European Heart Journal Advance Access originally published online on June 19, 2006
European Heart Journal 2006 27(14):1648-1650; doi:10.1093/eurheartj/ehl109
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Atrial secretion of B-type natriuretic peptide
1 Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
2 Department of Cardiology, Rigshospitalet, University of Copenhagen Denmark
Received 29 May 2006; accepted 1 June 2006; online publish-ahead-of-print 19 June 2006.
* Corresponding author. Tel: +45 3545 5509; fax: +45 3545 4640. E-mail address: jpg{at}dadlnet.dk
Abstract
In the normal heart, the endocrine capacity resides in the atria. Atrial myocytes express and secrete natriuretic hormones that regulate fluid homeostasis and blood pressure. But in ventricular disease, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression is also activated in ventricular myocytes. Plasma concentrations of natriuretic peptides and their biosynthetic precursors are accordingly increased in patients with marked ventricular dysfunction. In contrast, atrial peptide secretion in ventricular disease has received less attention, and our present understanding of the endocrine atria during ventricular dysfunction is still scarce. Although ventricular disease and increased circulating concentrations are associated, it does not entail that the ventricle is the sole or even the main source in all types of heart disease. Clearly, the endocrine atria are also active in heart failure. Plasma measurement of cardiac natriuretic peptides and their molecular precursors can perhaps help us to discriminate when, where and how.
Key Words: Atrial fibrillation • ANP • BNP • Heart failure • proANP • proBNP
In the normal heart, the endocrine capacity resides in the atria. Atrial myocytes express and secrete natriuretic hormones that regulate fluid homeostasis and blood pressure. Both atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) can be secreted in response to atrial distension. But in ventricular disease, the gene expression of ANP and BNP is also activated in the ventricular myocytes.1 Plasma concentrations of ANP, BNP, and their biosynthetic precursors are accordingly increased in patients with marked ventricular dysfunction, and particularly so in left ventricular heart failure.2,3 In contrast, secretion of the cardiac peptides from the atria in ventricular disease has received less attention, and our understanding of the endocrine atria during ventricular dysfunction is still scarce. Perhaps, due to this lack of information, it is often presumed that increased plasma concentrations of natriuretic peptides in ventricular disease in principal reflect a ventricular production and secretion. Clearly, ventricular disease and increased plasma concentrations are associated, but it does not necessarily entail that the ventricle is the sole or even the main source in all types of heart disease. Notably, clinical trials are usually not designed to address this question.
Atrial BNP secretion reflects the fact that normal atrial myocytes express both the ANP and the BNP genes.4 In this context, it should be stressed that the BNP precursor, i.e. proBNP, also is stored in atrial granules (Figure 1). Nevertheless, some reports only distinguish between ‘atrial ANP’ and ‘ventricular BNP’, which may be easy to remember. It fits neatly with a haemodynamic concept of ANP secretion in response to increased pre-load and BNP secretion in response to increased afterload.5 However, this may not be the case always. ANP and BNP regulate the same physiological effects through the same receptor, and the distinction between the two hormones is sometimes only a matter of biochemistry. The cardiac natriuretic peptides are often secreted simultaneously (but not necessarily on an equimolar basis). Moreover, cardiac ANP and BNP gene expression is almost always regulated synchronously in disease, which means that increased plasma concentrations of one peptide is followed by increased concentrations of the other. Only inflammatory cytokine-induced BNP, but not ANP, gene expression has so far revealed a clear distinction in the regulation of cardiac ANP and BNP gene expression.6 These in vitro findings in cultured cardiocytes may thus help explain some recent clinical findings of increased proBNP, but not proANP, concentrations in plasma from patients with lone atrial fibrillation.7
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400 mg) from the left atrial appendage were obtained from a patient with severely reduced left ventricular systolic function undergoing cardiac surgery. Paraformaldehyde-fixed tissue sections (7 µm) were prepared and incubated with rabbit proBNP antiserum (1:100), raised against the N-terminal decapeptide of human proBNP, or preimmune rabbit antiserum (control). Bound antibodies were visualized with swine antirabbit antiserum conjugated with fluorescein isothiocyanate (Dako, Denmark) and a confocal laser scanning microscope (Zeiss LSM510, Switzerland). The fluorescent image shows proBNP staining in the atrial myocytes extending along the contractile apparatus, and the adjacent grey panel shows the underlying anatomy of the tissue sample (Normarski).Because atrial fibrillation is the most common atrial disease in clinical practice affecting about 5% of persons >65 years, this condition deserves mentioning. The pathophysiology underlying atrial fibrillation is complex and its development involves at least two different mechanisms. First, a triggering mechanism with enhanced automaticity in one or several rapidly firing foci in the atria or pulmonary veins is essential. Secondly, the presence of multiple re-entrant circuits in the atria depending on both electrophysiological and anatomical substrates seems to be important. The electrophysiological substrate refers to the development of electrical inhomogeneity due to reduced duration of the refractory period and increased conduction velocity, whereas the anatomical substrate refers to changes in atrial tissue architecture due to dilatation and fibrosis. In combination, the functional and structural alterations act in concert to facilitate both initiation and perpetuation of atrial fibrillation. Interestingly, inflammation has also been associated with atrial fibrillation.8 For instance, atrial biopsies from patients with atrial fibrillation have disclosed inflammatory alterations.9,10 Although it remains to be established whether atrial fibrillation activates a local inflammatory response or whether a pre-existing inflammatory state promotes atrial fibrillation, these contributors may interrelate in such a way that inflammation is not only a response to the arrhythmic process but also an integral part of the process. Rapid atrial activation is also known to cause calcium overload in atrial myocytes and initiation of atrial apoptosis. Such tissue injury may further initiate a low-grade local inflammatory state and be part of the structural remodelling process causing an increased tendency to persistence of atrial fibrillation. Local inflammation causes release of cytokines such as TNF-alpha, interleukin-6beta, and IL-6, which are key stimulants for synthesis of acute-phase proteins such as C-reactive protein. Systemic inflammation with increased levels of circulating C-reactive protein may cause atrial fibrillation in pre-disposed patients with triggering foci in the atria or pulmonary veins. Moreover, C-reactive protein could have a direct role in the development of a local inflammation due to ligand binding and the ability to activate the compliment pathway.
