EDITORIAL COMMENT
The Use of B-Type Natriuretic Peptides in Coronary Artery Disease
Utile or Futile?*
Christian Mueller, MD, FESC1,*
Department of Internal Medicine, University Hospital Basel, Basel, Switzerland.
* Reprint requests and correspondence: Dr. Christian Mueller, Department of Internal Medicine, University Hospital Basel, Switzerland, Petersgraben 4, Basel, 4031, Switzerland. (Email: chmueller{at}uhbs.ch).
B-type natriuretic peptides (BNP and N-terminal [NT]-proBNP) have been shown to be extremely helpful in the diagnosis, prognosis, and monitoring of therapy of patients with heart failure (HF) (1). These neurohormones are predominately secreted from the left and the right cardiac ventricle in response to cardiac stress. The BNPs can be seen as quantitative markers of HF summarizing the extent of systolic and diastolic left ventricular dysfunction, valvular dysfunction, and right ventricular dysfunction (1).
Inspired by the overwhelming success in HF, several recent studies have addressed the use of BNP in the diagnosis, prognosis, and management of patients with coronary artery disease (CAD) (2–13).
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Diagnosis of stable CAD
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In patients with stable CAD, BNPs are associated with the presence of myocardial ischemia, and angiographic disease severity (2–4). These findings have lead to the hypothesis that myocardial ischemia is a major trigger for the release of BNPs, and measurement of either baseline levels or exercise-induced increase of BNPs might be clinically helpful in the diagnosis of myocardial ischemia and CAD. Larger studies including consecutive patients with suspected myocardial ischemia referred for stress testing confirmed the association between BNPs and myocardial ischemia. However, the diagnostic accuracy of BNPs for the detection of myocardial ischemia (
65%) was only moderate. Still, the combination of exercise electrocardiogram (ECG) and BNPs seemed to slightly improve diagnostic accuracy when compared with exercise ECG alone (5–7). The availability of more accurate noninvasive tests like perfusion imaging and stress echocardiography might determine whether the diagnostic accuracy of BNPs in this indication is high enough to justify clinical use. Importantly, recent evidence suggested that selection bias and comorbidity significantly influence the accuracy of BNPs to diagnose stable CAD (8).
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Diagnosis of acute coronary syndrome (ACS)
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Cardiac troponins (T and I) are currently the gold standard for the diagnosis of myocardial infarction (MI). Unfortunately, cardiac troponin is undetectable by current assays in peripheral blood within the first 3 to 6 h after the onset of chest pain in MI ("troponin-blind" period). Preliminary data suggested that BNPs might be clinically helpful in the early diagnosis in patients with chest pain and no ST-segment elevation. In a large series of consecutive patients, the BNP median level at presentation was 204 pg/ml in MI, 78 pg/ml in unstable angina, and 28 pg/ml in patients without ACS (9). At presentation, BNP was >100 pg/ml in 70% of patients subsequently diagnosed with MI, while cardiac troponin was elevated in only 50% of these patients initially. The specificity of BNP for MI was 69%. Several ongoing studies will further elucidate the role of BNPs in conjunction with novel high sensitivity cardiac troponin assays and possibly other markers including myeloperoxidase for the early diagnosis of ACS.
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Prognosis of stable CAD and ACS
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Multiple large cohort studies have consistently shown that BNPs are powerful predictors of death in patients with stable CAD or ACS (10–12). Already 6 years ago, the TIMI (Thrombolysis In Myocardial Infarction) study group demonstrated that after adjustment for independent predictors of the long-term risk of death, patients in the 4th quartile of BNP had nearly 6 times the risk of death as compared with patients in the 1st quartile. A single measurement of BNPs provides powerful information for use in risk stratification across the spectrum of CAD. This finding suggests that cardiac neurohormonal activation may be a unifying feature among CAD patients at high risk for death. The data from the PEACE (Prevention of Events with Angiotensin Converting Enzyme Inhibition) trial published in this issue of the Journal extend this observation to low-risk stable CAD patients (12). The BNPs are also powerful predictors for the development of HF and for the presence of impaired left ventricular systolic function. The accuracy of BNPs to detect a left ventricular ejection fraction of below 30% was about 80% (11). In contrast, BNPs do not seem to predict future nonfatal MI (10–12).
