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European Journal of Heart Failure 2002 4(3):255-262; doi:10.1016/S1388-9842(01)00232-X
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© 2002 European Society of Cardiology

Longstanding atrial fibrillation causes depletion of atrial natriuretic peptide in patients with advanced congestive heart failure

Maarten P. van den Berga,*, Geert Tjeerdsmaa, Pieter Jan de Kama, Frans Boomsmab, Harry J.G.M. Crijnsa and Dirk J. van Veldhuisena

a Department of Cardiology, Thorax Center University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
b COEUR/Department of Internal Medicine University Hospital Dijkzigt, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands

* Corresponding author. Tel.: +31-50-361-2355; fax: +31-50-361-4391. E-mail address: m.p.van.den.berg{at}thorax.azg.nl


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Background: Congestive heart failure (CHF) is characterized by neurohormonal activation, including increased plasma concentrations of atrial natriuretic peptide (ANP) and N-terminal ANP (N-ANP). Onset of atrial fibrillation (AF) further increases these peptides, but it may be hypothesized that concentrations decrease during longstanding AF due to inherent atrial degeneration.

Aim: We sought to investigate the relation between neurohormonal activation in patients with CHF and the duration of concomitant AF.

Methods: The study group comprised 60 patients (age 70±8 years) with advanced CHF due to left ventricular systolic dysfunction (left ventricular ejection fraction (LVEF) <0.35) and chronic AF (duration 21 (1–340) months). Plasma neurohormone concentrations were measured, and multiple regression analysis was performed to identify their clinical predictors.

Results: Median plasma neurohormone concentrations were: ANP 113 pmol/l, N-ANP 1187 pmol/l, norepinephrine 496 pg/ml, renin 127 µunits/l, aldosterone 128 pg/ml and endothelin 8.1 pg/ml. Norepinephrine, renin, aldosterone and endothelin were not significantly related to the duration of AF. In contrast, ANP decreased along with the duration of AF (P=0.03), while the same trend was observed for N-ANP (P=0.10). However, for these peptides a first order interaction with LVEF was present, which was not observed in the other neurohormones. In patients with LVEF >0.25 ANP and N-ANP increased along with the duration of AF, whereas in patients with LVEF≤0.25 an inverse relation between ANP (P=0.02) and N-ANP (P=0.04) and the duration of AF was present, longer-standing AF being associated with lower concentrations.

Conclusion: In patients with advanced CHF with low LVEF plasma ANP and N-ANP concentrations decrease during longstanding AF. This finding agrees with the concept that longstanding AF leads to impaired ability of the atria to produce these neurohormones due to inherent degenerative changes.

Key Words: Congestive heart failure • Atrial fibrillation • Atrial natriuretic peptide

Received February 28, 2001; Revised August 31, 2001; Accepted October 23, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Both congestive heart failure (CHF) and atrial fibrillation (AF) are very common disorders, and their incidence is still increasing. Moreover, the two often occur together due to shared predisposing conditions and a reciprocal causal relation [1,2]. As part of neurohormonal activation in CHF, the natriuretic peptides play an important role [3], since they counteract the deleterious effects of the renin–angiotensin system by promoting diuresis and vasodilation [4]. The two main natriuretic peptides are atrial natriuretic peptide (ANP) and brain natriuretic peptide. Brain natriuretic peptide is produced mainly by the ventricles, whereas the atria are the main site of ANP production [5]. 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 [6,7]. The principal stimulus for natriuretic peptide secretion is myocardial stretch due to volume or pressure overload [8].

Since onset of AF causes acute atrial stretch, AF per se also causes an increase in ANP [9], which adds to the effect of CHF on ANP [10,11]. However, when AF becomes longstanding the atria lose their capacity to produce ANP, due to atrial degeneration (myocyte atrophy) [12]. In a previous study we speculated that this could lead to a decrease in plasma ANP concentration in CHF patients with AF [13]. Indeed, in this exploratory study an inverse relation was demonstrated between the duration of AF and ANP. However, the number of patients was rather small and no other neurohormones were measured. In the present study we further explored this concept in a much larger patient group. In addition to ANP, we also analyzed N-ANP as well as norepinephrine, renin, aldosterone and endothelin with respect to the relation with the duration of AF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
2.1. Patient selection
All patients participated in the neurohormonal substudy of the Second Prospective Randomized study of Ibopamine on Mortality and Efficacy (PRIME II) [14]. PRIME II was an international study, carried out in 13 European countries; the neurohormonal substudy was performed only in The Netherlands [10,15]. In the present study we used the baseline data of the PRIME II neurohormonal substudy, i.e. before any study medication was given. PRIME II was designed to investigate the effect of the oral dopamine agonist ibopamine on all-cause mortality in patients with advanced CHF. In short, patients aged 18–80 years were eligible for PRIME II if they had signs and symptoms of CHF (New York Heart Association functional class III–IV). All patients had to be on optimal medical treatment for CHF, including angiotensin converting enzyme inhibitors and diuretics, and, if indicated, digoxin and beta-blockers. Evidence of heart disease had to be proved by a left ventricular ejection fraction (LVEF) <0.35 on radionuclide or contrast ventriculography. Echocardiography was performed when available. Chronic AF was defined using standard criteria: irregular undulation of the baseline, generally associated with irregular ventricular rhythm, which had to be recorded on consecutive electrocardiograms, at least 7 days apart. The second electrocardiogram was taken as the beginning of AF. The study protocol of PRIME II, including the neurohormonal substudy, was approved by each local ethics committee, and all patients gave their written informed consent before entry into the study. The investigation conforms to the principles outlined in the Declaration of Helsinki.

