QJM Advance Access originally published online on August 8, 2005
QJM 2005 98(10):765-769; doi:10.1093/qjmed/hci111
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Commentary |
B-type natriuretic peptide: a simple new test to identify coronary artery disease?
From the Division of Medicine & Therapeutics, Ninewells Hospital & Medical School, Dundee, UK
Address correspondence to Professor A.D. Struthers, Division of Medicine & Therapeutics, Ninewells Hospital & Medical School, Dundee DD1 9SY. email: a.d.struthers{at}dundee.ac.uk
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Summary |
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 Top Summary IntroductionDoes BNP identify coronary...Therapeutic implicationsBNP-guided therapyConclusionsReferences |
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A common key question in clinical medicine is whether coronary artery disease (CAD) is present in a patient. This applies not only to patients with symptomatic chest pain, but also to those at high risk of sudden unexpected death due to asymptomatic CAD, such as diabetics. In both groups of patients, it would be of great benefit if a simple blood test could identify those most likely to have CAD. Such individuals could then be selected for more definitive but more invasive tests for CAD, such as angiography, exercise testing, etc. In addition to its established role in diagnosing heart failure, it appears that BNP may fulfil this function of pre-screening for both symptomatic and asymptomatic CAD. We review the evidence for this new prospect, which has the potential to reduce cardiac deaths by using a simple blood test to better target cardioprotective strategies to those who most need them.
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Introduction |
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TopSummaryIntroductionDoes BNP identify coronary...Therapeutic implicationsBNP-guided therapyConclusionsReferences |
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B-type natriuretic peptide (BNP) now has an established role in identifying patients who have left ventricular dysfunction, especially left ventricular systolic dysfunction (LVSD). This use for BNP has been summarized recently by Cowie et al., and has been endorsed in the recent UK NICE guidelines on heart failure.1
However, BNP also has the potential to be useful in other patient populations who do not have heart failure or LVSD. Whereas a cut-off of 100 pg/ml is often used to identify LVSD, this new use for BNP is in a lower range of 20–100 pg/ml. In the Framingham study, for example, BNP levels above the 80% percentile for the population (i.e. >20 pg/ml) were independently associated by multivariate analysis with adjusted HRs of 1.62 for death, 1.76 for a major cardiovascular event and 1.99 for stroke or transient ischaemic attack (all p = 0.02).2 The same independent adverse prognostic role for BNP has been seen in at risk populations such as diabetics where the adjusted HR was 3.6 for cardiovascular events in one study3 and 2.28 for total mortality in another.4 Bhalla et al. corroborated these findings in diabetics.5 Similar findings were seen in patients with acute coronary syndromes, where BNP has repeatedly been shown to be the best prognostic marker, irrespective of LV function.6–9 The same is also true for patients with stable angina.10,11
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Does BNP identify coronary artery disease? |
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TopSummaryIntroductionDoes BNP identify coronary...Therapeutic implicationsBNP-guided therapyConclusionsReferences |
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The question that naturally arises is why BNP identifies a poor prognosis in so many populations, irrespective of LV function. One possible answer is that BNP identifies myocardial ischaemia itself. The first indication of this came in a 1997 coronary angiography study, where BNP was increased in left anterior descending coronary disease and circumflex disease, irrespective of LV end diastolic pressure (Tables 1 and 2).12 Indeed, BNP levels increased gradually as the number of diseased coronary arteries increased. Recently the reasons for this have become clearer. Firstly, myocardial ischaemia leads to increased cardiac expression of BNP, and secondly, when cardiomyocytes are made hypoxic, they degranulate and release BNP.13,14 Therefore, ischaemic tissue is primed with extra BNP, which is then released when further ischaemic episodes occur. Studies of percutaneous coronary angiography also support this idea, since BNP increases transiently during balloon inflation, and later falls when the ischaemia is resolved.15,16 This link between BNP and the extent of coronary disease has been confirmed in several recent studies. Bibbins-Domingo et al. found that patients in the highest quartile of BNP had twice as much inducible myocardial ischaemia as those in the lowest quartile, irrespective of LV function.17 Sadanandan et al. found that, in patients with acute coronary syndromes, an elevated BNP was associated with more LAD disease and with tighter culprit stenosis, implying that BNP is related to the extent and severity of myocardial ischaemia in such patients.18 Asada et al. found that BNP was independently predictive of ischaemia during dobutamine stress echocardiography.19 Similar data exist for N-terminal pro-BNP (NT pro-BNP), which was an independent predictor of coronary artery disease, with an area under the ROC curve of 0.72.20 Kragelund et al. also found that, in stable angina, N-terminal pro BNP increased as the number of diseased coronary arteries increased.11 Thus the evidence is now strong that in patients suspected of having coronary artery disease, a pre-screening test with BNP would be informative in deciding whether non-invasive tests for ischaemia will be positive and whether coronary angiography will be positive. It also seems likely that it is partly because BNP is identifying coronary artery disease that it is such a good prognostic marker even in patients without LV dysfunction.
