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European Journal of Heart Failure 2004 6(1):29-39; doi:10.1016/S1388-9842(03)00035-7
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© 2004 European Society of Cardiology

Basal and exercise-induced neuroendocrine activation in patients with heart failure and in normal subjects

Andreas Kjæra,b,*, Jon Appelc, Per Hildebrandtc and Claus Leth Petersena

a Department of Clinical Physiology and Nuclear Medicine, Frederiksberg Hospital University of Copenhagen, Nordre Fasanvej 57, DK-2000 Frederiksberg, Denmark
b Department of Medical Physiology, The Panum Institute University of Copenhagen, Copenhagen, Denmark
c Department of Cardiology E, Frederiksberg Hospital University of Copenhagen, Frederiksberg, Denmark

* Corresponding author. Tel.: +45-3816-4771; fax: +45-3816-4779. E-mail address: kjaer{at}mfi.ku.dk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Statistics
 4. Results
 5. Discussion
 References
 
Background: Neuroendocrine activation is a pathophysiological response and an important prognostic marker in patients with chronic heart failure (CHF). Although chronic activation is well described, data on the responsiveness of the hormone systems are more limited. Most previous studies have looked at activation during maximal exercise, whereas we believe that activation at a submaximal level might be more pathophysiologically relevant.

Aim: To compare exercise-induced neurohormonal activation between CHF patients and normal subjects using the same relative and submaximal workload.

Subjects: Twenty-three newly-diagnosed CHF patients and 18 age- and gender-matched healthy subjects were exercised at two workloads, which were calculated to correspond to 50 and 75% of each individual's heart rate response.

Results: In CHF patients, baseline levels of ANP, BNP, AVP, PRA and ET-1 were elevated compared to healthy subjects. Exercise induced an increase in ANP, A and NA in both CHF patients and in normal subjects, however BNP was only increased in CHF patients and not in normal subjects.

Conclusion: When CHF patients exercise at the same relative and submaximal level as age-matched healthy subjects, the relative increases in ANP, A and NA were similar, however, BNP levels only increased in the CHF group.

Key Words: Heart failure • Exercise • Atrial natriuretic peptide • Brain natriuretic peptide • Vasopressins • Catecholamines • Adrenaline • Noradrenaline • Renin • Endothelin-1

Received November 12, 2001; Revised October 8, 2002; Accepted January 23, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Statistics
 4. Results
 5. Discussion
 References
 
It is now generally accepted that neuroendocrine activation is a pathophysiological response and an important prognostic marker in patients with chronic heart failure (CHF). Several hormones are activated when measured at rest. The neurohormones activated in CHF have both beneficial and deleterious effects [1]. Since chronic activation of hormones often leads to compensatory down-regulation of specific receptors, an increased absolute level may not be important in the long term. However, since many of the neurohormones activated in CHF are important for hemodynamic balance, the responsiveness of the system may be more important during increases in workload (i.e. to remain well compensated during physical stress). In order to study this responsiveness or secretory capacity, it is necessary to compare exercise-induced changes in hormone levels in CHF patients, with age- and gender-matched healthy subjects. Relatively few studies have done this and the findings are not consistent. Most previous studies have used maximal, symptom-limited exercise protocols to test the increase in hormone levels. Although of value, this approach is not without problems. Firstly, the total exercise time will vary between the groups and subjects studied, which is not ideal considering the possible depletion of hormone stores and the time-delay before maximal activation is reached. Secondly, if the pathophysiology of the disease is to be studied, maximal workload and exhaustion is not something the patient typically experiences in everyday life, submaximal workload is more representative. We believe the best way to study the capacity to increase neurohormonal systems is by using a protocol where the same relative and submaximal workload is reached after a fixed time. In order to achieve this, the heart-rate response to different workloads in each individual was established in a separate session preceding the study. Furthermore, most of the studies performed to date have acknowledged that patients were receiving medication, which could potentially interfere with neuroendocrine parameters. We therefore limited our study to newly-diagnosed heart failure patients, who were only allowed to take diuretics, but not beta-blockers, ACE-inhibitors, angiotensin II antagonists, or calcium antagonists.

