonstrated the role of these peptides in the (patho)physiological mechanisms of the body to defend itselfagainst plasma volume expansion and hypertension. These peptides reflect the response against cardiac overload and as a result can be used clinically to identify cardiac overloading. BNP (brain R.R.J. van Kimmenade Department of Cardiology Y.M. Pinto H.J.G.M. Crins Department of Cardiology, Experimental and Molecular Cardiology Laboratory, CARIM J.A. Bakker M.P. van DIlJen-Vlsser Department of Clinical Chemistry, University Hospital Maastricht, P. Debeyelaan 25, P0 Box 5800, 6202 AZ Maastricht
Correspondence to: R.R.J. van Kimmenade E-mail: [email protected]
Netherlands Heart Journal, Volume 12, Number 2, February 2004
natriuretic peptide) and especially NT-proBNP (aminoterminal-proBNP) have proven their sensitivity and specificity in congestive heart failure (CHF) and have shown to be superior to other parameters for CHF, such as chest X-ray and physical examination. Finally, exogenously administered BNP can be used to treat CHF and hypertension. This latter application is also being studied in our hospital but is beyond the scope ofthis article. In the current paper we highlight current knowledge ofthe family ofnatriuretic peptides. Natriuretic peptldes The family ofnatriuretic peptides has several members: atrial natriuretic peptide, brain natriuretic peptide, Ctype natriuretic peptide, dendroaspis natriuretic peptide and urodilatin.
Atrial natriuretic peptide (ANP) is primarily produced in both atria, triggered by increased atrial wall tension, and reflects an increase in intravascular volume. The ventricles of normal adults produce only small amounts of ANP, but this production is enhanced in the ventricular tissue of foetuses/neonates and in hypertrophied ventricles. Brain natriuretic peptide (BNP), originally identified in the porcine brain, is also present in the human brain, but a much greater amount is produced in the cardiac ventricles. The plasma concentration of BNP is raised in patients with congestive heart failure and in some with ventricular hypertrophy. It is released in response to increased ventricular loading. Ofall natriuretic peptides, BNP and its related cleavage products have emerged as superior markers for CHF and left ventricular dysfunction because BNP is rapidly upregulated at the transcriptional level, is more stable than the other natriuretic peptides and is more sensitive to ventricular dysfunction. C-type natriuretic peptide (CNP) has two isoforms, which are both products from a different cleavage process of a pro-CNP precursor. CNP predominates in the vascular endothelial cells, central nervous system, kidney and pituitary gland. Plasma concentration of CNP is low. Dendroaspis natriuretic peptide (DNP) was isolated in the venom of the green mamba. Although 61
The value of (NT-pro) BNP in the diagnosis, prognosis and treatment of congestive heart failure
it has proven to induce natriuresis it remains unclear if it plays a role in the physiology of mammals. Urodilatin is a product of an alternative expression of the ANP gene in the kidney instead of in the heart. It probably has a function in the local sodium and water regulation. Molecular forms of BNP: which one Is useful to the physician? As mentioned above, BNP has proven to be a reliable marker in CHF, but NT-proBNP seems even more convenient than BNP in the diagnosis and treatment of CHF. ProBNP (108 amino acids) is produced in the myocyte and is cleaved to yield BNP (32 amino acids) and NT-proBNP (76 amino acids). BNP is the biologically active form and is responsible for several compensatory mechanisms in congestive heart failure, such as an increase of urine production and sodium excretion, a decrease ofthe aldosterone level, a lowering ofthe blood pressure and a lowering of the capillary wedge pressure. The level is congruent with age, female sex, left ventricular hypertrophy and renal dysfunction. For determination of BNP levels whole blood or plasma is used, NT-proBNP can be measured in serum as well. Unfortunately, absolute plasma BNP concentrations are low and BNP has a biological half-life of20 minutes. Besides that, BNP level increases after exercise and the patient should lie supine for 20 minutes before a blood sample can be taken to get a representative sample. This makes BNP less suitable for clinical applications than NT-proBNP. NT-proBNP is a more stable molecule and has lower intra-individual variations. Its absolute plasma concentrations are three to four times higher, its biological half-life is 60-120 minutes and there are no special conditions required for sampling. The result of an NT-proBNP blood sample is available after 18 minutes. The most frequently used cut-off values in the literature are 100 pg/ml for BNP and 33 pmol/l for NT-proBNP. Since methods for measurements of BNP levels were commercially available before methods that measure NT-proBNP levels, most trials so far have used BNP as a marker. A recent study demonstrated that NT-proBNP correlates as well as BNP with clinical variables in patients with heart failure. Future larger studies will show which molecule is the best marker in heart failure. All the studies discussed in our article used BNP as a marker unless mentioned otherwise.
