© 2004 by European Society of Cardiology
REVIEW ARTICLE
Depletion of atrial natriuretic peptide during longstanding atrial fibrillation
Department of Cardiology, Thorax Center, University Hospital Groningen Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Manuscript submitted 25 February 2003. Accepted after revision 15 April 2004.
*Corresponding author. Department of Cardiology, Thorax Center, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Tel.: +31-50-361-2355; fax: +31-50-361-4391. E-mail address: m.p.van.den.berg{at}thorax.azg.nl (M.P. van den Berg).
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Abstract |
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 Top Abstract IntroductionAtrial natriuretic peptide and...Potential implicationsAcknowledgementsReferences |
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This review focuses on the relation between atrial fibrillation (AF) and atrial natriuretic peptide (ANP). ANP is produced by the atria secondary to atrial stretch. By causing atrial stretch, acute AF leads to an increase in plasma ANP concentration, which serves to normalize haemodynamics through natriuresis and vasodilation. However, data have been reported suggesting that prolonged AF, by inflicting structural atrial damage, is associated with a reduced capacity by the atria to produce ANP. An inverse relation was thus demonstrated between the duration of AF and plasma ANP concentration. In addition, a reduced ANP response to exercise has been shown to be predictive of unsuccessful cardioversion of AF to sinus rhythm. Finally, ANP has also been shown to predict outcome after a maze operation. Outcome was poor when preoperative plasma ANP concentration was low. Moreover, a high atrial collagen content, as a measure of atrial degeneration, correlated with low ANP. These data indicate that ANP may serve as a marker of atrial integrity, which may help in selecting AF patients for therapeutic interventions.
Key Words: atrial natriuretic peptide, atrial fibrillation, heart failure, depletion, cardioversion, maze procedure
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Introduction |
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TopAbstractIntroductionAtrial natriuretic peptide and...Potential implicationsAcknowledgementsReferences |
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In 1981 de Bold et al. made the seminal observation that the atria contain a substance which causes natriuresis and vasodilation [1]
. Basic facts on atrial natriuretic peptide (ANP) have been previously reviewed [2]. Briefly, ANP is produced primarily by the atrial myocytes although under certain circumstances (in particular in the setting of hypertrophy) ventricular myocytes may also produce ANP. ANP is produced as pro-ANP, a 126-[1–126] amino acid prohormone, which after secretion is cleaved into an N-terminal peptide [1–98] (N-ANP) and a C-terminal peptide [99–126]. C-terminal ANP, usually referred to as ANP, is biologically active, whereas N-ANP, which has a much longer half-life, is not. The principal stimulus for ANP secretion is stretch of the atrial wall secondary to increased loading, but an increase in the rate of contraction also causes an increase in ANP. After secretion into the plasma, ANP binds to ANP receptors (type A and B), located in the brain, blood vessels, kidney and adrenal glands. Binding of ANP to these receptors activates guanylyl-cyclase, which in turn activates the cGMP signalling cascade. ANP thus counteracts the effects of the renin-angiotensin-aldosterone system (physiological antagonism). In addition, recent evidence indicates that ANP has metabolic effects since it stimulates lipolysis, which may in turn cause cachexia [3]. The clinical significance of this phenomenon remains to be fully elucidated, but it may be surmised that ANP, thus, plays a role in mediating cachexia in the setting of chronic heart failure (CHF). ANP is cleared from the plasma by binding to type C ANP-receptors and by cleavage by neutral endopeptidases present in the kidney and blood vessels. Given its beneficial haemodynamic effects, increasing the plasma ANP level would seem to be of interest. Indeed, infusion of ANP was shown to exert a beneficial effect for instance in patients with hypertension [4]. On the other hand, the results of a recent large CHF trial with the neutral endopeptidases inhibitor omapatrilat were somewhat disappointing [5].
Since ANP is produced by atrial myocytes, one may wonder whether loss of these myocytes (from whatever cause) leads to reduced ANP production capacity. In a previous study, Nagate and co-workers have investigated this issue in patients with atrial overloading due to longstanding mitral valve disease [6]. Structural damage (degeneration, interstitial fibrosis) to the left atrium was more severe than the damage to the right atrium, which was accompanied by lower ANP content in the left atrium than in the right atrium. These findings suggest that loss of atrial myocytes indeed leads to reduced ANP production capacity.