The aim of the present study was thus to compare the exercise-induced neurohormonal activation between CHF patients and normal subjects during the same relative and submaximal workload.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Statistics
 4. Results
 5. Discussion
 References
 
2.1. Subjects
Twenty-three patients with newly diagnosed, untreated (except for diuretics) congestive heart failure (CHF) defined as New York Heart Association (NYHA) class II or III and echocardiographic left ventricular ejection fraction (LVEF) below 0.45 were included. The majority of patients (78%) had heart failure of ischemic etiology (previous myocardial infarction or history of angina). The control group comprised 18 age- and gender-matched healthy volunteers. Characteristics of the two groups are shown in Table 1. None of the patients received beta-blockers, ACE-inhibitors, angiotensin II antagonists, or calcium antagonists during the study. Eighty-seven percent of the CHF patients received diuretics. Of the patients on diuretics, 85% received a loop diuretic, 20% a thiazide and 10% an aldosterone antagonist. All patients were in sinus rhythm. Written informed consent was obtained from all participants prior to the study and the investigation conformed with the principles outlined in the Declaration of Helsinki. The project was approved by the local scientific ethics committee.


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  		Table 1 Comparison of baseline characteristics of the two groups studied

 
2.2. Protocol
All subjects had their maximal exercise capacity and heart rate response established on an ergometer bicycle in a session prior to the start of the study. On the day of testing, individual workloads were chosen so that the subjects would achieve 50 and 75% of their individual heart rate response (i.e. all subjects were exercised at the same relative workload). Semi-arterialized blood samples were obtained via an intravenous line in the cephalic vein of the forearm. Baseline blood samples were drawn following a minimum of 45 min of seated rest. Subjects then exercised for 30 min on an ergometer bicycle: the first 15 min at the workload calculated to give 50% of the individual heart rate response and the last 15 min at a level calculated to give 75% of the individual heart rate response. Blood samples were drawn at 0, 5, 15, 20, 30, 40 and 60 min (i.e. after 5 and 15 min of each workload and 10 and 30 min after discontinuation of exercise). If subjects had to stop exercise before 30 min, post-exercise samples were drawn 10 and 30 min after discontinuation of exercise and referred to as ‘40’ and ‘60 min’ samples. ECG/HR was monitored continuously. Blood pressure was measured immediately prior to each blood sampling, and at the same time the subjects scored their perception of how hard the workload was, using the Borg score [2].

2.3. Blood sample analysis
Blood was drawn into tubes containing either: EDTA [for analysis of arginine-vasopressin (AVP) and plasma renin activity (PRA)], EDTA+aprotinin [for analysis of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and endothelin-1 (ET-1)], glutation-EGTA [for analysis of adrenaline (A) and noradrenaline (NA)] or heparin (for analysis of lactate) and immediately transferred to ice-cold water. The samples were centrifuged at 10,000xg for 10 min, transferred to polyethylene tubes and immediately frozen and kept at –20 °C until analyzed.

A and NA were determined simultaneously by a radioenzymatic assay [3]. The sensitivity of the assay was 10–20 pg/ml. The intraassay coefficients of variation for A and NA were 4.3 and 6.8%, respectively. The interassay coefficients of variation were 12.3 and 14.8%, respectively.

Determination of PRA was performed by a radioimmunoassay (RIA) [4]. The intra- and interassay coefficients of variation were 3.2 and 3.6%, respectively.

ANP was measured by a RIA of plasma extracted by means of C18 Sep-Pak cartridges according to a previously described procedure [5]. The sensitivity of the assay was 3.1 pg/ml and the intra- and interassay coefficients of variation were 4 and 5%, respectively.

