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A new use for B-type natriuretic peptide: to detect myocardial ischaemia in non-heart failure patients

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A new use for B-type natriuretic peptide: to detect myocardial ischaemia in non-heart failure patients
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    http://dvd.sagepub.com/  DiseaseThe British Journal of Diabetes & Vascular  http://dvd.sagepub.com/content/10/2/78The online version of this article can be found at: DOI: 10.1177/1474651409344927 2010 10: 78 British Journal of Diabetes & Vascular Disease  Awsan Noman, Jacob George and Allan Struthers A new use for B-type natriuretic peptide: to detect myocardial ischaemia in non-heart failure patients  Published by:  http://www.sagepublications.com  can be found at: The British Journal of Diabetes & Vascular Disease  Additional services and information for http://dvd.sagepub.com/cgi/alerts Email Alerts:  http://dvd.sagepub.com/subscriptions Subscriptions:  http://www.sagepub.com/journalsReprints.nav Reprints:  http://www.sagepub.com/journalsPermissions.nav Permissions: http://dvd.sagepub.com/content/10/2/78.refs.html Citations:  What is This? - Apr 12, 2010Version of Record >>  by guest on October 11, 2013dvd.sagepub.comDownloaded from by guest on October 11, 2013dvd.sagepub.comDownloaded from by guest on October 11, 2013dvd.sagepub.comDownloaded from by guest on October 11, 2013dvd.sagepub.comDownloaded from by guest on October 11, 2013dvd.sagepub.comDownloaded from by guest on October 11, 2013dvd.sagepub.comDownloaded from   78   VOLUME 10 ISSUE 2 . MARCH/APRIL 2010  ACHIEVING BEST PRACTICE AWSAN NOMAN, JACOB GEORGE, ALLAN STRUTHERS Abstract B -type natriuretic peptide (BNP) is a natriuretic pep-tide released primarily by ventricular myocytes in response to various physiological and pathological stimuli. In addition to its established diagnostic role in patients with heart failure, a growing body of evidence suggests that raised levels of BNP in the absence of heart failure can indicate myocardial ischaemia. This appears to be the case in patients with symptomatic, and even asymptomatic coronary artery disease (CAD). In this review, we discuss the current evidence supporting the role of BNP as a simple marker of cardiac ischaemia and CAD. We also propose some therapeutic interventions that may be use-ful when BNP detects silent myocardial ischaemia. Br J Diabetes Vasc Dis 2010; 10 :78-82 Key words: BNP, coronary artery disease, ischaemic heart disease, myocardial ischaemia Background The heart is now recognised as an endocrine organ. It releases a number of hormones, which belong to the natriuretic pep-tide family. The natriuretic peptide hormones are characterised by a 17-amino acid ring, which is essential for receptor interac-tion and physiological activity. There are currently four types of natriuretic peptides that have been described: ANP, BNP, CNP and DNP. ANP and BNP are primarily released from the heart, whereas CNP is expressed in the nervous system and endothe-lial cells. 1  The exact role of DNP is still being evaluated.In humans, BNP is primarily derived from the ventricular car-diomyocytes. It is synthesised as pre-pro BNP, a 132-amino acid peptide that later undergoes cleavage of its 26 amino acid signal peptide resulting in pro-BNP, a 108-peptide. Pro-BNP is subse-quently cleaved to the biologically active peptide BNP and the inactive N-BNP by the enzyme furin. 2,3  BNP has several systemic effects, which counteract CV volume overload. These effects include vasodilatation, diuresis, natriuresis, and inhibition of the renin–angiotensin–aldosterone system. 4,5 BNP synthesis is constitutive and its release is triggered by a variety of physiological and pathological stimuli (Table 1). Its release in response to LV stress and dilatation explains its estab-lished role in the diagnosis and prognostic evaluation of patients with heart failure. 6  Its role in diagnosis has been endorsed by NICE 7  and the recent SIGN 8  for the management of heart failure. In addition, an overwhelming body of evidence now indi-cates that BNP/N-BNP is not only of diagnostic use in heart failure but is also the best independent predictor of CV progno-sis over and above the traditional risk factors of BP, cholesterol and a wide range of echo abnormalities including LV ejection fraction and LV hypertrophy. The prognostic value for BNP/N-BNP has been seen in several populations including normal  A new use for B-type natriuretic peptide: to detect myocardial ischaemia in non-heart failure patients   © The Author(s), 2010. