Broader indications for B-type natriuretic peptide testing in coronary artery disease

Ralph A.H. Stewart*

University of Auckland and Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92024, Auckland 1030, New Zealand

* Tel: +64 9 630 9903; fax: +64 9 623 6422. E-mail address: rstewart{at}adhb.govt.nz

This editorial refers to ‘B-type natriuretic peptide: a novel early blood marker of acute myocardial infarction in patients with chest pain and no ST-segment elevation’{dagger} by R. Bassan et al., on page 234 and ‘Analysis of N-terminal-pro-brain natriuretic peptide and C-reactive protein for risk stratification in stable and unstable coronary artery disease: results from the AtheroGene study’{ddagger} by R. Schnabel et al., on page 241

B-type natriuretic peptide (BNP) is synthesized by cardiac myocytes when left ventricular wall stress increases. After secretion the pro-hormone is cleaved to the biologically active hormone (BNP) and an inactive N-terminal fragment (N-BNP). There is now reliable evidence that measuring the blood level of either BNP or N-BNP improves the ability to diagnose or exclude heart failure as the cause of acute dyspnoea,1 and provides powerful information on mortality risk both in patients with heart failure and in patients admitted to hospital with an acute coronary syndrome.2 Two papers in this issue of the European Heart Journal suggest that indications for BNP testing could be broadened further to include early diagnosis of myocardial infarction in patients with acute chest pain,3 and to risk assessment of patients with stable coronary artery disease.4

Bassan et al.3 assessed the value of admission BNP for diagnosis of myocardial infarction in patients presenting with chest pain without ST-elevation on the electrocardiogram. The plasma level of BNP on admission was >100 pg/mL in ~70% of patients subsequently diagnosed with myocardial infarction, while blood levels of creatinine kinase-MB (CK-MB) or troponin I were elevated in only ~50% of these patients on admission. The study did not include evaluation of myoglobin, an alternative early marker of myocyte necrosis. The specificity of BNP for infarction (~70%) was substantially lower than that of CK-MB and troponin I (~98%), which is consistent with the knowledge that BNP is released in other conditions which increase ‘myocardial stress’.

Modest sensitivity and specificity is a limitation of measuring BNP for early diagnosis of myocardial infarction, but BNP testing on admission has other advantages. First, a low level of BNP, CK-MB, and troponin on admission predicts a low risk of myocardial infarction: 2–3% in the study by Bassan et al.,3 although this rate will be influenced by the population in which the tests are applied. Secondly, a raised plasma level of BNP increases the likelihood of a cardiac cause of symptoms even if myocardial infarction is not confirmed. In the study by Bassan et al.,3 median BNP for patients with unstable angina was ~78 pg/mL compared with ~28 pg/mL for patients with no evidence of myocardial ischaemia. Thirdly, the plasma level of BNP is a powerful independent predictor of the risk of heart failure and cardiovascular death. Measurement of BNP on admission for chest pain could therefore help to determine whether myocardial infarction, unstable angina, or a non-cardiac cause of chest pain is more or less likely as well as to identify patients with a low or higher cardiovascular mortality risk. This information could improve outcome and reduce costs by more rapidly targeting investigations and treatments following admission. In a randomized clinical trial of BNP testing compared with usual care in patients presenting with acute dyspnoea, measuring BNP reduced time to appropriate treatment and decreased hospital costs.5 Similar studies in patients presenting with acute chest pain are now needed.

The mechanisms for the increase in BNP after myocardial infarction have not been precisely defined. BNP is secreted immediately after synthesis by ventricular myocytes, which have limited storage capacity. This suggests that only a small amount of BNP would be released on cell death. However, BNP mRNA synthesis increases rapidly in response to either myocyte stretch or ischaemia. BNP may therefore be secreted by cardiomyocytes during the prolonged ischaemia which precedes cell death, and by ischaemic myocytes which do not die. In a rat model of myocardial infarction, staining with anti-BNP antiserum was most intense in surviving myocytes in and around necrotic tissue in the infarct region.6 Goetze et al.7 demonstrated increased BNP mRNA in biopsies of hypoxic ventricular myocardium taken at the time of coronary artery bypass surgery. Plasma levels of BNP are elevated in patients with inducible ischaemia on exercise stress echocardiography, even when left ventricular ejection fraction is normal and there is no evidence of heart failure.8 BNP also increases after transient ischaemia induced by coronary angioplasty despite no increase in left ventricular filling pressure.9 Therefore, while plasma levels of BNP may increase after myocardial infarction in response to greater left ventricular wall ‘stress’, ischaemia may be an additional direct stimulus for BNP synthesis.

