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European Journal of Heart Failure 2006 8(3):263-269; doi:10.1016/j.ejheart.2005.09.001
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© 2005 European Society of Cardiology

Influence of atrial fibrillation on cardiac brain natriuretic peptide release during haemodynamic stress in heart failure

P.A. Goulda, J. D'Agostinob, H.G. Schneiderb and D.M. Kayea,*

a Baker Heart Research Institute, Wynn Department of Metabolic Cardiology PO Box 6492, St. Kilda Road Central, Melbourne Victoria 8008, Australia
b Biochemistry Department, Alfred Hospital Melbourne, Victoria, Australia

* Corresponding author. Tel.: +61 3 9276 3265; fax: +61 3 9207 1044. E-mail address: david.kaye{at}baker.edu.au. (D.M. Kaye).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
 References
 
Background: The determinants of release of brain natriuretic peptide (BNP) in heart failure (HF) are incompletely understood, particularly, the effect of heart rhythm and haemodynamic stress.

Aims: To investigate the effect of haemodynamic stress on cardiac BNP release in HF and differentiate this response for atrial fibrillation (AF) and sinus rhythm (SR).

Methods: In 18 HF patients (ejection fraction<40%, 9 in AF and 9 in SR) haemodynamics and BNP levels were measured from arterial and coronary sinus samples at baseline, after 10 min of 20° passive head up tilt (HUT) and after 10 min of isometric handgrip (IHG) exercise. From these data, we calculated a transcardiac BNP gradient and compared results between the AF and SR cohort.

Results: During haemodynamic stress in both groups, there were no significance differences in left sided filling pressures. At baseline, there were no differences in BNP measurements between the SR and AF group. The transcardiac BNP gradient increased significantly in the SR (p=0.02) but not the AF cohort, after HUT. During IHG exercise, there was a significant decrease in cardiac BNP release in the AF cohort (p=0.03) but not the SR cohort.

Conclusion: These data imply in HF, cardiac rhythm influences cardiac BNP release in response to haemodynamic stress.

Key Words: Brain natriuretic peptide • Atrial fibrillation • Heart failure

Received April 24, 2005; Revised July 6, 2005; Accepted September 6, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
 References
 
HF is a syndrome associated with neurohormonal activation [1]. In particular, the sympathetic nervous system and renin-angiotensin-aldosterone system have been shown to be activated [2-4] and are the most widely investigated. Activation of the natriuretic peptide system has also been shown, with particular focus on brain natriuretic peptide (BNP). It has been demonstrated that BNP is released from cardiac myocytes in response to increases in left ventricular wall stress and volume expansion [5,6], which potentially make it an ideal marker of HF severity. Yet the pathophysiological properties underlying its release, metabolism and clearance are currently incompletely understood [7]. This has caused problems with interpretation of plasma BNP levels given that multiple factors other than increased left ventricular wall stress may affect plasma levels of BNP, including obesity [8], female gender [9], myocardial infarction [10] and pharmacotherapy [11].

In addition, there is conflicting data regarding the effect of atrial fibrillation (AF), which commonly complicates HF, on plasma BNP [12,13]. In HF, elevated plasma BNP has been shown to be associated with an increased incidence of AF [14]. Furthermore, the response of plasma BNP to haemodynamic stress such as exercise may also influence its use as a HF marker. Several studies have investigated changes in plasma levels of BNP in patients with HF during exercise, and whilst some studies have shown a modest increase in BNP levels [15-17] other studies have reported a decrease [18,19].