BNP was measured in extracted plasma by RIA (Peninsula laboratories, Belmont, CA, USA). Extraction procedure: thawed plasma samples were centrifuged for 10 min at 4 °C and 2 ml of plasma was acidified to pH 2 to 3 by addition of 6 ml of 4% acetic acid. The C18 Sep-Pak cartridges (Waters, Milford, MA, USA) were attached to plastic syringes and connected to a peristaltic pump (1.2 ml/min). The cartridges were primed by passing 6 ml 96% ethanol/4% acetic acid, 6 ml 100% methanol, 6 ml distilled water and 6 ml 4% acetic acid through them. The acidified plasma samples were poured into the syringes. The cartridges were then washed by 6 ml of distilled water and allowed to suck air. BNP was eluted from the cartridges into polyethylene tubes containing 10 µl of 0.1% Triton-X by 3 ml of 96% ethanol/4% acetic acid. The extracts were dried by air overnight. The sensitivity of the assay was 5 pg/ml. The intra- and interassay coefficients of variation were 9 and 10%, respectively.

AVP was measured by RIA of plasma extracted by means of C18 Sep-Pak cartridges according to a previously described procedure [6]. The sensitivity of the assay was 0.11–0.32 pg/ml plasma, and the intra- and interassay coefficients of variation were 8 and 12%, respectively.

ET-1 was measured by ELISA (Peninsula laboratories, Belmont, CA, USA). The minimum sensitivity of the assay was 0.78 pg/ml and the intra- and interassay coefficients of variation were 6 and 9%, respectively.

Lactate was measured according to a previously described enzymatic method [7] using a commercial kit (Boehringer Ingelheim, Germany).


   3. Statistics
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistics
4. Results
 5. Discussion
 References
 
Absolute values and values relative to the individual baseline value for each group (CHF or controls) were compared with the baseline value of the same group by paired t-test, corrected according to the Bonferroni procedure. Comparisons between the two groups at the different time-points were performed by t-tests for independent groups. All analyses were performed by SPSS statistical software package version 9.0 (SPSS Inc., Chicago, IL, USA). P<0.05 was considered significant.


   4. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistics
 4. Results
5. Discussion
 References
 
4.1. Exercise test
The average workloads corresponding to 50 and 75% of the individual HR response were 35 W (range: 15–50 W) and 51 W (25–75 W) in the CHF group and 73 W (40–100 W) and 104 W (60–150 W) in the control group.

4.2. Neurohormonal activation at baseline
Compared to gender- and age-matched controls, patients with CHF had two- to fourfold higher levels of ANP (P<0.001), BNP (P<0.001), AVP (P<0.001) and PRA (P<0.05). ET-1 was more than 30% higher in patients with CHF than in normal subjects (P<0.01). In contrast, the baseline levels of A and NA did not differ between the CHF and control groups (Table 2).


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  		Table 2 Comparison of baseline levels of neurohormones in patients with chronic heart failure (CHF) and gender- and age-matched healthy subjects

 
4.3. Exercise-induced neurohormonal activation
The relative level of exercise achieved was similar in the two groups, as indicated by similar Borg scores [15 (range: 12–17) vs. 14 (range: 11–17) in the CHF and control groups, respectively] and similar maximal levels of lactate (2.99±0.24 and 2.85±0.29 mmol/l in control and CHF groups, respectively; P>0.05).

4.3.1. ANP
Exercise induced an approximately twofold increase in ANP levels in both the control and CHF groups but this was only statistically significant in the control group. The absolute ANP values were higher in the CHF than in the control group throughout the study. When hormone levels were converted to values relative to the individual baseline level, a statistically significant twofold exercise-induced increase was present in both groups, with no difference between the two groups. The average time to peak was shorter in the CHF group compared to the control group (20.0±2.6 vs. 27.5±2.1 min, P<0.05) (Fig. 1).


Figure 1
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  		Fig. 1 Effect of submaximal exercise on plasma levels of ANP in CHF patients (black bars) and age- and gender-matched normal healthy subject (white bars). All subjects exercised for 15 min at a workload individually calculated to give 50% of their maximal heart rate response (WL1) followed by 15 min at a workload calculated to give 75% of their maximal heart rate response (WL2). Blood samples were drawn at rest (0 min), after 5 and 15 of exercise at each workload (5, 15, 20, 30 min) and 10 and 30 min after discontinuation of exercise (40, 60 min). Absolute values (upper panel) or relative values, calculated according to individual baseline levels (lower panel) are presented as mean±S.E.M. #P<0.05; ##P<0.01 vs. value at rest (0 min) of same group. *P<0.05; **P<0.01 vs. other group at same time-point.

