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BNP—Considering a Heartfelt Message
ORIGINAL ARTICLE
Original Article
BNP—Considering a Heartfelt Message Dr. Ken Sikaris Department of Chemical Pathology, Melbourne Pathology, 103 Victoria Parade, Collingwood, 3066 Melbourne, Vic., Australia
The natriuretic hormones have been discovered as mediators of the cardiac response to volume overload and mechanical dysfunction. Although there are some physiological differences between atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), it is BNP that has been found to be most useful as a clinical test. BNP is secreted along with an N terminal proBNP cleavage product (NT-proBNP). The similarities between these two tests are far greater than the differences. They are both probably useful in the diagnosis of high-risk patients (e.g. dyspnoeic) and may be useful in monitoring cardiac failure treatment. Although BNP levels in the normal range predict the risk of cardiac events and mortality, there is little evidence to promote their use as a screening test. In such an important condition as cardiac failure we should consider any messages that are likely to be of value, particularly those that are heartfelt. (Heart Lung and Circulation 2004;13S:S31–S37) © 2004 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved. Keywords. Natriuretic peptides; Brain-natriuretic peptide; BNP; N terminal pro-BNP (NT-proBNP); Cardiac failure
Introduction
A
trial Natriuretic Peptide (ANP) was discovered in 1981 as a natriuretic factor derived from atrial extracts.1 Although ANP was usually elevated in cardiac failure,2 its use as a diagnostic test was never was established. Brain Natriuretic Peptide (BNP) was discovered in 1988 in porcine brain,3 and its cardiac production and role in heart failure soon realised in 1990.4 BNP’s reliable role in the diagnosis of cardiac failure followed in the late 1990s.5,6 Since that time the number of published papers on the application of BNP in heart failure has increased exponentially to hundreds each year. This review summarizes current evidence on the role and value of this new diagnostic test.
The Natriuretic Peptide Family ANP is produced by atrial myocytes and stored in granules, which can then be released in sudden bursts in response to atrial wall tension. This may be the main reason that ANP is probably the best marker of very rapid cardiac changes.7 BNP is produced by the ventricles, however it is not similarly stored for release but its mRNA can be synthesized rapidly.8 There are other hormones that belong to this family including C-type natriuretic hormone (CNP) which is produced by endothelium and also seems to be elevated in heart failure possibly is a compensatory response from the peripheral vasculature.9 There is considerable homology in the structures of the natriuretic peptides and the central 17 amino acid ring structure, formed Tel.: +61 3 9287 7720; fax: +61 3 9457 5114. E-mail address: [email protected].
by a disulphide bridge, determines the receptor binding (Fig. 1). BNP (like ANP) is manufactured as a prohormone and cleavage prior to secretion results in the release of the inactive amino-terminal pro-BNP (NT-proBNP) and active carboxy-terminal BNP (Fig. 2). Three natriuretic peptide receptors have been cloned. Two are coupled to guanylate cyclase and mediate the hormonal effects. Type A receptors are present in large blood vessels, the kidney and adrenal and preferentially respond to ANP and BNP while the type B receptors are present in brain, kidney and adrenal tissue and bind CNP with the highest affinity. Receptor responsiveness may also be modulated by nitric oxide.10 A recent study suggests that there may also be an attenuation of response to BNP in older patients (where levels are usually higher).11 The third receptor cannot mediate any hormonal effects and allows clearance of the peptides (type C)12 with the rank order of binding affinity for the clearance receptor is for ANP more than CNP or BNP in both humans and rats.13 Active peptides are also degraded by neutral endopeptidase. Recent studies indicate that this enzyme may be relatively more important for ANP than BNP and have consequently postulated other degradation enzymes for BNP14 that may also help to explain other findings of apparent BNP resistance to neutral endopeptidase.15 The half-life of ANP and CNP have half-lives of only about 4 min, however the clearance of BNP is also very rapid with a halflife of 22 min. Rapid changes are possible with BNP and it can potentially reflect sudden changes such as pulmonary wedge pressure changes.16 Clearance may vary and a possible reduction of clearance receptor binding with age may also occur.17 In contrast, the half-life of NT-proBNP is 2 h
© 2004 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
1443-9506/04/$30.00 doi:10.1016/j.hlc.2004.09.015
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Sikaris BNP—Considering a heartfelt message
Heart Lung and Circulation 2004;13S:S31–S37
Figure 1. The common ring structure of the natriuretic peptides.
resulting in both much higher serum levels, which are also more stable. The specific mechanisms of NT-proBNP clearance are poorly defined however it is known that its levels are more strongly inversely correlated with estimated GFR (r = −0.60) than BNP levels (r = −0.20).18 Although both NTproBNP and BNP levels are related to the usual loss of renal function with age, this trend is more marked with NT-proBNP.
Figure 3. The patent and licensing arrangements for the numerous manufacturers of BNP and NT-proBNP assays.