Accordingly, in the current study, we sought to investigate alterations in cardiac production of BNP in response to haemodynamic stress of passive head up tilt (HUT) and isometric handgrip exercise in a HF cohort. In addition, we sought to differentiate this response for AF and sinus rhythm (SR). The aim of the study was to understand further the relationship between haemodynamic stresses, cardiac rhythm and cardiac BNP release in HF. To achieve this we measured arterial and coronary sinus BNP levels and calculated a transcardiac BNP gradient to assess more accurately acute cardiac responses to haemodynamic stress, which theoretically could be missed by assessing only peripheral venous samples.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
 References
 
2.1. Patient characteristics
We enrolled 18 HF patients (9 patients in SR, 9 patients in AF), mean age 59±2 years, with left ventricular ejection fraction<40%. There were 16 males (8 in each group) and 2 females (1 in each group). The aetiology of HF was idiopathic dilated cardiomyopathy in six patients (3 in each group) and ischemic cardiomyopathy in 12 patients (6 in each group). Idiopathic dilated cardiomyopathy was confirmed by the absence of an alternative diagnosis for HF and by coronary angiography. Ischaemic cardiomyopathy was angiographically proven. Patients in the AF group had persistent AF secondary to impaired LV function and elevated left atrial pressures of at least 3 months duration. Five patients in each group had a history of hypertension, echocardiography did not reveal any significant difference in left ventricular hypertrophy or degree of mitral regurgitation between each cohort. All patients were haemodynamically stable at the time of evaluation, but all remained on anti-failure pharmacotherapy to avoid potential haemodynamic decompensation. All subjects were on β-blockers and angiotensin converting enzyme inhibitors as part of their HF management. Left ventricular ejection fraction was assessed in each patient within 1 month of the experimental procedure, using Simpson's biplane method on echocardiography or gated cardiac blood pool scanning.

2.2. Catheter studies
We performed right heart catheterisation and measured arterial and coronary sinus BNP and calculated the transcardiac BNP gradient. These measurements were performed at baseline, after 10 min of 20° passive HUT and after 10 min of isometric handgrip exercise. All patients gave written informed consent and the study was performed with the approval of the Alfred Hospital Ethics Review Committee and conformed with the principals outlined in the Declaration of Helsinki.

2.3. Experimental procedures
The radial artery was cannulated (3F, 5 cm, Cook, Brisbane, Australia) under local anaesthesia for arterial blood sampling and arterial pressure measurements. Venous introducer sheaths were placed either in the antecubital fossae if two suitable veins were available or if not one sheath was positioned in the right internal jugular vein. A pulmonary artery thermodilution catheter (7F, Arrow, Arrow International) was passed to the pulmonary circulation to measure right heart pressures and cardiac output (CO). Subsequently a sampling catheter (6 Fr multipurpose coronary catheter) was advanced under fluoroscopic guidance to the CS for sampling, as previously described [20]. Once all catheters were sited, baseline haemodynamic measurements including mean arterial pressure (MAP), heart rate (HR), pulmonary capillary wedge pressure (PCWP) and CO were performed, along with CS and arterial sampling for assessment of the BNP levels. Haemodynamic recordings for AF patients were performed over an average of five measurements.

2.4. Head Up Tilt (HUT)
The patient was then transferred to the tilt table and once stabilised underwent passive HUT to 20° for 10 min supporting their own weight. Haemodynamic data was recorded and samples collected at the end of this 10 min period. Patients were then returned to a supine position and continually monitored for a further 20 min to re-establish baseline steady state.

2.5. Isometric handgrip exercise
In the same cohort after 20 min of baseline steady state post HUT, isometric handgrip exercise was completed in seven patients in the SR cohort and five patients in the AF cohort (The remaining patients were unable to continue the handgrip for the required time period and were therefore excluded.). During the steady state period, a maximal voluntary handgrip contraction force was performed using a standard handgrip device. Then for ten minutes in time with a metronome (at a rate of 76 handgrips per minute), the subject was encouraged to repeatedly squeeze the handgrip performing isometric exercises at 20% maximal voluntary contraction force. Isometric handgrip exercise has previously been shown to increase heart rate acceleration and alter haemodynamics in stress test conditions [21]. Haemodynamic measures and blood sampling to measure transcardiac BNP gradient were performed after ten minutes of isometric handgrip exercise. Patients were continually monitored for a further 10 min post exercise and lines were then removed.