Diagnosis in systolic and diastolic heart failure BNP is helpful to distinguish pulmonary from cardiac causes of dyspnoea. Morrison et al. have shown the value ofBNP in differentiating cardiac and pulmonary causes of dyspnoea. Their study of 321 patients who presented with acute dyspnoea to the emergency department nicely shows that BNP has a higher level of sensitivity and specificity than any other diagnostic instrument including chest X-ray and physical
62
Table 1. Sensitivity and specificity of instruments used for diagnosing dyspnoea.
History of CHF Jugular venous pressure Cardiomegaly on chest X-ray Rales BNP
Sensitivity
Specificity
76% 81% 89% 74% 87%
81% 81% 76% 88% 95%
Multivariate analysis. Morrison et al. studied 321 patients with dyspnoea in an emergency department. Physicians who performed the physical examination at admission were blinded to BNP levels. As cut-off value for a BNPguided diagnosis for CHF, 80 pg/mI was used. Final diagnosis was based on independent conformation of two cardiologists with information about the hospital course and further cardiac testing including echocardiography, nuclear medicine ejection fraction and catheterisation. The table is a modified version of: Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnoea. J Am Coll Cardiol 2002 16;39:202-9.
examination (table 1). BNP has a positive predictive value of only 70%, because of a slightly elevated level in pulmonary pathology due to acute right ventricular pressure overload, but it should be mentioned that these levels are seldom as high as in acute cardiac dyspnoea from elevated LV pressures (systolic or diastolic). However, the negative predictive value of 98% is of even more importance and a nonnal BNP level practically excludes any form of heart failure. The table clearly demonstrates that diagnostic accuracy of serum BNP is better than any ofthe other routinely used clinical parameters. A normal BNP level with signs otherwise attributed to heart failure necessitates rethinking and surmising alternative diagnoses. For instance, cardiomegaly on the chest X-ray but a normal BNP level suggests tamponade, while an extremely ill patient with apparent 'cardiogenic' oedema on chest X-ray but a normal BNP level is likely to be suffering from acute adult respiratory distress syndrome (ARDS). BNP level is also raised in diastolic heart failure but does not attain the concentrations found in systolic heart failure. Kitzman et al. have shown that the BNP level is increased 20-fold in patients with diastolic heart failure compared with controls. As a result, serum BNP or NT-proBNP measurement adds important information particularly in difficult cases, such as 'diastolic' dysfunction, or when a cardiac or pulmonary cause cannot be easily distinguished. Prognosis and treatment BNP has also been suggested to effectively guide therapy and prognosis in CHF. For example, treatments with loop diuretics and ACE inhibitors have proven to lower the BNP levels in patients with CHF.
Netherlands Heart Journal, Volume 12, Number 2, February 2004
The value of (NT-pro) BNP in the diagnosis, prognosis and treatment of congestive heart failure
A high level ofBNP is associated with a poor prognosis and the absolute level is correlated to functional dyspnoea classes. The relative risk of death due to CHF in patients with a BNP level above 230 pg/ml is 24. Also in the most recent trials, where patients received ample ACE inhibition and f-blockade, increased baseline BNP level was associated with an adverse outcome: in 36 months, survival ranged from around 85% in the lowest BNP quartile, plunging to a mere 60% in the highest quartile of BNP. This exemplifies that the absolute level of BNP can make an important contribution to risk and prognosis assessment in CHF patients. The next question is whether the relation between BNP and prognosis is amenable to treatment. In other words, one could postulate that risk declines in the CHF patients in whom an initially high BNP is lowered by intensified treatment. This was demonstrated in an interesting study by Troughton et al. They randomised 69 clinically stable patients with CHF in New York Heart Association class II-IV with a left ventricular ejection fraction
The value of (NT-pro)
BNP
in the diagnosis,
prognosis and treatment of congestive heart failure R.R.J. van Kimmenade, J.A. Bakker, H.J.G.M. Crijns, M.P. van Dieijen-Visser, Y.M. Pinto
Congestive heart failure constitutes one of the major causes of morbidity and mortality in Western countries. However, it is often misdiagnosed and the validity of the diagnosis is often difficult to establish. The clinical signs are not very sensitive and symptoms are nonspecific. Secretion of natriuretic peptides is increased in situations of cardiac overload. Testing the levels of these peptides, especially BNP and NT-proBNP, appears to offer a significant advance in the diagnosis and treatment of heart failure. In this artide we would like to discuss the value of natriuretic peptides in congestive heart failure and give a short review of the literature. (Neth HeartJ2004;12:61-3.) Key words: natriuretic peptides, congestive heart failure, review A s early as 1981, De Bold et al. reported that atrial tissue extracts induced severe natriuresis in rats. This observation started further studies of a new class of natriuretic peptides derived from atria. Contributions from several investigators over the past two decades have demonstrated the role of these peptides in the (patho)physiological mechanisms of the body to defend itselfagainst plasma volume expansion and hypertension. These peptides reflect the response against cardiac overload and as a result can be used clinically to identify cardiac overloading. BNP (brain R.R.J. van Kimmenade Department of Cardiology Y.M. Pinto H.J.G.M. Crins Department of Cardiology, Experimental and Molecular Cardiology Laboratory, CARIM J.A. Bakker M.P. van DIlJen-Vlsser Department of Clinical Chemistry, University Hospital Maastricht, P. Debeyelaan 25, P0 Box 5800, 6202 AZ Maastricht