Variability of BNP Levels The instability of the active hormone (BNP) is also witnessed in vitro and requires collection into EDTA plasma or EDTA whole blood. EDTA will inhibit proteases and this can be further assisted by antiproteases such as aprotinin. NT-proBNP is relatively stable, even in separated serum without antiproteases for 24 h.19 The intra-individual changes in NT-proBNP and BNP are of the order of 30–50%. In addition to this usual variability in vivo, analytical imprecision is significant especially for BNP assays where CV% is usually about 10%. The analytical imprecision for NT-proBNP assays is about half that of BNP (CV% 5%), mainly because higher levels are easier to measure. Allowing for both in vivo variability and analytical imprecision, the change that must occur before we can be confident that the change is beyond the analytical and normal individual daily variability is at least 100% and possibly up to 150%.20,21 Strenuous exercise increases in BNP, particularly in patients with cardiac dysfunction22,23 or clinical heart failure.24 NT-proBNP increases following exercise are relatively less than the rises in BNP, which may be an advantage if trying to minimise short-term variability.25
Assays for BNP and NT-proBNP Compared There are two routinely available natriuretic peptide assays; BNP, an assay for the active hormone and NT-proBNP, an assay for the inactive peptide secreted simultaneously with BNP. Although these are the two assays there are numerous manufacturers of each of the assays. The ‘patent’ for BNP was owned by SCIOS and has been purchased by Johnson and Johnson, while Roche owns the patent for NT-proBNP. Other companies have obtained licences to produce each of these assays and these arrangements are summarised in Fig. 3. BNP may appear to be the logical measurand as it is the active hormone. However its blood levels are low and more variable in vivo and in vitro. NT-proBNP is secreted in an equimolar relationship with BNP and has the advantage of being easier to measure and has more stable sample characteristics. However, NT-proBNP clearance is more GFR dependent and therefore normal levels vary with age requiring equivalent age-related clinical decision levels to be determined. Despite these differences, virtually all clinical comparative studies have shown similar performance for BNP and NT-proBNP indicating that the similarities are far greater than any differences. The ability of one marker to perform better depends on assay imprecision as well as cut-offs and the study population chosen. Comparison of the performance of point of care BNP measurements against automated NT-proBNP often show the latter to be better,26,27 however this may be largely analytical.28
Actions of the Natriuretic Peptides
Figure 2. The intracellular cleavage of proBNP results in the secretion of inactive NT-proBNP and active BNP in equal proportion.
The actions of the natriuretic hormones are summarised in Table 1 and Fig. 4.29 A twofold increase in ANP is sufficient to induce a negative sodium balance, a fall in systolic and diastolic blood pressure and an increase in heart rate.30 BNP may be five to six times more potent in lowering blood pressure and CNP is more potent at dilating veins.31
Table 1. The Action of the Natriuretic Peptides Vasodilation (hypotension) Natriuresis (diuresis) Sympathetic nervous system inhibition Hormonal inhibition (renin/angiotensin/aldosterone, endothelins, cytokines, vasopressin) Inhibition of ventricular and vascular hypertrophy and remodelling Endothelial protection against atherosclerosis
Figure 4. The actions of the natriuretic peptides in controlling vascular volume.
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says do not differ in diagnosing ventricular dysfunction and NT-proBNP also correlates well with NYHA classification.34–36 BNP is elevated in diastolic dysfunction and significantly related to newer echocardiographic diastolic indexes.37 NT-proBNP assays are also able to diagnose diastolic dysfunction.38 BNP may be elevated in symptomatic patients with diastolic dysfunction that have restrictive filling pattern,39–42 however levels may be normal in those patients with milder symptoms and relaxation abnormalities.43 Therefore low levels may not rule out some forms of diastolic dysfunction. Similarly, BNP is not as reliable in distinguishing systolic heart failure from non-systolic failure.44 Healthy postmenopausal women have higher BNP levels than men of similar age suggesting a role of steroid hormones in regulation of BNP but this may also be due to more pronounced ventricular stiffening in elderly women. BNP levels also increase with age in both sexes, however this is most probably due to the combined effects of the gradual deterioration of renal and cardiac function in normal aging. Diseases that have an expanded extracellular fluid volume include not only cardiac failure, but also renal failure and liver cirrhosis. Elevated NT-proBNP is particularly elevated in ‘cardio-renal distress’.45 BNP is also elevated in pulmonary disease including COPD,46 cor pulmonale47,48 and pulmonary embolus.49
Pathophysiology Sudden release of the stored granules of ANP are thought to help control transient variations in volume status whereas the longer term changes such as those seen in heart failure and the hypertrophied heart results in the increased production and secretion BNP.32 BNP may be released as a ‘distress hormone’ when usual homeostasis, including regulation of renin/angiotensin and aldosterone, is no longer effective in maintaining the balance of vasoconstriction and vasodilation (Fig. 5). BNP increases more than ANP with increasing clinical severity of cardiac failure.33 BNP levels have been correlated to many measures of cardiac failure including LVEDP, PCW in dilated cardiomyopathy, ejection fraction, left ventricular dimension, cardiac output as well as clinical correlation with NYHA classification. BNP as-
BNP as a Diagnostic Test Diagnosis has relied on signs and symptoms although a medical history may not be available in the acutely ill patient. Specific features include raised JVP, a third heart sound, peripheral oedema and pulmonary crepitations, however these are insensitive especially in early failure. Dyspnoea is the most sensitive diagnostic feature however it is poorly specific. Differentiation of the causes of dyspnoea is important as inappropriate treatment of cardiac dyspnoea with sympathomimetic and beta agonists can induce angina and arrhythmias. BNP has repeatedly been shown to be useful in dyspnoeic patients and can be used to differentiate pulmonary disease from heart failure.50,51 Furthermore BNP
Figure 5. The functional balance between the renin-angiotensin system and the natriuretic hormones.
