Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
* Corresponding author. Tel: +45 3545 5509; fax: +45 3545 4640. E-mail address: jpg{at}dadlnet.dk
This editorial refers to Plasma N-terminal pro-brain natriuretic peptide concentration predicts coronary events in men at work: a report from the BELSTRESS study
by J. De Sutter et al., on page 2644
An experienced cardiologist recently reminded me that most heart failure patients have a medical history of arteriosclerosis and coronary artery disease (CAD) (Figure 1). With or without myocardial infarction, the ventricular myocardium becomes hypoxic during increased workload, which, in turn, strangulates cardiac performance and initiates pathological remodelling of the myocardium. In the course of reduced left ventricular systolic function, the endocrine heart compensates with increased production and secretion of natriuretic hormones, that is, the cardiac natriuretic peptides. In fact, the association between cardiac disease and increased concentrations of natriuretic peptides was reported more than 20 years ago.1 Since then, numerous clinical studies have established that the plasma concentrations of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) reflect left ventricular systolic function and accordingly are helpful markers in heart failure diagnostics. However, the most feasible clinical application today seems to be as rule-out markers, which means that low plasma concentrations efficiently can exclude left ventricular systolic dysfunction.2 In contrast, the relatively low diagnostic specificity in heart failure diagnosis suggests that also other pathophysiological stimuli besides left ventricular systolic dysfunction can trigger increased production and secretion of natriuretic peptides from the cardiac myocytes.
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Some speculation on what increased concentrations of cardiac natriuretic peptides actually reflect in a biological context seems appropriate. Although it is sometimes stated that the endocrine heart responds to cardiac strain, this is not a clear and well-defined pathophysiological mechanism. Cardiac strain neither has a uniform treatment strategy. Rather, the likely pathophysiological stimuli should be narrowed down to preferably measurable entities. For instance, some experimental data suggest that the BNP gene expression, in fact, is stimulated directly by myocardial hypoxia, which could well explain most of the new clinical results. In simple terms, that would mean that plasma concentrations of cardiac natriuretic peptides reflect the ischaemic burden, which in itself is predictive of later clinical outcome. We recently established that the myocardial BNP gene expression can be stimulated both in vivo and in vitro by reduced oxygen delivery.7 Others have shown that the related ANP gene promoter is directly activated by the hypoxia inducible transcription factor HIF 1, which is activated by low oxygen tension.8 In addition to myocardial hypoxia, another feasible mechanism may relate to the inflammatory process underlying arteriosclerosis. According to this suggestion, the inflammatory reaction in the coronary vasculature may stimulate local BNP gene expression by cytokines or other substances. De Bold and co-workers9 recently reported that cardiac myocytes in vitro respond to several pro-inflammatory cytokines by increased BNP gene expression. Whether such processes are also relevant in human CAD is by no means yet established, but this could potentially be worth exploring as the cardiac natriuretic peptides may be markers of diffuse coronary arteriosclerosis without significant luminal occlusion. Whether increased cardiac BNP secretion reflects myocardial hypoxia, vascular inflammation, or both, it has been reported that the increase in plasma concentrations is associated with the number of affected coronary arteries.10
Finally, it is reasonable to recapitulate that most of the earlier clinical studies on heart failure patients may be strongly related to CAD. In particular, the reports on so-called asymptomatic heart failure (an unfortunate term) often included patients with CAD, and the results are thus not necessarily that different from the new data. Heart failure patients have not been clearly divided into groups with or without CAD, which may be due to the fact that the prevailing focus has been on haemodynamic alterations and myocyte stretch as the principal BNP stimulus. However, if one applies the new paradigm of cardiac natriuretic peptides in CAD, it is sometimes almost impossible to differentiate between increased plasma concentrations elicited by either CAD (cause) or heart failure (consequence). In everyday life, this should probably remind us that increased plasma concentrations of cardiac natriuretic peptides should not only be pursued with echocardiography. Rather, it seems plausible that coronary angiography or some other test for ischaemic heart disease is in order. In most subjects without obvious cardiac disease signs and symptoms, these examinations may even be undertaken in the reverse order, as CAD precedes left ventricular systolic dysfunction.
After 20 years of clinical research on the diagnostic performance of cardiac natriuretic peptides in heart failure diagnostics, we are still somewhat restricted by the troublesome low specificity. The appreciation of increased concentrations in persons and patients with stable ischaemic heart disease may bring the future for clinical BNP measurement forward. If the plasma concentration is elevated but echocardiography does not reveal left ventricular systolic dysfunction, it should not be disregarded as a mistake or perhaps raise suspicion of some less defined cardiac disorder such as diastolic dysfunction. Rather, it seems more likely that it may reflect the most common cardiac disease of them all. Surely, many experienced cardiologists already would have guessed this without ever having worked with cardiac natriuretic peptides. In addition, the new era for the cardiac natriuretic peptides could somewhat ironically evolve from markers of heart failure to markers that may be useful in avoiding heart failure.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
References
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