Correspondence to: R.R.J. van Kimmenade E-mail: [email protected]
Netherlands Heart Journal, Volume 12, Number 2, February 2004
natriuretic peptide) and especially NT-proBNP (aminoterminal-proBNP) have proven their sensitivity and specificity in congestive heart failure (CHF) and have shown to be superior to other parameters for CHF, such as chest X-ray and physical examination. Finally, exogenously administered BNP can be used to treat CHF and hypertension. This latter application is also being studied in our hospital but is beyond the scope ofthis article. In the current paper we highlight current knowledge ofthe family ofnatriuretic peptides. Natriuretic peptldes The family ofnatriuretic peptides has several members: atrial natriuretic peptide, brain natriuretic peptide, Ctype natriuretic peptide, dendroaspis natriuretic peptide and urodilatin.
Atrial natriuretic peptide (ANP) is primarily produced in both atria, triggered by increased atrial wall tension, and reflects an increase in intravascular volume. The ventricles of normal adults produce only small amounts of ANP, but this production is enhanced in the ventricular tissue of foetuses/neonates and in hypertrophied ventricles. Brain natriuretic peptide (BNP), originally identified in the porcine brain, is also present in the human brain, but a much greater amount is produced in the cardiac ventricles. The plasma concentration of BNP is raised in patients with congestive heart failure and in some with ventricular hypertrophy. It is released in response to increased ventricular loading. Ofall natriuretic peptides, BNP and its related cleavage products have emerged as superior markers for CHF and left ventricular dysfunction because BNP is rapidly upregulated at the transcriptional level, is more stable than the other natriuretic peptides and is more sensitive to ventricular dysfunction. C-type natriuretic peptide (CNP) has two isoforms, which are both products from a different cleavage process of a pro-CNP precursor. CNP predominates in the vascular endothelial cells, central nervous system, kidney and pituitary gland. Plasma concentration of CNP is low. Dendroaspis natriuretic peptide (DNP) was isolated in the venom of the green mamba. Although 61
The value of (NT-pro) BNP in the diagnosis, prognosis and treatment of congestive heart failure
it has proven to induce natriuresis it remains unclear if it plays a role in the physiology of mammals. Urodilatin is a product of an alternative expression of the ANP gene in the kidney instead of in the heart. It probably has a function in the local sodium and water regulation. Molecular forms of BNP: which one Is useful to the physician? As mentioned above, BNP has proven to be a reliable marker in CHF, but NT-proBNP seems even more convenient than BNP in the diagnosis and treatment of CHF. ProBNP (108 amino acids) is produced in the myocyte and is cleaved to yield BNP (32 amino acids) and NT-proBNP (76 amino acids). BNP is the biologically active form and is responsible for several compensatory mechanisms in congestive heart failure, such as an increase of urine production and sodium excretion, a decrease ofthe aldosterone level, a lowering ofthe blood pressure and a lowering of the capillary wedge pressure. The level is congruent with age, female sex, left ventricular hypertrophy and renal dysfunction. For determination of BNP levels whole blood or plasma is used, NT-proBNP can be measured in serum as well. Unfortunately, absolute plasma BNP concentrations are low and BNP has a biological half-life of20 minutes. Besides that, BNP level increases after exercise and the patient should lie supine for 20 minutes before a blood sample can be taken to get a representative sample. This makes BNP less suitable for clinical applications than NT-proBNP. NT-proBNP is a more stable molecule and has lower intra-individual variations. Its absolute plasma concentrations are three to four times higher, its biological half-life is 60-120 minutes and there are no special conditions required for sampling. The result of an NT-proBNP blood sample is available after 18 minutes. The most frequently used cut-off values in the literature are 100 pg/ml for BNP and 33 pmol/l for NT-proBNP. Since methods for measurements of BNP levels were commercially available before methods that measure NT-proBNP levels, most trials so far have used BNP as a marker. A recent study demonstrated that NT-proBNP correlates as well as BNP with clinical variables in patients with heart failure. Future larger studies will show which molecule is the best marker in heart failure. All the studies discussed in our article used BNP as a marker unless mentioned otherwise.