Would repeat testing of BNP provide additional information? On average, plasma BNP levels increase several-fold during the first 24 h after myocardial infarction before decreasing over several days then gradually over weeks and months.10 A recent analysis from the PRISM study suggests that change in the plasma levels of N-BNP during the 72 hours after admission for an acute coronary syndrome is prognostically important.11 In patients with a high baseline N-BNP (>250 ng/L) who were clinically stable without refractory ischaemia after admission, plasma levels of N-BNP decreased significantly by 48 and 72 hours. These patients had a lower 30 day event rate than patients with persistently elevated N-BNP levels, and patients whose plasma N-BNP increased during the first 72 hours.

In a second study published in this edition of the European Heart Journal, Schnabel et al.4 report the prognostic value of N-BNP and C-reactive protein in patients referred for diagnostic coronary angiography in the ‘Atherogene study’. Raised plasma levels of N-BNP were associated with increased cardiovascular mortality in patients with both unstable and stable coronary artery disease. For subjects with stable coronary artery disease, the increased risk was most clear when N-BNP was in the highest quartile. Surprisingly, C-reactive protein added little to the prognostic value of N-BNP in this group of patients. These results suggest that the prognostic value of N-BNP can be extended from patients admitted with an acute coronary syndrome to those with stable coronary artery disease.

These studies raise several questions relevant to the more widespread use of BNP testing. Bassan et al.3 suggest a threshold for admission BNP of >100 pg/mL for diagnosing acute myocardial infarction. However, the probability of a cardiac cause for symptoms increases progressively with the BNP level. An alternative approach is to define BNP levels which predict a low, modest, high, and very high probability of a cardiac cause for symptoms. This would have the additional advantage of being consistent with the use of BNP to estimate cardiovascular risk. Interestingly, general population data from the Framingham study12 demonstrate a progressive increase in the long-term risk of cardiovascular death, heart failure, stroke, and atrial fibrillation with increase in BNP even within the normal range.

The most important question is how should the plasma level of BNP influence patient management? Limited evidence from heart failure populations supports the concept that patients with higher BNP levels benefit most from intensive treatment. In the ANZ-Carvedilol trial,13 the benefits of beta-blockade were greater when the plasma level of N-BNP was above the median for the study population. In a small randomized trial of BNP guided treatment for heart failure, targeting more intensive treatment to patients with high BNP levels improved outcomes.14 In the FRISC study, the mortality benefit from an early invasive strategy after non-ST-elevation myocardial infarction appeared greater when N-BNP was higher, but the statistical power of the study was not sufficient to draw a definite conclusion.15 BNP predicts sudden death in patients with coronary artery disease,16 but outcomes from implantable defibrillator trials have not been reported by BNP level. Given important gaps in the evidence needed to guide patient management, future clinical trials of a broad range of interventions for coronary artery disease should include evaluation of treatment outcomes by plasma level of BNP.

Footnotes

{dagger} doi:10.1093/eurheartj/ehi033 Back

{ddagger} doi:10.1093/eurheartj/ehi036 Back

References

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Related articles in EHJ:

B-type natriuretic peptide: a novel early blood marker of acute myocardial infarction in patients with chest pain and no ST-segment elevation
Roberto Bassan, Alfredo Potsch, Alan Maisel, Bernardo Tura, Humberto Villacorta, Mônica Viegas Nogueira, Augusta Campos, Roberto Gamarski, Antonio Cláudio Masetto, and Marco Aurélio Moutinho
EHJ 2005 26: 234-240. [Abstract] [Full Text]  

Analysis of N-terminal-pro-brain natriuretic peptide and C-reactive protein for risk stratification in stable and unstable coronary artery disease: results from the AtheroGene study
Renate Schnabel, Hans J. Rupprecht, Karl J. Lackner, Edith Lubos, Christoph Bickel, Jürgen Meyer, Thomas Münzel, François Cambien, Laurence Tiret, Stefan Blankenberg, and for the AtheroGene Investigators
EHJ 2005 26: 241-249. [Abstract] [Full Text]  




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