European Heart Journal Advance Access originally published online on June 14, 2007
European Heart Journal 2007 28(14):1678-1682; doi:10.1093/eurheartj/ehm234
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The potential to improve primary prevention in the future by using BNP/N-BNP as an indicator of silent ‘pancardiac’ target organ damage
BNP/N-BNP could become for the heart what microalbuminuria is for the kidney
Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
Received 8 March 2007; revised 4 May 2007; accepted 10 May 2007; online publish-ahead-of-print 14 June 2007.
* Corresponding author. Tel: +44 1382 632180; fax: +44 1382 644972. E-mail address: a.d.struthers{at}dundee.ac.uk
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Abstract |
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Abstract
IntroductionBrain natriuretic peptide (BNP) or N-terminal pro-BNP (N-BNP) now appears to be the best independent predictor of cardiovascular mortality over and above the conventional ones like blood pressure. This may be because a high BNP/N-BNP is identifying any form of asymptomatic cardiac target organ damage (TOD) [especially silent ischaemia, left ventricular hypertrophy (LVH), left atrial dilatation/atrial fibrillation (LAD/AF) and LV systolic dysfunction (LVSD)]. There are strong hints that BNP/N-BNP will also identify those who are going to develop LVH, LAD/AF, and LVSD in a few years' time. Thus, the prospects are good that BNP/N-BNP could be used to identify ‘pancardiac’ TOD, even when it is silent and that this information could be ‘harnessed’ to improve primary prevention. BNP/N-BNP could become to the heart what microalbuminuria is to the kidneys, i.e. an indicator of early, silent TOD.
Key Words: Hypertension • Hypertrophy • Coronary circulation • Echocardiography • Other diagnostic testing • Heart failure • Congestive
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Introduction |
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Cardiovascular (CV) deaths are still the commonest cause of death. A particular problem is that 40–50% of sudden cardiac deaths (SCDs) still occur in those with no apparent previous history of overt heart disease.1,2 Another problem is that even if all known risk factors could be controlled perfectly, CV events would only partially be prevented.3,4 These two problems highlight that new approaches to primary prevention are required.
It seems likely that many of those apparently healthy individuals who suffer acute cardiac events (CEs) or even SCD actually have silent CV target organ damage (TOD), e.g. silent ischaemia. In fact, we know this is the case because those with silent myocardial ischaemia have a 21-fold increased risk of a coronary event.5 Furthermore, coronary artery disease (CAD) is the commonest autopsy finding in cases of SCD.6 Therefore, a promising option should be if we could devise a simple means of detecting when silent myocardial ischaemia is already present. Plasma levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (N-BNP) may be a new way to detect silent myocardial ischaemia (discussed subsequently). Natriuretic peptide activity can best be measured by either BNP itself or by measuring N-BNP. There are theoretical benefits to N-BNP over BNP such as its better in vitro stability and its higher value which should in theory make it more sensitive. In practice, however, they currently appear to perform equally well.7
CAD is not the only form of silent cardiac disease that worsens prognosis. There is a triad of left atrial (LA) and left ventricular (LV) abnormalities that are relevant here. The first part of this triad is LV hypertrophy (LVH). It is well known that echo LVH confers a poor prognosis and that this is independent of other risk factors including blood pressure (BP).8 The risk ratio is commonly around 2.5. Indeed, after age, LVH is claimed to be the single strongest predictor of CV events, CV deaths, and total deaths.9 Furthermore, regressing LVH confers a prognostic advantage, independent of BP changes.10 The second part of the triad is LA dilatation (LAD) which often produces atrial fibrillation (AF). LAD and AF are both independently predictive of future CV events with adjusted hazard ratios between 1.8 and 3.4 for different CV sequelae.11,12 The third part of the triad is LV dysfunction (LVD). The independent hazard ratio is 2.2 for LV systolic dysfunction (LVSD) with a similar figure for LV diastolic dysfunction (LVDD). Tsang et al.13 have shown clearly that echocardiography for this triad of abnormalities markedly improves the prediction of CV events in a population over and above BP, cholesterol, etc. However, echo for all would be difficult and it would be better if there is a simple screening method to identify those who need an echo because they have a high prevalence of this triad. As it happens, plasma levels of BNP or N-BNP may do this also (discussed subsequently).