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potentially corrects most misdiagnoses made by emergency department physicians. However, if there is a strong association of BNP with symptoms—therefore why not use symptoms.52 BNP prediction has been found to be independent of symptoms.53 BNP measurement is useful in discriminating non-cardiac causes of dyspnoea regardless of age and gender.54 The Breathing Not Properly study showed that BNP measurement with clinical judgement is superior to clinical judgement alone.55,56 Although a number of ECG and chest X-ray changes are associated with cardiac failure, it is also possible to have a normal ECG and/or chest X-ray in the presence of heart failure. Nevertheless, European guidelines indicate that ECG, CXR or natriuretic hormones can be used to exclude heart failure and avoid echocardiography. Cardiac echocardiography is the recommended diagnostic tool for patients who are thought to have heart failure.57 It not only can display impaired ventricular function but also can provide clues to the aetiology of heart failure. This is a relatively expensive test whose use can be optimised by selecting high-risk patients by clinical criteria. Cost can also be reduced by up to 50% by using BNP levels to rule out heart failure,58 although the cost savings will depend on the relative cost of these tests in each institution.59 The use of BNP to guide judicious use of echocardiography60 has been adopted by the European Society of Cardiology in their 2001 guidelines.61 Overall costs for cardiac failure can be decreased by 30% as reflected in time to discharge and time to treatment.62
BNP as a Screening Test Results from the large Framingham Heart Study suggest that BNP and NT-proANP have limited usefulness as mass screening tools.63 Interestingly, BNP levels are often lower in patients with obesity alone.64 BNP is also generally not useful for screening for cardiac dysfunction in patients with stable coronary disease65 or hypertension alone.66 NT-proBNP has similarly been found to be not suitable as a screening test in hospitalised patients.67 Although the sensitivity of the test in normal to low risk populations may be poor, the high specificity of elevated levels make it a good test to rule out significant left ventricular dysfunction in higher risk groups. In addition to the diagnostic value in dyspnoeic patients, BNP has been found to be useful in identifying LVH or dysfunction in high-risk groups68 such as those having multiple risk factors for heart failure,69 diabetes mellitus,70 patients on dialysis71 or aortic stenosis.72 The cost effectiveness of screening programs using BNP and echocardiography in high-risk patients is similar to other accepted health interventions; they depend on the estimation of quality of life and income improvements.73
BNP Use in Guiding Treatment Many investigators have shown better outcome (death, hospital admission, or heart failure decompensation) for BNP guided treatment compared to controls.74,75 BNP
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levels have predicted treatment outcome for heart failure therapies76 and correlate to the drug effectiveness in treated patients.77–80 Treatment with antihypertensives that that results in a left ventricular mass index reduction will also be reflected as a fall in BNP.81 Lack of a fall in BNP levels with treatment will similarly predict mortality and early readmission.82 BNP itself is an effective injectable therapy (nesiritide/Natricor® ) for congestive heart failure,83 however this is beyond the scope of the review.
BNP as a Risk Predictor Troponin levels have been shown to be very useful risk predictors in acute coronary syndromes.84 BNP can also predict risk in acute coronary syndromes.85 However, a patient with a normal troponin level may still have a significant risk and this may be largely predicted by BNP.86 In non-STEMI acute coronary syndromes, patients with raised NT-proBNP show increased mortality risk,87,88 and an increase in all cardiac events.89 These strong associations seem to be helpful in identifying patients that will benefit from early invasive strategies.90 In patients with cardiac failure, risk is apparent at natriuretic peptide levels well below current thresholds used to diagnose heart failure.91 Furthermore, plasma natriuretic peptide levels predicted the risk of death and cardiovascular events after adjustment for traditional risk factors.92 NT-proBNP was actually found to be a better predictor than left ventricular ejection fraction.93,94 BNP levels are predictive of future cardiac events in all patients presenting with dyspnoea in emergency departments.95 Preoperative BNP levels predict postoperative complications and 1-year mortality after heart surgery96,97 but it should also be noted that BNP generally rises after all forms of cardiac surgery.98 In a community-based sample, BNP levels are prognostic in an asymptomatic population.99 A level above the 80th percentile predicts heart failure, fibrillation, a cardiac event, stroke and death. This confirms an earlier study that showed circulating concentrations of BNP predict 5-year mortality in an elderly population.100 However, there are no specific studies that help to advise on what do we do with patients with elevated risk according to BNP?