Since atrial stretch is the principal determinant of ANP secretion, plasma ANP concentration reflects the degree of loading of the atria. Volume expansion, supine posture and exercise thus lead to an increase in ANP in healthy subjects [7]. Plasma ANP concentration is also increased in several disease states that cause atrial loading. For instance, ANP is increased in subjects with essential hypertension, particularly during exercise, in patients with mitral valve disease, and in the setting of complete atrioventricular block [8]. Most data on ANP, however, concern CHF. ANP was thus shown to be an early and sensitive marker of CHF [9], and ANP is increasingly used to titrate medication (including diuretics) [10]. Moreover, ANP is a powerful prognostic marker, a high plasma ANP concentration predicting poor survival [11]. This paper presents a new viewpoint regarding ANP in the setting of atrial fibrillation (AF).
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Atrial natriuretic peptide and atrial fibrillation |
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TopAbstractIntroductionAtrial natriuretic peptide and...Potential implicationsAcknowledgementsReferences |
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ANP is also increased in the setting of atrial tachyarrhythmias, including AF. Previous work in isolated rat atria demonstrated that positive chronotropic stimulation per se (high atrial contraction frequency) increases ANP [12]
. However, other studies in intact animals and humans indicate that the contribution of atrial contraction in increasing ANP is limited, and that atrial stretch secondary to the effect on haemodynamics is the key factor [13–15]. ANP, thus, acutely increases in the event of both regular atrial tachyarrhythmias and AF [16]. Conversely, several studies have investigated the effect restoration of sinus rhythm after persistent AF [17]. Firstly, plasma ANP concentration immediately prior to electrical cardioversion was on average increased compared with normal, indicating that the surge in ANP is not confined to the onset of AF but persists beyond the acute stage. Secondly, restoration of sinus rhythm caused rapid lowering of plasma ANP concentration in most patients, in conjunction with filling pressures. Given the physiological properties of ANP, its increase in the setting of AF (like in the other disease states) can be considered to constitute a useful mechanism, serving to restore and maintain cardiovascular homeostasis.
In recent years data have been published which shed a new light on the effect of AF on ANP. Before reviewing these studies, however, it is important to consider the time-dependent structural and functional effects of AF per se on the atria. Briefly, acute AF is a metabolically demanding, energy-consuming state, which is associated with increased atrial myocardial blood flow. After the acute stage, AF causes structural changes. In an experimental study, AF, which was maintained for 9–23 weeks, led to structural changes in the myocytes representing a form of cellular dedifferentiation, resembling hibernating (ventricular) myocardium [18]. When AF becomes longstanding degenerative changes occur which are irreversible. In a pathology study, patients with longstanding AF (up to 10 years) were thus characterized by loss of myocytes (atrophy) and an increase in adipose and fibrous tissue [19]. In another study, the presence of apoptotic cell death secondary to longstanding AF was demonstrated [20]. Finally, it was shown that atrial standstill is characterized by very low ANP plasma concentrations [21]. In all three patients plasma concentrations were very low, even after exercise. Low plasma concentrations were also observed for the second messenger cGMP. Furthermore, extensive degenerative changes were found in all biopsy specimens.
Combining the above observations we surmised that longstanding AF, by causing atrial structural remodelling and eventually irreversible damage, leads to reduced ANP production capacity. As a logical consequence, we argued that patients with longstanding AF might on average have a relatively low plasma ANP concentration compared with patients with AF of short duration. This hypothesis was tested in two different sets of CHF patients with AF. The first study comprised 26 patients with mild-to-moderate CHF with concomitant AF. Indeed, an inverse relation was demonstrable between AF duration and plasma ANP concentration, patients with longstanding AF showing low concentrations compared with patients having AF of shorter duration [22]. Recently, this observation was confirmed in a group of 60 patients with moderate-to-severe CHF with concomitant AF [23]. Not surprisingly given the presence of moderate-to-severe CHF, in the group as a whole ANP was significantly increased. However, in the subgroup of patients with severe left ventricular dysfunction (ejection fraction <0.20) an inverse relation (albeit modest) between the duration of AF and plasma ANP concentration could again be demonstrated (Fig. 1). In the multiple regression analysis, this effect was independent of other factors with a potential impact on ANP, including age, functional class, left ventricular function (ejection fraction), renal function, and medication (including angiotensin converting enzyme inhibitors and diuretics). Of note, a similar pattern was present for N-ANP. Serving as negative controls, norepinephrine, renin, aldosterone and endothelin, which are not produced in the atria, did not show such a relation.