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/1474651409344927   78 Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, UK. Correspondence to: Dr Awsan Noman Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK.Tel: +44 (0)1382 632180; Fax: +44 (0)1382 644972E-mail: awsannoman@nhs.net Abbreviations and acronyms ANP atrial natriuretic peptide BNP B-type (brain) natriuretic peptideCAD coronary artery diseaseCNP C-type natriuretic peptideCV cardiovascularDNP Dendroaspis-type natriuretic peptideLV left ventricularN-BNP N-terminal pro-BNPNICE National Institute for Health and Clinical ExcellenceSCD sudden cardiac deathSIGN Scottish Intercollegiate Guidelines Network Table 1. Causes of raised B-type (brain) natriuretic peptide levels Congestive heart failureLeft ventricular systolic dysfunctionLeft ventricular diastolic dysfunctionLeft ventricular hypertrophyAtrial fibrillationOther cardiac conditions (e.g. cardiac tamponade, valvular heart disease)Pulmonary disease (e.g. pulmonary embolism)Renal dysfunctionAdvanced age  THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE   79  ACHIEVING BEST PRACTICE subjects, 9,10  elderly populations with no apparent disease 11,12  and diabetic patients. 13,14 BNP/N-BNP have also been shown to predict CV mortality and other adverse CV outcomes, such as stroke and heart failure in patients presenting with an acute myocardial infarction, 15,16  non-ST elevation acute coronary syndrome 17,18  and stable CAD. 19,20 CAD and myocardial ischaemia As discussed above, BNP appears to be a good prognostic marker in a wide range of populations. A possible common denominator in these patients, which may explain their poor prognosis, is the presence of myocardial ischaemia. Therefore, an important question here is whether the raised BNP levels in these individuals could reflect the presence of myocardial isch-aemia, even without LV dysfunction. In fact, there are now several studies that link BNP to CAD and myocardial ischaemia. These are summarised in Table 2.The first of these studies was published in 1997. 21  This study demonstrated elevated BNP levels in left anterior   descend-ing CAD and circumflex disease, irrespective   of intracardiac pressure. In addition, BNP   levels increased gradually as the number of diseased coronary   arteries increased. Baseline BNP measurements were 11.8 󰀶  1.7 pmol/L, 15.8 󰀶  2.9 pmol/L, 19.1 󰀶  2.5 pmol/L and 39.1 󰀶  8.4 pmol/L in patients with normal coronary arteries, one, two and three CAD, respectively. This link between BNP and the extent of coronary   disease has Table 2.  Summary of studies linking B-type (brain) natriuretic peptide (BNP)/N-terminal pro-BNP (N-BNP) to myocardial ischaemia Author Year No. of Patients Main Outcome Mega et al. 16  2004 438 Increased BNP at presentation in patients with STEMI is associated with impaired reperfusion after thrombolysis and higher short-term mortalityMorrow et al. 17  2003 4,266 Serial BNP levels after ACS predict long-term risk of heart failure and death James et al. 18  2003 6,809 Increased N-BNP in ACS patients is related to short- and long-term mortalityOmland et al. 19  2007 3,761 BNP and N-BNP are related to heart failure, stroke and cardiovascular mortality in chronic stable angina patients Kragelund et al. 20  2005 1,034 N-BNP is a marker of long-term mortality in patients with stable coronary diseaseDavidson et al. 21  1997 100 Higher resting BNP with increased number of stenosed coronary arteries Bibbins-Domingo et al. 22  2003 355 Elevated BNP is independently associated with myocardial inducible ischaemia in patients with stable CADSadanandan et al. 23  2004 276 Elevated BNP is associated with tighter culprit stenosis and LAD involvement in UA/NSTEMI patientsAsada et al. 24  2004 317 Resting BNP is predictive of dobutamine-induced ischaemia in patients with suspected CADBergeron et al. 29  2006 60 Resting and exertional change in BNP is related to the positive exercise stress echocardiography in patients with suspected CADWeber et al. 25  2004 94 N-BNP is