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Management of CAD
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The key question still remains to be addressed. How should BNPs influence patient management? Is there a specific medication or intervention that should be initiated based on elevated levels of BNPs? Obviously, BNPs can only be used in conjunction with other clinical information to guide management in patients with suspected or proven CAD. Despite this caveat, many clinicians including this editorialist had hoped that B-type natriuretic peptides might help to target angiotensin-converting enzyme (ACE) inhibitors in CAD. As BNPs are closely associated with impaired left ventricular function and cardiac stress, those patients with elevated BNPs should derive particular benefit of ACE inhibitors. Unfortunately, neither the data from the PEACE trial nor the data from the HOPE (Heart Outcomes Prevention Evaluation) study (S. Blankenberg, personal communication, March 4, 2007) support this hypothesis. In both randomized controlled trials, no significant interaction between levels of BNPs and benefit from ACE inhibition was found.
High-risk patients with non–ST-segment elevation ACS seem to derive maximal benefit from an early revsacularization strategy (13,14). Could BNPs, therefore, be useful in the selection of initial ACS management? In the FRISC (Fragmin and fast Revascularization during InStability in Coronary artery disease) study, the mortality benefit from an early invasive strategy after non–ST-segment elevation ACS was slightly greater when BNPs were higher. However, no interaction between BNPs and the benefit of early revascularization was observed in the TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy) study.
As BNPs predict both left ventricular systolic dysfunction and the risk of sudden cardiac death, it is reasonable to assume that BNPs might be helpful to achieve a higher cost effectiveness in our patient selection for implantation of a defibrillator (15,16). Additional studies are necessary to verify this hypothesis.
In conclusion, BNPs are very attractive tools also in CAD. However, we still have to learn how to make the best clinical use of the information provided.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
1 Dr. Mueller was supported by research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, the Novartis Foundation, the Krokus Foundation, Abbott, Brahms, Biosite, Roche, and the University of Basel.
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References
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- Marumoto K, Hamada M, Hiwada K. Increased secretion of atrial and brain natriuretic peptides during acute myocardial ischaemia induced by dynamic exercise in patients with angina pectoris Clin Sci 1995;88:551-556.[ISI][Medline]
- Foote RS, Pearlman JD, Siegel AH, Yeo KTJ. Detection of exercise-induced ischemia by changes in B-type natriuretic peptides J Am Coll Cardiol 2004;44:1980-1987.[Abstract/Free Full Text]
- 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;148:612-620.[CrossRef][ISI][Medline]
- Sabatine MS, Morrow DA, de Lemos JA, et al. Acute changes in circulating natriuretic peptide levels in relation to myocardial ischemia J Am Coll Cardiol 2004;44:1988-1995.[Abstract/Free Full Text]
- Staub D, Jonas N, Zellweger M, et al. Use of N-terminal pro-B-type natriuretic peptide to detect myocardial ischemia Am J Med 2005;118:1287.e9-1287.e16.
- Staub D, Nusbaumer C, Zellweger MJ, et al. Use of B-type natriuretic peptide in the detection of myocardial ischemia Am Heart J 2006;151:1223-1230.[CrossRef][ISI][Medline]
- Conen D, Jander N, Trenk D, Neumann FJ, Mueller C. The use of B-type natriuretic peptides in the detection of myocardial ischemia in settings with rapid access to coronary angiography Int J Cardiol. 2006Oct 23;[Epub ahead of print].
- Bassan R, Potsch A, Maisel A, et al. B-type natriuretic peptide: a novel early blood marker of acute myocardial infarction in patients with chest pain and no ST-segment elevation Eur Heart J 2005;26:234-240.[Abstract/Free Full Text]
- 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;345:1014-1021.[Abstract/Free Full Text]
- Richards M, Nicholls MG, Espiner EA, et al. Comparison of B-type natriuretic peptides for assessment of cardiac function and prognosis in stable ischemic heart disease J Am Coll Cardiol 2006;47:52-60.[Abstract/Free Full Text]
- 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;50:205-214.[Abstract/Free Full Text]
- Jernberg T, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic peptide in relation to inflammation, myocardial necrosis, and the effect of an invasive strategy in unstable coronary artery disease J Am Coll Cardiol 2003;42:1909-1916.[Abstract/Free Full Text]
- 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 infarctionB-type natriuretic peptide and prognosis in TACTICS-TIMI 18. J Am Coll Cardiol 2003;41:1264-1272.[Abstract/Free Full Text]
- Berger R, Huelsmann M, Strecker K, et al. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure Circulation 2002;105:2392-2397.[Abstract/Free Full Text]
- Christ M, Sharkova Y, Bayrakcioglu S, Herzum I, Mueller C, Grimm W. B-type natriuretic peptide levels predict event-free survival in patients with implantable cardioverter defibrillators Eur J Heart Fail 2007;9:272-279.[CrossRef][ISI][Medline]
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Diagnosis of stable CAD
Diagnosis of acute coronary...