Some patients with idiopathic atrial fibrillation have circulating autoantibodies against myosin heavy chain, which highlights the possibility of an autoimmune inflammatory process in these patients.11 Also, patients with atrial fibrillation have higher concentrations of C-reactive protein than patients in sinus rhythm, and if atrial fibrillation persists, the C-reactive protein concentrations are even higher compared to patients with paroxysmal atrial fibrillation. Longer duration of atrial fibrillation is thus associated with both increased C-reactive protein concentrations and larger anatomical size of the atria, which supports a biological relationship between atrial fibrillation and inflammation. So far, a few studies have investigated the relationship between IL-6 and atrial fibrillation, and most have found increased IL-6 levels in patients with atrial fibrillation compared with healthy subjects. In addition, the 174G/C IL-6 promoter gene variant appears to influence the risk of developing post-operative atrial fibrillation.12 Clinical studies employing anti-inflammatory drugs in atrial fibrillation have so far involved treatment with steroids and statins. Administration of glucocorticoids in patients undergoing cardiac surgery has been shown to reduce the risk of early (within 3 days) post-operative atrial fibrillation.13 Another small, randomized study has disclosed that treatment with glucocorticoids in patients with their first episode of persistent atrial fibrillation is followed by a lower incidence of relapse and decreased C-reactive protein concentrations.14
Atrial fibrillation in the absence of left ventricular disease is associated with increased concentrations of BNP,15 and restoration of sinus rhythm can decrease plasma BNP concentrations.16 As mentioned earlier, it has recently been reported that the peripheral concentration of proBNP, but not proANP, is increased in lone atrial fibrillation.7 Taken together with the in vitro findings of selective BNP gene regulation by inflammatory cytokines, it seems reasonable to suggest that BNP concentrations in blood could reflect mostly atrial secretion. A study by Inoue et al.17 has in fact suggested mostly atrial BNP secretion in atrial fibrillation. In extension, it will be interesting to also elucidate the chamber-specific secretion of the precursor peptides, as both proANP and proBNP in plasma are markers of left ventricular dysfunction. Atrial myocytes contain a complex biosynthetic apparatus for peptide storage and maturation, and it may be argued that increased secretion of poorly processed proANP and proBNP could dominantly be a feature of ventricular release.18 According to this hypothesis, the ventricular myocytes may secrete unprocessed precursor peptides in a constitutive manner. In fact, there are data that do suggest such a mechanism.19,20 Moreover, the necessary biochemical tools for examining such molecular differences in the secreted peptides are now emerging.21 Processed, bioactive peptides may accordingly reflect atrial release, whereas ventricular peptide secretion could be estimated by measurement of immature precursor forms. If this turns out to be true, the ratio between unprocessed precursor and mature, bioactive product could further reflect the degree of atrial involvement in ventricular disease. In turn, such an index could even have diagnostic or prognostic value. Regional secretion of the biosynthetic precursors to ANP and BNP should therefore also be pursued.
Another open issue is regional peptide secretion within the cardiac chambers. In the atria, the appendages seem to be the logical sources for natriuretic peptide release, as they represent anatomical ‘overload sensors’. But in the much larger ventricles, the site of ANP and BNP expression may be more difficult to identify. Hypertrophic ventricular myocardium may cope differently with increased end-diastolic pressure than normal myocardium, which could be subjected to more stretch. Moreover, local expression of factors from either the cardiac myocytes or the vasculature could stimulate ANP and BNP gene expression in a particular region within the ventricle. Finally, some reports have suggested the endocardium as the dominant site of ANP and BNP gene expression in failing hearts.22 Taken together, there seems to be ample evidence that all myocytes within the ventricle will not respond equally to pathophysiological changes.
But why should physicians bother with the cardiac sources of proANP- and proBNP-derived peptides? Measurement of natriuretic peptides and their precursors in plasma can be used as rule-out markers of severe left ventricular dysfunction. However, major troubles still haunt the markers, which in particular relates to the spectacular variation in plasma concentrations between patients with otherwise similar degree of cardiac disease often classified according to their left ventricular function. There is a clear need to focus more on ‘the grey zone’ patient, which means patients with increased BNP and/or proBNP concentrations but under certain cutoff values. Notably, these patients will be common and could easily be a patient with paroxysmal atrial fibrillation. A better understanding of the local sources of natriuretic peptides could perhaps lead to a more problem-orientated use of the markers. The local peptide response could be an integral part of an algorithm, where echocardiography and peptide measurements are used together rather than as complementary tests (this is most likely already being implemented). Patients with ventricular dysfunction may be further classified according to different atrial and ventricular peptide forms, which in turn could help explain the troublesome variation in plasma concentrations in patients with otherwise similar degree of ventricular disease. Clearly, the endocrine atria are also active in heart failure. Plasma measurement of cardiac natriuretic peptides and their molecular precursors may perhaps help us to discriminate when, where, and how.
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.
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