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Two other studies concerned the prediction of successful electrical cardioversion of AF to sinus rhythm. The first study comprised 19 patients with non-rheumatic AF (mean duration 6±5 months) [24]
. In the patients with failed cardioversion or recurrent AF (n=11) ANP did not increase during exercise prior to cardioversion, whereas a normal increase was observed in the patients (n=8) with maintenance of sinus rhythm (follow up 3 months). The second study was performed in a group of 42 AF patients [25]. Cardioversion was successful in 23 patients in whom sinus rhythm was restored and maintained for 6 months; in the other 19 patients cardioversion either failed or there was a recurrence of AF. Importantly, AF duration was shorter in the former group compared with the latter group (5.5±6.5 and 9.0±7.5 months, respectively), but this difference did not reach statistical significance. Plasma ANP concentrations were comparable at baseline, but the mean increase in ANP during exercise was significantly greater in the 23 patients than in the 19 patients. In the multivariate logistic regression analysis, an increase in ANP was associated with successful cardioversion and maintenance of sinus rhythm, independent of the usual clinical factors, including duration of AF and left atrial dimension.
The value of plasma ANP concentration for predicting outcome after the maze procedure was reported recently [26]. The study group consisted of 62 consecutive patients with AF who underwent the maze procedure in conjunction with other surgical corrections (mostly mitral valve operations). On the basis of postoperative AF recurrence (mean duration after surgery 31.2±20.7 months), the patients were divided into a ‘sinus rhythm group’ (n=49) or an ‘AF group’ (n=13). Preoperative plasma ANP concentration was significantly lower in the AF group than in the sinus rhythm group (24.2±9.6 vs. 71.3±55.3 pg/ml, P=0.0009). Multiple logistic regression analysis indicated that duration of AF and plasma ANP concentration were independently associated with postoperative rhythm status. Among 41 patients with a higher ANP or shorter duration of AF than the median value, sinus rhythm was restored in 95% of patients. In contrast, in 21 patients with lower ANP and a longer duration of AF than the median value, sinus rhythm was restored only in 48% of patients. Histological examination demonstrated that collagen content in left atrial tissue, which is a measure of atrial degeneration, was higher in the AF group than in the sinus rhythm group and inversely related to plasma ANP concentration.
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Potential implications |
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TopAbstractIntroductionAtrial natriuretic peptide and...Potential implicationsAcknowledgementsReferences |
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What conclusions can be drawn from the available data? In terms of pathophysiology, there appears to be an intricate relation between AF and ANP, the effect of AF on ANP changing over time. Acute AF causes a surge in ANP, but there is increasing evidence that ongoing AF, by causing structural atrial damage, eventually leads to reduced ANP production capacity. In other words, by inflicting irreversible damage to the very site of ANP production, that is, the atrial myocytes, ongoing AF would reduce the capacity to produce ANP commensurate with physiological demand. Of note, the evidence is largely circumstantial and definitive proof for this concept is lacking. Moreover, ANP production in patients with AF is a complex process with involvement of many structural and functional factors. Even if reduced ANP production capacity secondary to structural damage does play a role, other factors inevitably weaken its relative importance. Among these factors, the potential role of brain natriuretic peptide (BNP) seems of interest. BNP, which has largely similar effects to ANP, is mainly produced in the ventricles, but BNP may also be produced in the atria [27]
. However, the latter is relatively minor, which would imply that the effect of longstanding AF on BNP is probably minor. Future studies should resolve this interesting issue.
Provided that the above concept is valid, there are potentially important implications. By using ANP as a marker of atrial integrity, ANP may serve to optimize the therapeutic strategy in patients with AF. The available studies have already shown that determination of ANP may help in selecting patients for a routine therapeutic intervention like electrical cardioversion. Appropriate patient selection is even more important when considering invasive procedures. It was already shown that ANP is of value in selecting patients for the maze procedure [26], but it is conceivable that the same applies to other procedures like antitachycardia pacing and radiofrequency ablation. Additional studies are mandatory in the further exploration of these possibilities. In addition, the concept that AF reduces ANP production capacity may be of relevance in the treatment of CHF patients with concomitant AF. Since ANP counteracts the deleterious effects of the renin-angiotensin-aldosterone system, reduced ANP production secondary to concomitant AF might promote progression of CHF. Indeed, several studies have shown that AF contributes to CHF progression [28], although other factors (e.g. loss of atrial systole) obviously also play a role in this connection.
The above data indicate that AF is not an innocent bystander and would suggest that sinus rhythm should be restored whenever possible. However, recent clinical studies [29,30] indicate that a ‘rate control’ strategy is not inferior to a strategy aimed at restoration and maintenance of sinus rhythm (‘rhythm control’). Rate control thus remains the first option for the broad range of patients with AF until future data suggests otherwise.
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Acknowledgements |
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TopAbstractIntroductionAtrial natriuretic peptide and...Potential implicationsAcknowledgementsReferences |
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Dr van Veldhuisen is a Clinical Established Investigator of the Netherlands Heart Foundation (D97.017).
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References |
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TopAbstractIntroductionAtrial natriuretic peptide and...Potential implicationsAcknowledgementsReferences |
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