elevated in patients with stable angina pectoris and closely correlates to the severity of CAD; it also improves the accuracy of exercise testing in predicting CADFoote et al. 30  2004 95 Exercise-induced increase in BNP and N-BNP improves the sensitivity of the exercise test for detecting ischaemia with no loss of specificityTateishi et al. 31  2000 30 Plasma BNP is increased by transient myocardial ischaemia induced by PTCA McClure et al. 33  2007 26 N-BNP decreases 8 weeks after PTCA to LAD in patients with stable CAD and normal LV systolic functionRana et al. 35  2006 121 BNP predicts silent myocardial ischaemia on exercise testing in asymptomatic patients with type 2 diabetes Wong et al. 36 2006 56 BNP predicts silent myocardial ischaemia in asymptomatic patients following CVA Key: ACS = acute coronary syndrome; CAD = coronary artery disease; CVA = cerebrovascular accident; LAD = left anterior descending artery; LV = left ventricular; PTCA = percutaneous transluminal coronary angioplasty; STEMI = ST elevation myocardial infarction; UA/NSTEMI = unstable angina/non-ST elevation myocardial infarction  80   VOLUME 10 ISSUE 2 . MARCH/APRIL 2010  ACHIEVING BEST PRACTICE been confirmed in several other studies. Elevated BNP levels, for example, were shown to be associated with more extensive inducible myocardial ischaemia, irrespective of LV function. 22  Furthermore, in patients with acute coronary syndromes, a raised BNP was associated with more LAD disease and with tighter   culprit stenosis, reflecting the extent   and severity of myocardial ischaemia. 23  BNP was also found to independently predict myocardial ischaemia   during dobutamine stress echocar-diography. 24  Similarly, Bergeron et al  . found BNP to correlate well with wall motion score index and exercise capacity in patients with suspected CAD and preserved LV function. 29  Similar data exist   for N-BNP, which was found by Weber et al. 25  to be an independent   predictor of CAD, with an area under the   ROC curve of 0.72. Weber et al.  also found that when N-BNP was added to exercise testing, this significantly improved the positive predictive value of the test. 25  Similarly, Kragelund et al. 20  found that, in stable   angina, N-BNP increased as the number of diseased   coronary arteries increased. Furthermore, the measurement of exercise-induced increases in N-BNP or BNP was found to improve the sensitivity of the exercise test for detecting myocardial ischaemia without compromising its specificity. 30 This association between CAD and BNP/N-BNP has been explained to some extent by Goetze et al. 26  They showed increased BNP gene expression and BNP release by cardiomyo-cytes in response to ischaemia per se. Studies of percutaneous coronary   intervention also support this idea, since BNP increases transiently   during balloon inflation (when ischaemia occurs), and later falls when the ischaemia   is resolved. 31,32  Furthermore, a recent study by McClure et al  . 33  in patients with stable angina demonstrated a reduction in N-BNP concentration when measured 8 weeks following percutaneous coronary revascularisation of LAD stenosis. Asymptomatic CAD and silent myocardial ischaemia The above studies refer to patients who are symptomatic and suspected of having CAD. However, BNP may also help to iden-tify CAD in asymptomatic patients. This is particularly impor-tant as patients with silent myocardial ischaemia have a 21-fold increased risk of a coronary event. 27  In addition, almost 50% of SCD still occurs in people with no documented previous history of overt cardiac disease. 28  However, in these cases where SCD is the first manifestation of cardiac disease, CAD is the com-monest autopsy finding. 34 Therefore, screening high-risk groups   with this simple blood test may be a logical approach, if it identified those with asymptomatic   CAD with reasonable accuracy. Diabetic patients are a clear example of such higher risk patients as they are known to have a   high incidence of silent coronary disease. We found BNP to perform well at identifying silent myocardial ischaemia in asymptomatic diabetics (p=0.002). 35  A BNP >20 pg/mL produced 87% sensitivity, 37% specificity, and a negative predictive accuracy of 90% at detecting silent CAD. Indeed, the area under the ROC curve in this study   was almost identical (0.76, p=0.001) 35  to that found by Weber et al.  in symptomatic angina patients. 