2.6. Measurement of transcardiac BNP gradient
Blood samples were collected into ice-chilled tubes containing an ethylenediaminetetra-acetic acid (EDTA). After centrifugation at 4 °C, plasma samples were stored at –70 °C until assayed. Prior to assay, the plasma samples were thawed on ice. The AxSYM BNP Assay (Abbott Diagnostics, Abbott Park, IL, U.S.A.) was employed to measure plasma BNP, this assay uses a micro-particle enzyme immunoassay designed to measure plasma BNP and has been correlated with the point of care TRIAGE Assay (Biosite, San Diego, CA, U.S.A.) [22]. Plasma BNP was measured in arterial and coronary sinus samples and a transcardiac BNP gradient was calculated as follows:


Formula

where CSBNP represents coronary sinus BNP level and ArtBNP represents arterial BNP level.

2.7. Statistical analysis
Data are presented as mean value±SEM, unless otherwise stated. Statistical analysis and graphical presentation was performed using statistical software (SigmaStat, version 2.03, Chicago, Illinois). Within group data was compared using a paired t-test and between group data were compared using an unpaired t-test for normally distributed data, and non-normal data were analysed by a Mann-Whitney test. A p value of <0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Limitations
 6. Conclusion
 References
 
3.1. Baseline haemodynamic and BNP data
The demographic data for the AF and SR cohort are presented in Table 1. The AF cohort tended to be older however this did not reach significance (p=0.06). Otherwise, there were no significant differences between the AF and SR cohorts with respect to the use of heart failure medications or left ventricular ejection fraction. Haemodynamic data for HUT are presented in Table 2. The baseline haemodynamic data was similar between the groups except the AF cohort tended to be more hypertensive with increased MAP (AF 91±6 mmHg, SR 75±4 mmHg, p=0.05).


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  		Table 1 Demographic data for HF patients in the atrial fibrillation and sinus rhythm cohorts

 


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  		Table 2 Haemodynamic response to 20° passive head up tilt in HF patients in the sinus rhythm (SR) and atrial fibrillation (AF) cohorts

 
At baseline, plasma BNP levels for arterial, coronary sinus and transcardiac BNP gradient samples were not significantly different between SR and AF cohorts. There was however a significant step up in BNP across the heart in both the SR (p=0.002) and AF (p<0.001) cohorts (Fig. 1).


Figure 1
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  		Fig. 1 Arterial and coronary sinus BNP levels in HF patients for the SR (Black Bar) and AF (White Bar) Cohorts. *p<0.05. Comparison of arterial and CS BNP (pg/ml).

 
3.2. Haemodynamic and BNP responses to HUT
Haemodynamic data during HUT are presented in Table 2. During HUT, from baseline to 20° HUT, left sided filling pressures fell significantly in the AF group, while non-significantly in the SR group, although there was a trend. The right atrial pressure did however significantly decrease in the SR group (p=0.03) after HUT. A comparison of the haemodynamic response between the groups also showed no difference during HUT.

During HUT, the coronary sinus plasma BNP level (p=0.025) and transcardiac BNP gradient (p=0.02) rose significantly in the SR cohort (Fig. 2), however there was no change in the AF cohort. The plasma arterial BNP did not significantly alter in the SR cohort in response to HUT. Transcardiac BNP response within the AF cohort was not significantly different during HUT compared with baseline values (Fig. 3). With respect to between group comparisons during HUT, the transcardiac BNP gradient during HUT was significantly greater in the SR cohort (p=0.03).


Figure 2
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  		Fig. 2 Comparison of Coronary Sinus (CS) and transcardiac BNP gradients in HF patients for the SR cohort at baseline and in response to head up tilt. A. CS BNP in the SR cohort, B. Transcardiac BNP gradient in the SR cohort.

 


Figure 3
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  		Fig. 3 Transcardiac BNP gradient in response to head up tilt (HUT) in the AF cohort.