Conclusions Current evidence generally shows that the BNP and NTproBNP are both probably useful for diagnosis of heart failure in at risk groups, especially those with dyspnoea. There is also strong evidence supporting the information obtained from BNP and NT-proBNP levels when monitoring treatment. There is certainly no clear support for the use of BNP or NT-proBNP in screening low risk or asymptomatic patients, even though there is some evidence that high normal levels of BNP can act as a risk predictor in community populations. There are no simple, objective rules than can be applied to diagnosis of heart failure. NYHA classification and specialist opinion are subjective and this may blur our in-
terpretation of the objective evidence supplied by natriuretic hormone measurement. Even echocardiography reflects mechanical dysfunction while natriuretic hormones reflect the neuroendocrine response to dysfunction. BNP, unlike troponin, is not a marker of tissue damage but more of a marker of cardiac stress. Furthermore, cardiac dysfunction is part of a continuum that may become clinically symptomatic at different stages for each individual. It is important that in such a vitally important condition as cardiac failure that we consider any messages that are likely to be of value, particularly those that are heartfelt.
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51. Maisel AS, Krishnaswamy P, Nowak R, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161–7. 52. Wieczorek SJ, Wu AH, Christenson R, et al. A rapid B-type natriuretic peptide assay accurately diagnoses left ventricular dysfunction and heart failure: a multicenter evaluation. Am Heart J 2002;144:834–9. 53. Baughman KL. B-type natriuretic peptide—a window to the heart. N Engl J Med 2002;347:158–9. 54. Knudsen CW, Riis JS, Finsen AV, et al. Diagnostic value of a rapid test for B-type natriuretic peptide in patients presenting with acute dyspnea: effect of age and gender. Eur J Heart Fail 2004;6:55–62. 55. Lainchbury JG, Campbell E, Frampton CM, Yandle TG, Nicholls MG, Richards AM. Brain natriuretic peptide and Nterminal brain natriuretic peptide in the diagnosis of heart failure in patients with acute shortness of breath. J Am Coll Cardiol 2003;42:728–35. 56. McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgement in emergency diagnosis of heart failure. Analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 2002;106:416–22. 57. Task Force on Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis of heart failure. Eur Heart J 1995;16:741–51. 58. Nielsen OW, McDonagh TA, Robb SD, Dargie HJ. Retrospective analysis of the cost-effectiveness of using plasma brain natriuretic peptide in screening for left ventricular systolic dysfunction in the general population. J Am Coll Cardiol 2003;41:113–20. 59. Clerico A, Emden D. Diagnostic accuracy and prognostic relevance of the measurement of cardiac natriuretic peptides: a review. Clin Chem 2004;50:33–50. 60. Maisel AS, Koon J, Krishnaswamy P, et al. Utility of Bnatriuretic peptide as a rapid, point of care test for screening patients undergoing echocardiography to determine left ventricular dysfunction. Am Heart J 2001;141:367–74. 61. Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Task Force Report. Eur Heart J 2001;22:1527–60. 62. 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;350:647–54. 63. Vasan RS, Benjamin EJ, Larson MG, et al. Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: the Framingham heart study. JAMA 2002;288:1252–9. 64. Wang TJ, Larson MG, Levy D, et al. Impact of obesity on plasma natriuretic peptide levels. Circulation 2004;109:594–600. 65. Bibbins-Domingo K, Ansari M, Schiller NB, Massie B, Whooley MA. Is B-type natriuretic peptide a useful screening test for systolic or diastolic dysfunction in patients with coronary disease? Data from the Heart and Soul Study. Am J Med 2004;116:509–16. 66. Nakamura M, Tanaka F, Yonezawa S, Satou K, Nagano M, Hiramori K. The limited value of plasma B-type natriuretic peptide for screening for left ventricular hypertrophy among hypertensive patients. Am J Hypertens 2003;16:1025–9. 67. Pfister R, Scholz M, Wielckens K, Erdmann E, Schneider CA. Use of NT-proBNP in routine testing and comparison to BNP. Eur J Heart Fail 2004;6:289–93. 68. McDonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet 1998;351:9–13.