2.2. Neurohormonal measurements
Methods have been described in detail previously [10,15]. Briefly, blood was collected from a peripheral intravenous cannula after patients had rested in the supine position for >30 min. All samples were drawn in the morning prior to taking medication. Samples were poured into chilled 10-ml heparinized polystyrene tubes containing 12 mg of glutathione (for measurement of norepinephrine, renin and aldosterone) and chilled 10-ml tubes containing EDTA (19 mg) and apronitin (1000 kIU) (for measurement of ANP, N-ANP and endothelin). The tubes were centrifuged within 30 min (40 °C, 10 min, 2000xg) and the plasma was separated and stored in polyethylene tubes at –70 °C. All samples were transported (on dry ice) to the Core Laboratory at the University Hospital Dijkzigt, Rotterdam, The Netherlands, where all measurements were performed. Plasma norepinephrine concentration (normal value: 100–500 pg/ml) was determined by high-performance liquid chromatography with fluorimetric detection after isolation from plasma by a specific liquid-liquid extraction method and derivatization with the selective fluorogenic agent 1,2-diphenylethylenediamine. For measurement of aldosterone (normal value: 50–250 pg/ml) a commercially available kit (Coat-a-Count, Diagnostic Products Corporation, Los Angeles, CA) was used. Active plasma renin concentration (normal value: 5–50 µunits/ml) was determined in terms of angiotensin I production using radioimmunoassay. Measurement of ANP (normal value: 15–35 pmol/l) and endothelin (normal value: 1–5 pg/ml) was performed after SepPak extraction, with commercially available radioimmunoassay kits (Nichols Institute, Wijchen, The Netherlands). Finally, N-ANP (normal value: 150–500 pmol/l) was also measured with radioimmunoassay (Biotop, Oulu, Finland).

2.3. Data analysis
Data are given as mean±standard deviation in case of a normal distribution, whereas median values with ranges are given for non-normally distributed variables. Continuous, normally distributed variables were compared with ANOVA and categoric variables with Fisher's exact test. In the case of non-normally distributed variables, differences were tested with Wilcoxon's two-sample test. To identify the predictors of the plasma neurohormone concentrations, univariate analysis was performed first, using the proportional odds model for ordered categorical data [16]. Thus, to examine linearity, continuous variables were divided in quartiles. If the quartiles showed a linear relation with the neurohormone, the variable was taken in the model as continuous. If a non-linear relation was apparent, quartiles with comparable odds-ratios were combined and included in the model as a dichotomous variable. Studied variables consisted of the clinical characteristics (as listed in Table 1), including the duration of AF. Because the distribution of neurohormone values was skewed, we performed log transformation thereby creating a normal distribution. Clinical characteristics with a univariate P-value <0.1 were then included in a multiple regression analysis using backward selection to identify the independent predictors of each neurohormone. After thus identifying the independent predictors, we checked for first order interactions between the duration of AF and the other predictors. Graphs were computed based on the regression analysis using the intercept and regression coefficients. Two-sided P-values <0.05 were considered significant. All analyses were performed using the Statistical Analysis System program (SAS), version 6.12 (Cary, NC).