 
3.3. Haemodynamic and BNP responses to isometric handgrip exercise
Baseline and exercise haemodynamic data are presented in Table 3. At Baseline the AF cohort had a significantly higher MAP (p=0.006), SBP (p=0.02) and DBP (p=0.012) compared with the SR cohort. The SR cohort had a tendency to greater baseline CO (p=0.05). Otherwise, there were no differences in baseline haemodynamics. In particular, ventricular filling pressures were not different.


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  		Table 3 Haemodynamic data at baseline and after isometric handgrip exercise in HF patients in the sinus rhythm and atrial fibrillation cohorts

 
In response to exercise, there was a significant increase in heart rate in the AF cohort (p=0.03). Other changes in haemodynamic parameters with exercise in the AF cohort failed to reach significance. In the SR cohort in response to exercise there were significant increases in heart rate (p=0.03) and blood pressure (p=0.03), and PCWP (p=0.06) tended to increase. A comparison of haemodynamic response between the two groups revealed a significantly greater SBP (p=0.03), DBP (p=0.03) and an increased MAP (p=0.06) and CO (p=0.05) with exercise in the AF cohort. Otherwise, the haemodynamic response was the same with exercise. In particular, ventricular filling pressures were not significantly different.

Data for change in transcardiac BNP gradient at baseline and during isometric exercise in the SR and AF cohort are presented in Fig. 4. At Baseline the AF group tended to have a lower CS BNP level, however this did not reach significance (p=0.08). Otherwise, there were no differences in baseline BNP measurements. During isometric handgrip exercise the AF cohort had significant decreases in CS BNP (p=0.04) and transcardiac BNP gradient (p=0.03). The arterial BNP level did not significantly alter with exercise. In contrast, the SR cohort had a non-significant rise in CS and transcardiac BNP measurements. The CS (p=0.02) and transcardiac BNP (p=0.01) level post-exercise was significantly greater in the SR cohort compared with the AF cohort.


Figure 4
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  		Fig. 4 Transcardiac BNP release in response to isometric exercise in the SR and AF cohorts.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Limitations
 6. Conclusion
 References
 
Recent studies have established venous plasma BNP as a useful prognostic marker in HF [23,24], in addition it has been shown that left ventricular filling pressures and ejection fraction are the predominant factors correlated with BNP levels [5,25-27]. In this study, we have observed a variation in cardiac BNP release in HF in response to haemodynamic stress and further differentiated this response for cardiac rhythm. In the SR cohort during HUT, there was a significant increase in cardiac BNP release but no significant change in response to exercise. The cardiac BNP release in response to these same haemodynamic stressors was different in the AF cohort.

The mechanism of increase in BNP in the SR cohort with HUT is unclear; given the left ventricular end diastolic pressure would have tended to fall as reflected by PCWP measurements. This being so, recent data has shown the relationship between plasma BNP and filling pressures to be weak [28]. The increase in BNP may be compensatory in response to increased sympathetic activity with HUT, our group has previously shown that BNP can decrease sympathetic activity, in particular renal sympathetic activity, in HF [29]. Other possibilities include the involvement of BNP in the peripheral baroreflex response, which is activated in the heart during HUT to maintain haemodynamic homeostasis [30]. Natriuretic peptides can enhance the sensitivity of cardiac baroreflex and chemoreflex responses via sensitization of cardiac vagal afferent pathways to enhance bradycardia in response to rapid increases in blood pressure and the greatest effect is observed with BNP [31,32]. Immunoreactive BNP has been co-localised with ANP in the purkinje fibres and atrioventricular bundle but not in nerve varicosities in the conduction system [33], indicating possible direct local effects on cardiac conduction which could potentially be affected by cardiac rhythm. Furthermore the conflicting effects of natriuretic peptides on the peripheral vasculature also indicate potential involvement in baroreflex response, studies have demonstrated evidence for vasodilatation [34], no effect [34] and even vasoconstriction [35].