25  Similar results were found in stroke survivors. 36  These two small studies provide early   evi-dence that BNP could be useful in identifying silent   myocardial ischaemia, in high-risk populations. The potential therapeutic implication of using BNP screening to detect their silent myocardial ischaemia is discussed below.Thus, the above evidence strongly suggests   that a pre-screening test with BNP may help in deciding whether a patient is likely to have myocardial ischaemia and CAD. In addition, the ability of BNP to identify myocardial ischaemia and CAD may explain its excellent prognostic value   in symptomatic and asymp-tomatic patients, irrespective of their LV systolic function. However, the cut-off level for BNP to identify myocardial ischae-mia has not yet been established. Whereas a level above 100 pg/mL is recommended for LV systolic dysfunction, a lower cut-off value in the range of 20–100 pg/mL may be appropriate for myocardial ischaemia. Therapeutic implications Identifying asymptomatic individuals with elevated levels of BNP raises a crucial question: what therapeutic measures could be offered to these individuals to reduce their CV risk? The first step in evaluating these patients should be directed towards exclud-ing other more established causes of raised BNP (namely LV sys-tolic dysfunction, LV hypertrophy, LV diastolic dysfunction, atrial fibrillation and renal failure). This step would involve a routine biochemistry test of renal function and an echocardiogram.Once the above causes have been excluded, then the ele-vated level of BNP may reflect underlying silent myocardial ischaemia. This may be confirmed using non-invasive tests, such as the exercise treadmill test or myocardial perfusion imaging. There are several possible therapeutic interventions, which could be offered to those asymptomatic patients with a positive non-invasive test for myocardial inducible ischaemia. However, it has to be stressed here that there is little evidence as yet to support any of these interventions in this setting.The first possible intervention is to use BNP to identify high-risk patients. This may be used as part of assessing patients in the CV risk outpatient clinic. Identifying these patients with an elevated BNP level may help doctors to aim for a more rigorous control of risk factors such as BP and cholesterol. This is particularly important as, in the real world, risk factor control has been found to be poor even in the secondary prevention setting. 37 Another possible intervention is to aim for lower than conventional targets for BP and cholesterol in these high-risk patients with elevated levels of BNP. This strategy is, to some extent, already in practice in some high-risk groups, such as systolic BP and cholesterol targets being lower in diabetic and post-myocardial infarction patients.Finally, a small proportion of the patients with elevated BNP and positive non-invasive tests of myocardial ischaemia may be considered for coronary angiography, with a view to either percutaneous or surgical revascularisation. This approach may be appropriate in the younger patient with fewer co-morbidities  THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE   81  ACHIEVING BEST PRACTICE and strongly positive non-invasive test, since this may reflect high-risk coronary anatomy (e.g. severe left main stem stenosis).The other attractive feature is that interventions could be targeted towards people who fail two screening tests (elevated BNP and proven end organ damage), both of which are prog-nostically important. This would be a good method of targeting those at high risk. Conclusion The use of BNP in the diagnosis and prognosis of heart failure patients is now well-established. However, recent evidence points towards a new and exciting role for BNP in identifying patients with myocardial ischaemia and CAD. Patients with symptomatic (and possibly asymptomatic) CAD appear to have elevated levels of BNP. This link between BNP and cardiac isch-aemia may explain, at least in part, why BNP is such a strong independent predictor of CV outcome in a variety of different population groups. More research is needed to further define this new role for BNP with particular emphasis on its clinical application and therapeutic implication. References  1. Daniels LB, Maisel AS. Natriuretic peptides.  