69. Silver MA, Pisano C. High incidence of elevated B-type natriuretic peptide levels and risk factors for heart failure in an unselected at-risk population (stage A): implications for heart failure screening programs. Congest Heart Fail 2003;9:127–32. 70. Epshteyn V, Morrison K, Krishnaswamy P, et al. Utility of B-type natriuretic peptide (BNP) as a screen for left ventricular dysfunction in patients with diabetes. Diabetes Care 2003;26:2081–7. 71. Mallamaci F, Zoccali C, Tripepi G, et al. The cardiovascular risk extended evaluation. Diagnostic potential of cardiac natriuretic peptides in dialysis patients. Kidney Int 2001;59:1559–66. 72. Qi W, Mathisen P, Kjekshus J, et al. Natriuretic peptides in patients with aortic stenosis. Am Heart J 2001;142:725–32. 73. Heidenreich PA, Gubens MA, Fonarow GC, Konstam MA, Stevenson LW, Shekelle PG. Cost-effectiveness of screening with B-type natriuretic peptide to identify patients with reduced left ventricular ejection fraction. J Am Coll Cardiol 2004;43:1019–26. 74. Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000;355:1126–30. 75. Nicholls MG, Lainchbury JG, Richards AM, Troughton RW, Yandle TG. Brain natriuretic peptide-guided therapy for heart failure. Ann Med 2001;33:422–7. 76. Richards AM, Doughty R, Nicholls MG, et al. Plasma Nterminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. AustraliaNew Zealand Heart Failure Group. J Am Coll Cardiol 2001;37:1781–7. 77. Kawai K, Hata K, Takaoka H, Kawai H, Yokoyama M. Plasma brain natriuretic peptide as a novel therapeutic indicator in idiopathic dilated cardiomyopathy during beta-blocker therapy: a potential of hormone-guided treatment. Am Heart J 2001;141:925–32. 78. Anan F, Takahashi N, Ooie T, Hara M, Yoshimatsu H, Saikawa T. Candesartan, an angiotensin II receptor blocker, improves left ventricular hypertrophy and insulin resistance. Metabolism 2004;53:777–81. 79. van Veldhuisen DJ, Genth-Zotz S, Brouwer J, et al. Highversus low-dose ACE inhibition in chronic heart failure. a double blind, placebo-controlled study of imidapril. J Am Coll Cardiol 1998;32:1811–8. 80. Motwani JG, McAlpine H, Kennedy N, Struthers AD. Plasma brain natriuretic peptide as an indicator for angiotensin converting enzyme inhibition after myocardial infarction. Lancet 1993;341:1109–13. 81. Kohno M, Horio T, Yokokawa K, et al. Brain natriuretic peptide as a marker for hypertensive left ventricular hypertrophy: changes during 1 year antihypertensive therapy with angiotension-converting enzyme inhibitor. Am J Med 1995;98:257–65. 82. Cheng V, Kazanagra R, Garcia A, et al. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study. J Am Coll Cardiol 2001;37:386–91. 83. Keating GM, Goa KL. Nesiritide: a review of its use in acute decompensated heart failure. Drugs 2003;63:47–70. 84. Kaul P, Newby LK, Fu Y, et al. Troponin T and quantitative ST-segment depression offer complementary prognostic information in the risk stratification of acute coronary syndrome patients. J Am Coll Cardiol 2003;41:371–80.
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85. de Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345:1014–21. 86. Morrow DA, de Lemos JA, Sabatine MS, et al. Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18. J Am Coll Cardiol 2003;41:1264–72. 87. James SK, Lindahl B, Siegbahn A, et al. N-terminal probrain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: a Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV substudy. Circulation 2003;108:275–81. 88. Jernberg T, Stridsberg M, Venge P, Lindahl B. N-terminal pro brain natriuretic peptide on admission for early risk stratification of patients with chest pain and no ST-segment elevation. J Am Coll Cardiol 2002;40:437–45. 89. Zeller M, Cottin Y, Laurent Y, et al. N-terminal pro-brain natriuretic peptide levels in patients with non-ST-elevation myocardial infarction. Cardiology 2004;102:37–40. 90. Jernberg T, James S, Lindahl B, Stridsberg M, Venge P, Wallentin L. NT-proBNP in unstable coronary artery disease—experiences from the FAST, GUSTO IV and FRISC II trials. Eur J Heart Fail 2004;6:319–25. 91. 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;350:655–63. 92. Tsutamoto T, Wada A, Maeda K. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 1997;96:509–16. 93. Richards AM, Doughty R, Nicholls MG, et al. Plasma N-terminal pro-brain natriuretic peptides and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. J Am Coll Cardiol 2001;37:1781–7. 94. Kirk V, Bay M, Parner J, et al. N-terminal proBNP and mortality in hospitalised patients with heart failure and preserved vs. reduced systolic function: data from the prospective Copenhagen Hospital Heart Failure Study (CHHF). Eur J Heart Fail 2004;6:335–41. 95. Harrison A, Morrison LK, Krishnaswarmy P, et al. B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea. Ann Emerg Med 2002;39:131–8. 96. Hutfless R, Kazanegra R, Madani M, et al. Utility of B-type natriuretic peptide in predicting postoperative complications and outcomes in patients undergoing heart surgery. J Am Coll Cardiol 2004;43:1873–9. 97. Berendes E, Schmidt C, Van Aken H, et al. A-type and B-type natriuretic peptides in cardiac surgical procedures. Anesth Analg 2004;98:11–9. 98. Georges A, Forestier F, Valli N, Plogin A, Janvier G, Bordenave L. Changes in type B natriuretic peptide (BNP) concentrations during cardiac valve replacement. Eur J Cardiothorac Surg 2004;25:941–5. 99. 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;350:655–63. 100. Wallen T, Landahl T, Herner T, et al. Brain natriuretic peptide predicts mortality in the elderly. Heart 1997;77: 264–7.