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The above refers to a possible use of BNP in patients who are symptomatic and who are suspected of having coronary artery disease. However, if BNP helps to identify symptomatic coronary artery disease, it may also help to identify asymptomatic coronary artery disease. Since myocardial infarction and even cardiac death are sometimes the first manifestations of coronary artery disease, it could be very useful to screen certain populations with this simple blood test if it identified those with asymptomatic coronary artery disease with reasonable accuracy. Those identified could then be selected for further more definitive tests for ischaemia, e.g. exercise testing, or myocardial perfusion scans. A screening test such as BNP might be useful in several at-risk populations, for example diabetics, who are known to have a high incidence of silent coronary disease, or even in patients who have made a good recovery from a stroke or TIA. This latter group of patients is also well known to have a high incidence of asymptomatic coronary disease. Indeed, if a stroke patient survives the initial stroke, the most likely cause of death from 6 months onwards is a non-stroke cardiovascular death, i.e. a cardiac death.21 Yet the residual neurological deficit might make them unable to exercise enough to develop warning symptoms of angina or dyspnoea. There is as yet nothing published on the ability of BNP to identify silent cardiac ischaemia, but in as-yet unpublished work, we found that BNP performed well at identifying silent myocardial ischaemia in diabetics (p = 0.002).22 Indeed, the area under the ROC curve in our study was almost identical (0.76, p = 0.001) to that found by Weber et al. in symptomatic anginal patients.20 Although this is less than the area under the ROC curve for BNP identifying heart failure (0.88), it is still an impressive figure.23 In pilot work in stroke survivors, we have found basically the same, i.e. BNP identifies the presence and the extent of silent myocardial ischaemia in stroke survivors. Therefore, there is now early evidence that BNP is useful at identifying those with silent myocardial ischaemia, who could then be targeted for more definitive tests.
It used to be thought that the best indicator of ischaemia would be the exercise-induced increase in BNP rather than the baseline value. Davidson et al. investigated this possibility and found, somewhat surprisingly, that the baseline BNP was much better at identifying coronary disease than the exercise-induced increment in BNP,12 although this remains controversial.
A complicating issue is that other abnormalities increase BNP. These are: renal failure, LVSD, LV hypertrophy and even diastolic dysfunction. Therefore echocardiography is mandatory in a patient with a high BNP to assess these possibilities before considering if ischaemia is present. If any of these other abnormalities are present, the BNP level will be harder to interpret as a possible indicator of ischaemia.
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Therapeutic implications |
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TopSummaryIntroductionDoes BNP identify coronary...Therapeutic implicationsBNP-guided therapyConclusionsReferences |
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As mentioned, if an elevated BNP is found, then the patient should first undergo echocardiography and routine biochemistry testing in order to exclude renal failure, LVSD, LV hypertrophy or diastolic dysfunction, since these are alternative causes of an elevated BNP. If these are excluded, then an otherwise unexplained high BNP may indicate myocardial ischaemia.. In such patients, an exercise test or a myocardial perfusion scan might be indicated. If these latter tests were positive, what therapeutic interventions might follow?