J Am Coll Cardiol 2007; 50 :2357-68. 2. Espiner EA, Richards AM, Yandle TG, Nicholls MG. Natriuretic hormones. Endocrinol Metab Clin North Am  1995; 24 :481-509. 3. George J, Struthers AD. Natriuretic Peptides. 1st ed. Philadelphia: Mosby Elsevier, 2007;1222. 4. Nakao K, Ogawa Y, Suga S, Imura H. Molecular biology and biochem-istry of the natriuretic peptide system. II: Natriuretic peptide receptors.  J Hypertens 1992; 10 :1111-14. 5. Nakagawa O, Ogawa Y, Itoh H et al  . Rapid transcriptional activation and early mRNA turnover of brain natriuretic peptide in cardiocyte hypertrophy. Evidence for brain natriuretic peptide as an ‘emergency’ cardiac hormone against ventricular overload.  J Clin Invest 1995; 96 :1280-7. 6. Cowie MR, Jourdain P, Maisel A et al  . Clinical applications of B-type natriuretic peptide (BNP) testing. Eur Heart J   2003; 24 :1710-18. 7. National Institute for Health and Clinical Excellence. NICE Clinical Guideline 5. Chronic Heart Failure. July 2003. www.nice.org.uk (Accessed 1 st  August 2008). 8. Scottish Intercollegiate Guidelines Network. SIGN Guideline 95: Management of chronic heart failure. Feb 2007. www.sign.ac.uk (Accessed 1 st  August 2008). 9. 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 : 655-63.10. McKie PM, Rodeheffer RJ, Cataliotti A et al  . Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide: biomarkers for mortality in a large community-based cohort free of heart failure. Hypertension 2006; 47 :874-80.11. Witham MD, Gillespie ND, Hutcheon SD et al  . B-type natriuretic peptide is associated with mortality in older functionally impaired patients.  J Am Geriatr Soc 2005; 53 :1991-5.12. Kistorp C, Raymond I, Pedersen F et al  . N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults.  JAMA  2005; 293 :1609-16.13. Tarnow L, Hildebrandt P, Hansen BV et al  . Plasma N-terminal pro-brain natriuretic peptide as an independent predictor of mortality in diabetic nephropathy. Diabetologia  2005; 48 :149-55.14. 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James SK, Lindahl B, Siegbahn A et al  . N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coro-nary artery disease: a Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV substudy. Circulation 2003; 108 :275-81.19. Omland T, Sabatine MS, Jablonski KA et al  . Prognostic value of B-Type natriuretic peptides in patients with stable coronary artery disease: the PEACE Trial.  J Am Coll Cardiol   2007; 50 :205-14.20. Kragelund C, Gronning B, Kober L et al  . N-terminal pro-B-type natri-uretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med   2005; 352 :666-75.21. Davidson NC, Pringle SD, Pringle TH et al  . Right coronary artery stenosis is associated with impaired cardiac endocrine function during exercise. Eur Heart J   1997; 18 :1749-54.22. Bibbins-Domingo K, Ansari M, Schiller NB et al  . B-type natriuretic peptide and ischemia in patients with stable coronary disease: data from the Heart and Soul study. Circulation  2003; 108 :2987-92.23. Sadanandan S, Cannon CP, Chekuri K et al  . Association of elevated B-type natriuretic peptide levels with angiographic findings among patients with unstable angina and non-ST-segment elevation myocardial infarction.  J Am Coll Cardiol 2004; 44 :564-8.24. Asada J, Tsuji H, Iwasaka T et al  . Usefulness of plasma brain natriuretic peptide levels in predicting dobutamine-induced myocardial ischemia.  Am J Cardiol   2004; 93 :702-04.25. Weber M, Dill T, Arnold R et al  . N-terminal B-type natriuretic peptide predicts extent of coronary artery disease and ischemia in patients with stable angina pectoris.  Am Heart J 2004; 148 :612-20.26. Goetze JP, Christoffersen C, Perko M et al  . Increased cardiac BNP expression associated with myocardial ischemia. FASEB J 2003; 17 : 1105-07. Key messages ●  BNP is primarily derived from cardiac myocytes ●  The role of BNP in the diagnosis and follow-up of patients with heart failure is now well-established ●  Elevated levels of BNP are found in patients with CAD without heart failure ●  BNP may be raised in patients with silent myocardial ischaemia ●  Delineation of the diagnostic value of BNP in patients with symptomatic and asymptomatic CAD is required
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