ORIGINAL ARTICLE
Heart Lung and Circulation 2004;13S:S31–S37
Original Article
BNP—Considering a Heartfelt Message Dr. Ken Sikaris Department of Chemical Pathology, Melbourne Pathology, 103 Victoria Parade, Collingwood, 3066 Melbourne, Vic., Australia
The natriuretic hormones have been discovered as mediators of the cardiac response to volume overload and mechanical dysfunction. Although there are some physiological differences between atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), it is BNP that has been found to be most useful as a clinical test. BNP is secreted along with an N terminal proBNP cleavage product (NT-proBNP). The similarities between these two tests are far greater than the differences. They are both probably useful in the diagnosis of high-risk patients (e.g. dyspnoeic) and may be useful in monitoring cardiac failure treatment. Although BNP levels in the normal range predict the risk of cardiac events and mortality, there is little evidence to promote their use as a screening test. In such an important condition as cardiac failure we should consider any messages that are likely to be of value, particularly those that are heartfelt. (Heart Lung and Circulation 2004;13S:S31–S37) © 2004 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved. Keywords. Natriuretic peptides; Brain-natriuretic peptide; BNP; N terminal pro-BNP (NT-proBNP); Cardiac failure
Introduction
A
trial Natriuretic Peptide (ANP) was discovered in 1981 as a natriuretic factor derived from atrial extracts.1 Although ANP was usually elevated in cardiac failure,2 its use as a diagnostic test was never was established. Brain Natriuretic Peptide (BNP) was discovered in 1988 in porcine brain,3 and its cardiac production and role in heart failure soon realised in 1990.4 BNP’s reliable role in the diagnosis of cardiac failure followed in the late 1990s.5,6 Since that time the number of published papers on the application of BNP in heart failure has increased exponentially to hundreds each year. This review summarizes current evidence on the role and value of this new diagnostic test.
The Natriuretic Peptide Family ANP is produced by atrial myocytes and stored in granules, which can then be released in sudden bursts in response to atrial wall tension. This may be the main reason that ANP is probably the best marker of very rapid cardiac changes.7 BNP is produced by the ventricles, however it is not similarly stored for release but its mRNA can be synthesized rapidly.8 There are other hormones that belong to this family including C-type natriuretic hormone (CNP) which is produced by endothelium and also seems to be elevated in heart failure possibly is a compensatory response from the peripheral vasculature.9 There is considerable homology in the structures of the natriuretic peptides and the central 17 amino acid ring structure, formed Tel.: +61 3 9287 7720; fax: +61 3 9457 5114. E-mail address: [email protected].
by a disulphide bridge, determines the receptor binding (Fig. 1). BNP (like ANP) is manufactured as a prohormone and cleavage prior to secretion results in the release of the inactive amino-terminal pro-BNP (NT-proBNP) and active carboxy-terminal BNP (Fig. 2). Three natriuretic peptide receptors have been cloned. Two are coupled to guanylate cyclase and mediate the hormonal effects. Type A receptors are present in large blood vessels, the kidney and adrenal and preferentially respond to ANP and BNP while the type B receptors are present in brain, kidney and adrenal tissue and bind CNP with the highest affinity. Receptor responsiveness may also be modulated by nitric oxide.10 A recent study suggests that there may also be an attenuation of response to BNP in older patients (where levels are usually higher).11 The third receptor cannot mediate any hormonal effects and allows clearance of the peptides (type C)12 with the rank order of binding affinity for the clearance receptor is for ANP more than CNP or BNP in both humans and rats.13 Active peptides are also degraded by neutral endopeptidase. Recent studies indicate that this enzyme may be relatively more important for ANP than BNP and have consequently postulated other degradation enzymes for BNP14 that may also help to explain other findings of apparent BNP resistance to neutral endopeptidase.15 The half-life of ANP and CNP have half-lives of only about 4 min, however the clearance of BNP is also very rapid with a halflife of 22 min. Rapid changes are possible with BNP and it can potentially reflect sudden changes such as pulmonary wedge pressure changes.16 Clearance may vary and a possible reduction of clearance receptor binding with age may also occur.17 In contrast, the half-life of NT-proBNP is 2 h
© 2004 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
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Heart Lung and Circulation 2004;13S:S31–S37
Figure 1. The common ring structure of the natriuretic peptides.
resulting in both much higher serum levels, which are also more stable. The specific mechanisms of NT-proBNP clearance are poorly defined however it is known that its levels are more strongly inversely correlated with estimated GFR (r = −0.60) than BNP levels (r = −0.20).18 Although both NTproBNP and BNP levels are related to the usual loss of renal function with age, this trend is more marked with NT-proBNP.
Figure 3. The patent and licensing arrangements for the numerous manufacturers of BNP and NT-proBNP assays.