The cardiac release of BNP potentially may be altered by cardiac rhythm such that the lack of increase in the AF group may imply impairment of these compensatory baroreflex mechanisms. Atrial remodelling and loss of atrial compliance secondary to processes such as atrial fibrosis associated with AF [36] may impair cardiopulmonary baroreceptor function more than in SR and HF. Subsequent to this, control mechanisms for cardiac release of BNP may be impaired in response to haemodynamic stress. It is also conceivable that myocardial tissue stores of BNP could be modified by secondary adverse changes resulting from long-term AF. Indeed it has been previously shown that while an acute hemodynamic stimulus may trigger cardiac BNP release, the response is finite in duration, even in the presence of ongoing physiologic challenge [37]. It is therefore plausible that in AF, the myocardium becomes unable to respond to physiologic stimulation.

With isometric handgrip exercise, the SR cohort had a more significant haemodynamic response but the AF group was significantly more hypertensive and had greater cardiac output during exercise. In addition, the increment in PCWP with exercise was almost significant in the SR group but not the AF group. The differences in haemodynamics may have contributed to the differences in cardiac BNP release with exercise; however, these differences alone would not appear to be enough to adequately explain the significant decrease in cardiac BNP release in the AF cohort. As previously observed, hypertension in association with diastolic dysfunction has been demonstrated to elevate plasma BNP levels [38,39].

Previous studies have demonstrated conflicting plasma BNP responses to exercise in HF, with increases [15-17] and decreases [18,19] in plasma BNP observed. The amount and degree of exercise in these studies were generally greater than in our study and this may account for the lack of increase in cardiac BNP release in our SR cohort. One study demonstrated that decreased BNP response during exercise was associated with increased mortality [19], however this study did not differentiate response for cardiac rhythm. Previously, AF in a HF cohort has been associated with elevated BNP plasma levels in comparison to SR post direct current cardioversion [40]. A further study not in HF patients, however, supported the association of AF and elevated plasma BNP levels [12]. Yet this association was not demonstrated in another larger study in HF [13]. In this study, it was demonstrated that the degree of left ventricular dysfunction was the main determinant of plasma BNP. These studies were all performed at rest. Our current study extends these findings with the observation of a differential release of BNP from the heart in HF patients, in response to haemodynamic stress, dependent on cardiac rhythm, albeit in a modest sized cohort.

Apart from one study [15], which sampled pulmonary venous blood, all other studies sampled peripheral venous blood to analyse BNP response to haemodynamic stress of exercise. Our current study is the only one to examine a BNP gradient across the heart in response to haemodynamic stress. Sampling peripheral venous blood introduces the potential for interference from non-cardiac sources and inability to gauge acute changes in cardiac release. It also does not allow for other potential confounding factors such as removal from the blood by clearance, degradation and excretion [41]. In HF, it has previously been demonstrated that there is a step up in BNP across the heart [42,43] and again in this study we have observed this in both the SR and AF cohort. It is from data such as this that the source of BNP is believed to be predominantly from the ventricle [43]. The level of BNP measured in this study is higher than venous plasma levels of other studies but consistent with previous studies measuring trans-cardiac BNP levels [42].


   5. Limitations
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
6. Conclusion
 References
 
By virtue of the invasive nature of our study, the sample size in the current study is relatively modest, limiting the statistical power of our conclusions. In addition it is also possible that other factors not measured in this study may have influenced BNP release in each cohort. The current study did not include a normal control group, since the protocol was particularly invasive, and accordingly did not ethically permit the recruitment of a normal control group.


   6. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
References
 
In the present study we found that while in patients in sinus rhythm, hemodynamic stressors appear to influence the cardiac release of BNP from the myocardium, this response is ameliorated in patients in atrial fibrillation. This finding may provide some explanation for the apparent influence of heart rhythm on outcome for heart failure patients. Further research is required to understand the mechanism of release of BNP from the heart in HF and the clinical significance of variations in release as observed in this study.


   Acknowledgements
 
This study was performed with support from the Atherosclerosis Research Trust (UK) and National Health and Medical Research Council of Australia.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations
 6. Conclusion
 References
 

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