Diagnosis in systolic and diastolic heart failure BNP is helpful to distinguish pulmonary from cardiac causes of dyspnoea. Morrison et al. have shown the value ofBNP in differentiating cardiac and pulmonary causes of dyspnoea. Their study of 321 patients who presented with acute dyspnoea to the emergency department nicely shows that BNP has a higher level of sensitivity and specificity than any other diagnostic instrument including chest X-ray and physical
62
Table 1. Sensitivity and specificity of instruments used for diagnosing dyspnoea.
History of CHF Jugular venous pressure Cardiomegaly on chest X-ray Rales BNP
Sensitivity
Specificity
76% 81% 89% 74% 87%
81% 81% 76% 88% 95%
Multivariate analysis. Morrison et al. studied 321 patients with dyspnoea in an emergency department. Physicians who performed the physical examination at admission were blinded to BNP levels. As cut-off value for a BNPguided diagnosis for CHF, 80 pg/mI was used. Final diagnosis was based on independent conformation of two cardiologists with information about the hospital course and further cardiac testing including echocardiography, nuclear medicine ejection fraction and catheterisation. The table is a modified version of: Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnoea. J Am Coll Cardiol 2002 16;39:202-9.
examination (table 1). BNP has a positive predictive value of only 70%, because of a slightly elevated level in pulmonary pathology due to acute right ventricular pressure overload, but it should be mentioned that these levels are seldom as high as in acute cardiac dyspnoea from elevated LV pressures (systolic or diastolic). However, the negative predictive value of 98% is of even more importance and a nonnal BNP level practically excludes any form of heart failure. The table clearly demonstrates that diagnostic accuracy of serum BNP is better than any ofthe other routinely used clinical parameters. A normal BNP level with signs otherwise attributed to heart failure necessitates rethinking and surmising alternative diagnoses. For instance, cardiomegaly on the chest X-ray but a normal BNP level suggests tamponade, while an extremely ill patient with apparent 'cardiogenic' oedema on chest X-ray but a normal BNP level is likely to be suffering from acute adult respiratory distress syndrome (ARDS). BNP level is also raised in diastolic heart failure but does not attain the concentrations found in systolic heart failure. Kitzman et al. have shown that the BNP level is increased 20-fold in patients with diastolic heart failure compared with controls. As a result, serum BNP or NT-proBNP measurement adds important information particularly in difficult cases, such as 'diastolic' dysfunction, or when a cardiac or pulmonary cause cannot be easily distinguished. Prognosis and treatment BNP has also been suggested to effectively guide therapy and prognosis in CHF. For example, treatments with loop diuretics and ACE inhibitors have proven to lower the BNP levels in patients with CHF.
Netherlands Heart Journal, Volume 12, Number 2, February 2004
The value of (NT-pro) BNP in the diagnosis, prognosis and treatment of congestive heart failure
A high level ofBNP is associated with a poor prognosis and the absolute level is correlated to functional dyspnoea classes. The relative risk of death due to CHF in patients with a BNP level above 230 pg/ml is 24. Also in the most recent trials, where patients received ample ACE inhibition and f-blockade, increased baseline BNP level was associated with an adverse outcome: in 36 months, survival ranged from around 85% in the lowest BNP quartile, plunging to a mere 60% in the highest quartile of BNP. This exemplifies that the absolute level of BNP can make an important contribution to risk and prognosis assessment in CHF patients. The next question is whether the relation between BNP and prognosis is amenable to treatment. In other words, one could postulate that risk declines in the CHF patients in whom an initially high BNP is lowered by intensified treatment. This was demonstrated in an interesting study by Troughton et al. They randomised 69 clinically stable patients with CHF in New York Heart Association class II-IV with a left ventricular ejection fraction