There are three possible outcomes of using BNP to detect silent ischaemia. In a small group (especially the younger ones), who turned out to have extensive coronary disease, it might be considered appropriate to undertake coronary angiography followed where necessary by angioplasty or even revascularization. However, there is as yet little evidence to justify invasive intervention in asymptomatic patients. The second possible intervention follows from the observation in EUROASPIRE that risk factor control in the real world is very poor even in high-risk individuals needing secondary prevention.24 One way to spur doctors on to achieve better risk factor control is to identify those at highest risk even more explicitly. This was shown to work in practice by Hall et al.25 It seems likely that if BNP was known to identify silent ischaemia, then a high BNP level could act as a spur to the consulting doctor, so that those with silent ischaemia would then get better risk factor control than the EUROASPIRE average, which is known to be poor. The third possibility is that patients with an elevated BNP and silent ischaemia ought perhaps to be selected for lower target levels of BP, cholesterol etc than conventional target levels. This is already done to some extent, in that the target systolic BP for a diabetic patient is lower than that for an equivalent non-diabetic patient, because the former is at higher risk than the latter. This idea is also endorsed in general by the Heart Protection Study, where benefit was seen in high-risk individuals when their cholesterol was reduced from ‘normal’ to subnormal. A WHO/ISH report in 1999 also endorsed this idea in general.26 Therefore, there are several therapeutic options which might flow from knowing that a given patient had a high BNP and silent myocardial ischaemia. However, how best to respond to a high BNP in individual patients is a topic that would need extensive investigation in its own right in the future.
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BNP-guided therapy |
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TopSummaryIntroductionDoes BNP identify coronary...Therapeutic implicationsBNP-guided therapyConclusionsReferences |
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Another even more speculative possibility for the future is that BNP could be used as a way of guiding the intensity of anti-ischaemic therapy and/or the intensity of risk factor control. This radical idea is tentatively endorsed by at least two sets of data where changes in BNP were found to predict future cardiac events. In the Steno-2 study, a decrease in NT-pro BNP of 10 pg/ml in diabetics was associated with a highly significant (p < 0.001) reduction in future cardiovascular events.3 Secondly, in patients with stable angina, BNP spontaneously increased in those who subsequently had a recurrence of angina, while BNP fell in those with no recurrence (p < 0.0001).27 The idea which arises is that risk factor control and/or anti ischaemic therapy could be guided by BNP levels, i.e. such therapy ought perhaps to be intensified in each individual until their BNP level falls into an acceptable range.
The possibility of using ‘BNP guided therapy’ in this clinical situation is highly speculative, but it is given some credence by the fact that ‘BNP-guided therapy’ looks promising in the analogous but different disease of heart failure, where in initial studies it produced a 65% decrease in cardiovascular events.28
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Conclusions |
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TopSummaryIntroductionDoes BNP identify coronary...Therapeutic implicationsBNP-guided therapyConclusionsReferences |
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A whole new role for BNP may be on the horizon, in addition to its established role as an indicator of LV dysfunction. BNP levels may be able to identify coronary artery disease and possibly even its extent. This is best established for symptomatic patients with chest pain, but there are also early positive data for its potential use in detecting silent ischaemia. Much more work is required to see how accurate and clinically useful such a role might be for BNP, and to see whether such a strategy could ultimately reduce cardiac deaths in a cost-effective manner by better targeting of cardioprotective therapies.
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Acknowledgments |
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ADS has received research funding and consultancy fees in the past (expired October 2003) from Axis Shield, who manufacture BNP assay kits.
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References |
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TopSummaryIntroductionDoes BNP identify coronary...Therapeutic implicationsBNP-guided therapyConclusionsReferences |
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