Variability of BNP Levels The instability of the active hormone (BNP) is also witnessed in vitro and requires collection into EDTA plasma or EDTA whole blood. EDTA will inhibit proteases and this can be further assisted by antiproteases such as aprotinin. NT-proBNP is relatively stable, even in separated serum without antiproteases for 24 h.19 The intra-individual changes in NT-proBNP and BNP are of the order of 30–50%. In addition to this usual variability in vivo, analytical imprecision is significant especially for BNP assays where CV% is usually about 10%. The analytical imprecision for NT-proBNP assays is about half that of BNP (CV% 5%), mainly because higher levels are easier to measure. Allowing for both in vivo variability and analytical imprecision, the change that must occur before we can be confident that the change is beyond the analytical and normal individual daily variability is at least 100% and possibly up to 150%.20,21 Strenuous exercise increases in BNP, particularly in patients with cardiac dysfunction22,23 or clinical heart failure.24 NT-proBNP increases following exercise are relatively less than the rises in BNP, which may be an advantage if trying to minimise short-term variability.25
Assays for BNP and NT-proBNP Compared There are two routinely available natriuretic peptide assays; BNP, an assay for the active hormone and NT-proBNP, an assay for the inactive peptide secreted simultaneously with BNP. Although these are the two assays there are numerous manufacturers of each of the assays. The ‘patent’ for BNP was owned by SCIOS and has been purchased by Johnson and Johnson, while Roche owns the patent for NT-proBNP. Other companies have obtained licences to produce each of these assays and these arrangements are summarised in Fig. 3. BNP may appear to be the logical measurand as it is the active hormone. However its blood levels are low and more variable in vivo and in vitro. NT-proBNP is secreted in an equimolar relationship with BNP and has the advantage of being easier to measure and has more stable sample characteristics. However, NT-proBNP clearance is more GFR dependent and therefore normal levels vary with age requiring equivalent age-related clinical decision levels to be determined. Despite these differences, virtually all clinical comparative studies have shown similar performance for BNP and NT-proBNP indicating that the similarities are far greater than any differences. The ability of one marker to perform better depends on assay imprecision as well as cut-offs and the study population chosen. Comparison of the performance of point of care BNP measurements against automated NT-proBNP often show the latter to be better,26,27 however this may be largely analytical.28
Actions of the Natriuretic Peptides
Figure 2. The intracellular cleavage of proBNP results in the secretion of inactive NT-proBNP and active BNP in equal proportion.
The actions of the natriuretic hormones are summarised in Table 1 and Fig. 4.29 A twofold increase in ANP is sufficient to induce a negative sodium balance, a fall in systolic and diastolic blood pressure and an increase in heart rate.30 BNP may be five to six times more potent in lowering blood pressure and CNP is more potent at dilating veins.31
Table 1. The Action of the Natriuretic Peptides Vasodilation (hypotension) Natriuresis (diuresis) Sympathetic nervous system inhibition Hormonal inhibition (renin/angiotensin/aldosterone, endothelins, cytokines, vasopressin) Inhibition of ventricular and vascular hypertrophy and remodelling Endothelial protection against atherosclerosis
Figure 4. The actions of the natriuretic peptides in controlling vascular volume.
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says do not differ in diagnosing ventricular dysfunction and NT-proBNP also correlates well with NYHA classification.34–36 BNP is elevated in diastolic dysfunction and significantly related to newer echocardiographic diastolic indexes.37 NT-proBNP assays are also able to diagnose diastolic dysfunction.38 BNP may be elevated in symptomatic patients with diastolic dysfunction that have restrictive filling pattern,39–42 however levels may be normal in those patients with milder symptoms and relaxation abnormalities.43 Therefore low levels may not rule out some forms of diastolic dysfunction. Similarly, BNP is not as reliable in distinguishing systolic heart failure from non-systolic failure.44 Healthy postmenopausal women have higher BNP levels than men of similar age suggesting a role of steroid hormones in regulation of BNP but this may also be due to more pronounced ventricular stiffening in elderly women. BNP levels also increase with age in both sexes, however this is most probably due to the combined effects of the gradual deterioration of renal and cardiac function in normal aging. Diseases that have an expanded extracellular fluid volume include not only cardiac failure, but also renal failure and liver cirrhosis. Elevated NT-proBNP is particularly elevated in ‘cardio-renal distress’.45 BNP is also elevated in pulmonary disease including COPD,46 cor pulmonale47,48 and pulmonary embolus.49
Pathophysiology Sudden release of the stored granules of ANP are thought to help control transient variations in volume status whereas the longer term changes such as those seen in heart failure and the hypertrophied heart results in the increased production and secretion BNP.32 BNP may be released as a ‘distress hormone’ when usual homeostasis, including regulation of renin/angiotensin and aldosterone, is no longer effective in maintaining the balance of vasoconstriction and vasodilation (Fig. 5). BNP increases more than ANP with increasing clinical severity of cardiac failure.33 BNP levels have been correlated to many measures of cardiac failure including LVEDP, PCW in dilated cardiomyopathy, ejection fraction, left ventricular dimension, cardiac output as well as clinical correlation with NYHA classification. BNP as-
BNP as a Diagnostic Test Diagnosis has relied on signs and symptoms although a medical history may not be available in the acutely ill patient. Specific features include raised JVP, a third heart sound, peripheral oedema and pulmonary crepitations, however these are insensitive especially in early failure. Dyspnoea is the most sensitive diagnostic feature however it is poorly specific. Differentiation of the causes of dyspnoea is important as inappropriate treatment of cardiac dyspnoea with sympathomimetic and beta agonists can induce angina and arrhythmias. BNP has repeatedly been shown to be useful in dyspnoeic patients and can be used to differentiate pulmonary disease from heart failure.50,51 Furthermore BNP
Figure 5. The functional balance between the renin-angiotensin system and the natriuretic hormones.