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  		Table 1 Clinical characteristics of the total group and dichotomized according to median left ventricular ejection fraction

 

   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
The neurohormonal substudy comprised 372 patients. At entry into the study chronic AF was diagnosed in 78 patients, but in 18 of them the duration of AF could not be determined reliably. The remaining 60 patients constitute the present study group. The clinical characteristics are given in Table 1. Most patients were male and in New York Heart Association functional class III. Coronary artery disease was the most common cause of CHF. As judged by the LVEF and end diastolic dimension, left ventricular function was markedly impaired. Accordingly, the vast majority of patients were on angiotensin converting enzyme inhibitors, diuretics and digoxin. When dichotomizing according to the median LVEF (see below), the patients with the lower LVEF (≤0.25) had a lower systolic blood pressure and a higher serum urea concentration. The other variables did not differ significantly. Data on neurohormones are given in Table 2. For the total group, the plasma concentrations were within normal limits for aldosterone and norepinephrine (borderline), whereas the other neurohormones were increased, particularly the natriuretic peptides. In addition, plasma concentrations of both ANP and N-ANP were higher in the patients with lower LVEF. In contrast, there were no significant differences between the two groups with respect to the other neurohormones.


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  		Table 2 Plasma neurohormone concentrations in the total group and dichotomized according to median left ventricular ejection fraction

 
3.1. Multiple regression analysis
The results of the univariate and multiple regression analysis are given in Table 3. Several indices of functional status (e.g. New York Heart Association functional class) and disease severity (e.g. serum urea) were identified as significant independent predictors of the plasma concentrations of norepinephrine, renin, aldosterone and endothelin. However, the duration of AF did not emerge as a significant predictor of these neurohormones. If anything, a longer duration of AF tended to be associated with a higher plasma norepinephrine concentration, but this was not significant (P=0.11) (Fig. 1). In contrast, a significant inverse relation was observed between the plasma ANP concentration and the duration of AF (P=0.03), while a similar trend was observed for N-ANP (P=0.10). However, when checking for first order interactions, there was an interaction between AF duration and LVEF for both ANP and N-ANP. In order to clarify and visualize this interaction, LVEF was dichotomized according to its median value. Results of this additional analysis are shown in Fig. 2. In patients with LVEF>0.25 ANP was higher along with a longer duration of AF, whereas an inverse relation was observed in patients with LVEF≤0.25 (P=0.02), longer duration of AF being associated with lower ANP. A similar pattern was also observed for plasma N-ANP concentration (P=0.04) (Fig. 2). No first order interactions were present for the other neurohormones, in particular LVEF did not play a role in this respect.


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  		Table 3 Independent predictors of ANP, N-ANP, norepinephrine, renin, aldosterone and endothelin

 


Figure 1
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  		Fig. 1 Relation between the duration of atrial fibrillation and plasma concentrations of norepinephrine (upper left), renin (upper right), aldosterone (lower left) and endothelin (lower right). Plasma concentrations of all four neurohormones tended to increase (P=NS) along with the duration of atrial fibrillation. See text for further discussion. Of note, the graphs were computed based on the regression analysis using the intercept and regression coefficients.

 


Figure 2
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  		Fig. 2 Relation between the duration of atrial fibrillation and plasma concentrations of ANP (left) and N-ANP (right), dichotomized according to median left ventricular ejection fraction (0.25). Plasma concentrations of both neurohormones decreased along with the duration of atrial fibrillation in the patients with the lower ejection fraction (P=0.02 and P=0.04, respectively). See text for further discussion. Of note, the graphs were computed based on the regression analysis using the intercept and regression coefficients.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
After the initial insult to the myocardium, CHF is a self-perpetuating, progressive disorder, in which neurohormonal activation plays an important role [17]. Indeed, neurohormonal activation, a marker of disease severity, has been shown to increase gradually over time [18]. These studies, however, have been mainly conducted in patients in sinus rhythm. In the present study we focused on CHF complicated by AF. Our principal finding is that patients with advanced CHF due to severe left ventricular dysfunction are characterized by an inverse relation between plasma ANP and N-ANP and the duration of concomitant AF. This finding agrees with the concept that longstanding AF leads to a reduced capacity of the atria to produce these neurohormones due to inherent degenerative changes.

4.1. Effects of atrial fibrillation on the atria
The time-dependent structural and functional effects of AF per se on the atria have recently been reviewed by Allessie [19]. Briefly, acute AF a metabolically demanding, energy-consuming state, which is associated with increased atrial myocardial blood flow [20]. A semi-acute atrial effect of AF is so-called electrical remodeling [21]. Beyond the (semi)acute stage, AF causes more 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 [22]. When AF becomes longstanding, degenerative changes occur which are irreversible. Davies and Pomerance studied 100 patients with AF of varying duration [23]. Patients with longstanding AF (up to 10 years) were characterized by loss of myocytes (atrophy) and an increase in adipose and fibrous tissue. Comparable findings were reported by Mary-Rabine et al. in patients with atrial tachyarrhythmias of various etiologies [24]. In that study, the atrial myocardium was characterized by degenerative changes which were more pronounced when the underlying pathology was aggravated by longstanding AF. More recently, Aimé-Sempé et al. demonstrated the presence of apoptotic cell death secondary to longstanding AF [25]. As a functional correlate, Seino et al. showed that atrial standstill after longstanding AF (without CHF) is characterized by very low ANP plasma concentrations [12]. In some of their patients plasma concentrations were even undetectably low (‘endocrinologic silence’). Extensive degenerative changes were found in all biopsy specimens. It thus appears that AF per se, that is, irrespective of underlying structural heart disease and ventricular function, eventually leads to irreversible atrial damage, including endocrine deficiency.