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The role of brain natriuretic peptide/N-terminal pro-brain natriuretic peptide in identifying coronary artery disease |
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It now transpires that BNP is not just an indicator of raised intracardiac pressure. It appears that ischaemic or injured myocardial tissue releases extra BNP irrespective of haemodynamic factors. This was first seen in 1997 when BNP was found to be more closely related to the presence of CAD than it was to intracardiac pressure.14 Goetze et al.15 went on to show that in vitro ischaemic tissue expresses increased BNP. Thus, when myocardial tissue is injured by ischaemia, extra BNP is made and released, irrespective of haemodynamic considerations.16 This is why myocardial ischaemia per se can be identified by increased BNP/N-BNP levels. Many clinical studies have now shown this for symptomatic individuals.17–20 We have also recently found the same for asymptomatic individuals, although the current data for this come from one small study in diabetics and another even smaller study in stroke survivors.21,22 In the former study, a BNP > 20 pg/mL produced 87% sensitivity, 37% specificity, and a negative predictive accuracy of 90% at detecting silent CAD. The clinical situation in which identifying silent CAD would be particularly useful are primary prevention patients attending a hospital CV risk clinic. It is in this group that using BNP to achieve better risk stratification and therefore better targeting of therapies might well prevent CEs and possibly even prevent the scenario where SCD is the first ever manifestation of their TOD.23
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Brain natriuretic peptide/N-terminal pro-brain natriuretic peptide also identifies left atrial/ventricular abnormalities |
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Aside from BNP's ability to identify CAD, a more traditional role for BNP/N-BNP is to identify patients with raised intracardiac pressure, e.g. LVSD.14 However, BNP/N-BNP is well known to also identify patients with either LVH or LA dilatation.24–27
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Brain natriuretic peptide/N-terminal pro-brain natriuretic peptide and pancardiac target organ damage |
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It appears therefore that BNP/N-BNP may be able to identify all of the main forms of cardiac TOD, even when they are asymptomatic. This applies to CAD, LVD, LVH, and LAD/AF. BNP/N-BNP could therefore become an indicator of ‘pancardiac TOD’ including when the TOD is silent. In the well-known ‘CV continuum’ of Braunwald and Dzau, it is easy to see how BNP/N-BNP could fit in as a way of recognizing when longstanding risk factors have produced any form of cardiac TOD in an individual and even how BNP/N-BNP increases progressively as the patient goes from silent TOD to symptomatic TOD to frank heart failure (Figure 1). In a sense, BNP/N-BNP could be to the heart what microalbuminuria is to the kidneys, since both identify silent early TOD, which then enables protective therapies to be begun earlier. Figure 2 illustrates schematically how BNP/N-BNP could contribute to better overall risk stratification by identifying silent pancardiac TOD and how this could complement current research looking for novel longstanding risk factors.
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Brain natriuretic peptide/N-terminal pro-brain natriuretic peptide independently predicts total risk |
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If BNP/N-BNP was indeed picking up pancardiac TOD, then it would be expected that BNP/N-BNP would strongly predict actual prognosis, over and above the traditional risk factors of BP, cholesterol, etc. In fact, there is an overwhelming body of evidence that this is indeed the case. This has been seen consistently in all populations including normal populations such as Framingham, Olmstead County, and Finland, elderly populations with no apparent disease, anginal patients, diabetic patients, and heart failure patients.26–39 Typical adjusted odds ratios for first CV event are 3.2, 2.7, and 1.8 in normal populations and 3.6 in diabetic populations.25,28,32,33 In addition, N-BNP outperforms other proposed novel risk markers such as C-reactive protein.32,39 The Framingham and Olmstead County population studies also go on to show that natriuretic peptides predict prognosis over and above a wide range of echo abnormalities including LV ejection fraction, LVH, and LA diameter, although, as would be expected, each of these echo abnormalities explained part of the BNP/N-BNP risk.26,28 The unexplained extra part of the BNP/N-BNP risk not accounted for by an echo may be due to two other properties of BNP/N-BNP: first, its ability to detect silent CAD and secondly, its ability to predict future but not yet apparent echo abnormalities (discussed subsequently). It has also been noted that BNP is the best independent predictor of post-operative CEs in patients undergoing non-cardiac surgery (odds ratio 34.5).40 This indirectly supports the hypothesis that BNP/N-BNP may be detecting risk by identifying silent pancardiac TOD.
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What would the therapeutic response be to a high brain natriuretic peptide/N-terminal pro-brain natriuretic peptide indicating high risk? |
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It would only be worthwhile identifying pancardiac TOD if this led to effective interventions. In fact, the identification of pancardiac TOD could lead to two responses. First, it could lead to more use of antihypertensives and statins since BNP/N-BNP should change the patient into a secondary prevention patient if it truly indicated TOD. However, each of these different types of cardiac TOD (CAD, LVH, LAD/AF, and LVD) deserves a specific form of treatment. Therefore, the correct response to a high BNP/N-BNP could be to identify in each individual which types of cardiac TOD exist in that individual in order that treatment could be targeted to the precise form of TOD seen in that individual (as well as more intensively treating their BP, cholesterol, etc.). These ‘specific’ treatments for CAD, LVH, LAD/AF and LVD are described briefly in Table 1. However, it is important to consider the future as well as the present. This is because it is inconceivable that the treatments for CAD, LVH, LAD/AF, and LVD will remain static over time and yet the use of BNP/N-BNP to detect silent TOD should be relevant for a long time. It is important to realize that targeting therapies here could in theory be very precise since the targeted group could be those who not only have a high BNP/N-BNP but also have TOD on investigation, i.e. the targeted group would have failed two screening tests for high risk.