ORIGINAL ARTICLE
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Sikaris BNP—Considering a heartfelt message
potentially corrects most misdiagnoses made by emergency department physicians. However, if there is a strong association of BNP with symptoms—therefore why not use symptoms.52 BNP prediction has been found to be independent of symptoms.53 BNP measurement is useful in discriminating non-cardiac causes of dyspnoea regardless of age and gender.54 The Breathing Not Properly study showed that BNP measurement with clinical judgement is superior to clinical judgement alone.55,56 Although a number of ECG and chest X-ray changes are associated with cardiac failure, it is also possible to have a normal ECG and/or chest X-ray in the presence of heart failure. Nevertheless, European guidelines indicate that ECG, CXR or natriuretic hormones can be used to exclude heart failure and avoid echocardiography. Cardiac echocardiography is the recommended diagnostic tool for patients who are thought to have heart failure.57 It not only can display impaired ventricular function but also can provide clues to the aetiology of heart failure. This is a relatively expensive test whose use can be optimised by selecting high-risk patients by clinical criteria. Cost can also be reduced by up to 50% by using BNP levels to rule out heart failure,58 although the cost savings will depend on the relative cost of these tests in each institution.59 The use of BNP to guide judicious use of echocardiography60 has been adopted by the European Society of Cardiology in their 2001 guidelines.61 Overall costs for cardiac failure can be decreased by 30% as reflected in time to discharge and time to treatment.62
BNP as a Screening Test Results from the large Framingham Heart Study suggest that BNP and NT-proANP have limited usefulness as mass screening tools.63 Interestingly, BNP levels are often lower in patients with obesity alone.64 BNP is also generally not useful for screening for cardiac dysfunction in patients with stable coronary disease65 or hypertension alone.66 NT-proBNP has similarly been found to be not suitable as a screening test in hospitalised patients.67 Although the sensitivity of the test in normal to low risk populations may be poor, the high specificity of elevated levels make it a good test to rule out significant left ventricular dysfunction in higher risk groups. In addition to the diagnostic value in dyspnoeic patients, BNP has been found to be useful in identifying LVH or dysfunction in high-risk groups68 such as those having multiple risk factors for heart failure,69 diabetes mellitus,70 patients on dialysis71 or aortic stenosis.72 The cost effectiveness of screening programs using BNP and echocardiography in high-risk patients is similar to other accepted health interventions; they depend on the estimation of quality of life and income improvements.73
BNP Use in Guiding Treatment Many investigators have shown better outcome (death, hospital admission, or heart failure decompensation) for BNP guided treatment compared to controls.74,75 BNP
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levels have predicted treatment outcome for heart failure therapies76 and correlate to the drug effectiveness in treated patients.77–80 Treatment with antihypertensives that that results in a left ventricular mass index reduction will also be reflected as a fall in BNP.81 Lack of a fall in BNP levels with treatment will similarly predict mortality and early readmission.82 BNP itself is an effective injectable therapy (nesiritide/Natricor® ) for congestive heart failure,83 however this is beyond the scope of the review.
BNP as a Risk Predictor Troponin levels have been shown to be very useful risk predictors in acute coronary syndromes.84 BNP can also predict risk in acute coronary syndromes.85 However, a patient with a normal troponin level may still have a significant risk and this may be largely predicted by BNP.86 In non-STEMI acute coronary syndromes, patients with raised NT-proBNP show increased mortality risk,87,88 and an increase in all cardiac events.89 These strong associations seem to be helpful in identifying patients that will benefit from early invasive strategies.90 In patients with cardiac failure, risk is apparent at natriuretic peptide levels well below current thresholds used to diagnose heart failure.91 Furthermore, plasma natriuretic peptide levels predicted the risk of death and cardiovascular events after adjustment for traditional risk factors.92 NT-proBNP was actually found to be a better predictor than left ventricular ejection fraction.93,94 BNP levels are predictive of future cardiac events in all patients presenting with dyspnoea in emergency departments.95 Preoperative BNP levels predict postoperative complications and 1-year mortality after heart surgery96,97 but it should also be noted that BNP generally rises after all forms of cardiac surgery.98 In a community-based sample, BNP levels are prognostic in an asymptomatic population.99 A level above the 80th percentile predicts heart failure, fibrillation, a cardiac event, stroke and death. This confirms an earlier study that showed circulating concentrations of BNP predict 5-year mortality in an elderly population.100 However, there are no specific studies that help to advise on what do we do with patients with elevated risk according to BNP?
Conclusions Current evidence generally shows that the BNP and NTproBNP are both probably useful for diagnosis of heart failure in at risk groups, especially those with dyspnoea. There is also strong evidence supporting the information obtained from BNP and NT-proBNP levels when monitoring treatment. There is certainly no clear support for the use of BNP or NT-proBNP in screening low risk or asymptomatic patients, even though there is some evidence that high normal levels of BNP can act as a risk predictor in community populations. There are no simple, objective rules than can be applied to diagnosis of heart failure. NYHA classification and specialist opinion are subjective and this may blur our in-
terpretation of the objective evidence supplied by natriuretic hormone measurement. Even echocardiography reflects mechanical dysfunction while natriuretic hormones reflect the neuroendocrine response to dysfunction. BNP, unlike troponin, is not a marker of tissue damage but more of a marker of cardiac stress. Furthermore, cardiac dysfunction is part of a continuum that may become clinically symptomatic at different stages for each individual. It is important that in such a vitally important condition as cardiac failure that we consider any messages that are likely to be of value, particularly those that are heartfelt.
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