4.2. Present study
Based on the above assumptions we hypothesized that in patients with CHF an inverse relation might exist between ANP and N-ANP and the duration of concomitant AF. The results of the present study confirm this hypothesis: the patients with longstanding AF had lower plasma ANP concentrations than the patients with AF of shorter duration. A similar pattern, though less outspoken, was apparent 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. If anything, plasma norepinephrine concentration tended to increase along with longer duration of AF. Although there was no independent relation with the duration of CHF as such, this finding is in agreement with the concept of progressive neurohormonal activation in CHF [18]. The relation between the duration of AF and ANP, however, was related to LVEF. More precisely, when checking for first order interactions, the inverse relation was confined to patients with LVEF≤0.25. Importantly, the same phenomenon was found for N-ANP, which strongly argues against a chance observation. Moreover, this dichotomy may be pathophysiologically plausible. On average, that is irrespective of the duration of AF, plasma ANP and N-ANP concentrations were higher in the patients with the lower LVEF, unlike the other neurohormones. It is conceivable that the degenerative effect of AF becomes more readily apparent in cases of higher initial concentrations. In other words, if production capacity is already stretched to the limit, any disruptive process (e.g. atrial degeneration) is likely to exert a strong effect. Furthermore, CHF per se adds to atrial degeneration [26,27]. In fact, Ohtani et al. demonstrated an inverse relation between LVEF fraction and the degree of left atrial fibrosis in patients (in sinus rhythm) with CHF due to coronary artery disease [26]. In addition to the effect of hemodynamics (atrial loading), neurohormonal activation as part of CHF presumably also exerts a detrimental structural effect on the atria, especially the renin–angiotensin system [28]. It is reasonable to assume that these effects are stronger along with worsening of left ventricular dysfunction.

4.3. Limitations
Whereas the duration of AF can be determined fairly reliable in most cases, determination of the duration of CHF is rather difficult. This might be the reason why the duration of CHF as such did not emerge as a predictor. Further, plasma concentrations of the natriuretic peptides not only reflect their production and secretion but are also determined by clearance of these neurohormones from the plasma. It is actually rather likely that clearance kinetics were different in patients with a different degree of left ventricular dysfunction, particularly since the kidneys play an important role in extracting the natriuretic peptides from the plasma [29] and renal function (as judged by serum urea and creatinine) was poorer in the patients with the lower LVEF. However, this does not negate the observed relation with the duration of AF. Angiotensin converting enzyme inhibitors are known to affect neurohormone levels (e.g. renin). The same holds true for diuretics. Use of these medications did, however, not emerge as independent predictors in the multiple regression analysis. Perhaps the most important limitation is the fact that this was a cross-sectional study. To prove our hypothesis a longitudinal study with serial neurohormonal measurements would be necessary.

4.4. Implications
The present study provides evidence for a subtle form of deficiency of the atria to produce ANP in patients with advanced CHF, presumably caused by degenerative changes in the atria inherent to concomitant longstanding AF. From a broader perspective this would imply that plasma ANP concentrations in these patients are the net result of two opposing mechanisms. Initially the effect of hemodynamic burden prevails, causing ANP to increase; eventually, however, atrial degeneration supervenes causing ANP to decrease. As a result, the renin–angiotensin system is unopposed, which may be surmised to cause further progression of CHF. Among other factors, this might explain the detrimental effect of AF reported in some studies on the clinical course in patients with CHF [30]. From a practical point of view, this study emphasizes the notion that AF is not an innocent bystander and that sinus rhythm should be restored whenever possible.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
Dr van Veldhuisen is a Clinical Established Investigator of the Netherlands Heart Foundation.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 

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Europace, January 1, 2004; 6(5): 433 - 437.
[Abstract] [Full Text] [PDF]

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B. Wozakowska-Kaplon and G. Opolski
Concomitant recovery of atrial mechanical and endocrine function after cardioversion in patients with persistent atrial fibrillation
J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1716 - 1720.
[Abstract] [Full Text] [PDF]

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