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It is worth noting that we have not discussed the ability of BNP/N-BNP to detect asymptomatic LVDD. Although it is likely to be able to detect this also, the detection of silent LVDD is not currently a priority because diagnostic criteria for silent LVDD are not fully established, nor is any treatment for silent LVDD.
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Can brain natriuretic peptide/N-terminal pro-brain natriuretic peptide predict future target organ damage also? |
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A standard well-accepted mantra is that ‘Prevention is better than cure’. This is particularly desirable when death can be the first ever manifestation of the disease. This concept of prevention has not hitherto really been applied to LVH or to LAD/AF. Two facts mean that we should now focus on the prevention of LVH and LAD/AF rather than just their cure. First, the patient could well suffer a CV event or death while they had the abnormality of LVH or LAD/AF even if future therapy could then ‘cure’ them. Secondly, reversal or cure of LVH or LAD/AF is not always possible anyway. The success rate of cardioversion for AF is low in that only 30% remain in sinus rhythm after 1 year.41 Indeed, Boriani et al.42 recently said that ‘Europe is facing an epidemic of AF’ and that ‘identification of effective strategies for preventing AF could turn out to be a wise investment for our health care systems’. BNP could well help prevent AF. Similarly, with LVH, a sizeable proportion of hypertensives (20%) do not fully regress their LVH even once they receive an ACE-inhibitor and their BP is at target.43
The first step in preventing a disease requires us to identify those at high risk in order to target preventative therapies and BNP looks like it may predict future LVH or LAD/AF also. With regard first to LAD/AF, BNP was an independent predictor of future death, future AF, and future heart failure in Framingham with risk ratios of 2.7, 4.9, and 7.4 between the lowest and highest tercile of BNP.28 Future AF was also well predicted by natriuretic peptides in a Finnish study.29 However, one of the most interesting aspects of this Framingham study is that echocardiography was also performed and BNP was still predictive of future AF, heart failure, and stroke, independent of the echo variables of LV mass, LA diameter, and LVSD. Recent data also confirm that N-BNP predicts adverse CV events over and above all echo parameters.44 The observation that BNP predicts future AF and future heart failure over and above echo parameters means that BNP may be more sensitive at identifying future LA/LV abnormalities than echo abnormalities at baseline. This is perhaps unsurprising because BNP can vary from 10 to > 10 000 pg/mL, whereas all echo variables change over a relatively small range. The hypothesis that all these intriguing data raise is that the driver for LVH, LAD/AF, and LVD is raised intracardiac pressure, and an early subtle elevation in intracardiac pressure can be picked up by BNP before the LVH, LAD/AF, or LVD is either present or obvious on an echo.
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Levels of brain natriuretic peptide/N-terminal pro-brain natriuretic peptide |
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It should be emphasized that the cutoff levels for BNP or N-BNP to identify pancardiac TOD are not yet established by any means. Furthermore, the proposed cutoff values will probably be different for LVSD as opposed to the other abnormalities. For example, a BNP level of > 100 pg/mL is recommended for LVSD, whereas it is likely to be much lower to identify ischaemia, LAD, or LVH. Age and renal function corrected values for BNP/N-BNP may be necessary ultimately which will require much more research in the future to validate any precise cutoff values that are proposed.27 On the other hand, age and renal dysfunction might elevate BNP/N-BNP levels because they are associated with more pancardiac TOD. Other factors such as obesity and gender may also impact on cutoff values in subgroups of patients, but little is known for now about that.
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The wider picture |
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There are, of course, other new risk biomarkers being proposed such as C-reactive protein or fibrinogen. However, the latter are new (longstanding) risk factors reflecting inflammation or thrombogenicity and their likely position in risk stratification will be for them to sit aside other longstanding risk factors such as BP and cholesterol. In contrast BNP/N-BNP is unique in that it is instead identifying the end process of TOD itself, however produced, by both known and unknown longstanding risk factors. This means that BNP/N-BNP should complement the need to identify all longstanding risk factors by giving risk stratification the extra and different dimension of identifying when silent TOD is already present. This ‘extra dimension’ would represent a bit of a paradigm shift from current research into risk stratification which focuses more on finding new (longstanding) risk factors such as C-reactive protein, etc. This is why measuring BNP/N-BNP and C-reactive protein, etc., should be seen as complementary rather than competing new approaches to improving primary prevention.
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Conclusions |
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CEs and SCDs are too often the first manifestation of cardiac TOD which has hitherto been silent. BNP/N-BNP could therefore become a useful way to identify silent yet potentially lethal pancardiac TOD which is either already present or about to develop in the next few years. This could help move BNP/N-BNP from using it for better risk prediction to using it for better risk reduction. Clearly, further large-scale studies will be required before the hypothesis described here could be fully accepted.
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Acknowledgments |
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Conflict of interest: A.D.S. was, until 3 years ago, a consultant for Axis Shield who make BNP kits.
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Footnotes |
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The opinions expressed in this article are necessarily not those of the Editors of European Heart Journal or of the European Society of Cardiology.
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