 
4.3.2. BNP
Exercise induced a slight increase (30%) in BNP levels in the CHF group whereas levels were unchanged in the control group. Absolute BNP values were higher in the CHF than in the control group throughout the study. When hormone levels were converted to values relative to the individual baseline level, no differences were found between the two groups (Fig. 2).


Figure 2
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  		Fig. 2 Effect of submaximal exercise on plasma levels of BNP in CHF patients (black bars) and age- and gender-matched normal healthy subject (white bars). For further details please see Fig. 1. #P<0.05; ##P<0.01 vs. value at rest (0 min) of same group. *P<0.05; **P<0.01 vs. other group at same time-point.

 
4.3.3. AVP
Exercise did not induce any significant increase in AVP levels in any of the groups. The absolute levels were higher in the CHF group than in the control group throughout the study. When hormone levels were converted to values relative to the individual baseline level, an average three- to fourfold increase was observed in both groups, but due to large variations, only the increase in the control group was statistically significant. No differences in relative AVP levels between the two groups were present at any time (Fig. 3).


Figure 3
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  		Fig. 3 Effect of submaximal exercise on plasma levels of AVP in CHF patients (black bars) and age- and gender-matched normal healthy subject (white bars). For further details please see Fig. 1. #P<0.05; ##P<0.01 vs. value at rest (0 min) of same group. *P<0.05, **P<0.01 vs. other group at same time-point.

 
4.3.4. A and NA
A and NA increased two- to fourfold in response to exercise in both groups. When converted to relative values, the increase in response to exercise was similar in the two groups (Figs. 4 and 5)


Figure 4
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  		Fig. 4 Effect of submaximal exercise on plasma levels of A in CHF patients (black bars) and age- and gender-matched normal healthy subject (white bars). For further details please see Fig. 1. #P<0.05; ##P<0.01 vs. value at rest (0 min) of same group. *P<0.05; **P<0.01 vs. other group at same time-point.

 


Figure 5
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  		Fig. 5 Effect of submaximal exercise on plasma levels of NA in CHF patients (black bars) and age- and gender-matched normal healthy subject (white bars). For further details please see Fig. 1. #P<0.05; ##P<0.01 vs. value at rest (0 min) of same group. *P<0.05; **P<0.01 vs. other group at same time-point.

 
4.3.5. PRA
No significant increases in PRA levels, absolute or relative, were seen in response to exercise (data not shown).

4.3.6. ET-1
No significant changes in absolute or relative ET-1 levels were seen in response to exercise (Fig. 6)


Figure 6
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  		Fig. 6 Effect of submaximal exercise on plasma levels of ET-1 in CHF patients (black bars) and age- and gender-matched normal healthy subject (white bars). For further details please see Fig. 1. *P<0.05 vs. other group at same time-point.

 

   5. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistics
 4. Results
 5. Discussion
References
 
We found that patients with CHF had elevated baseline levels of ANP, BNP, AVP, PRA and ET-1. This indicates general neuroendocrine activation in our CHF group. For ANP, our findings are in agreement with several other studies [8–12]. ANP is primarily produced in the atria and released by atrial distention [13]. It dilates arterioles and increases sodium excretion from the kidneys. In CHF, the activation of ANP initially counteracts the effect of the vasoconstrictor systems and is thereby beneficial, although the effect is not permanent. Our finding of increased BNP levels in CHF is also in accordance with other studies [14–17]. As for ANP, the effect of BNP is vasodilatation and natriuresis. BNP is especially located in the ventricles of the heart and is released primarily from the left ventricle in response to increased filling pressure [15]. Our finding of increased levels of AVP in CHF is also in accordance with other studies [18]. AVP is produced in the hypothalamus and released from the neurohypophysis. The physiological actions of AVP are vasoconstriction and decrease in free-water clearance. Our finding of increased levels of PRA in CHF is also in accordance with others [8,19]. Concomitant medication can cause problems in interpreting data on renin in CHF. Diuretics, ACE-inhibitors and angiotensin II receptor blockers are known to increase renin levels, whereas beta-blockers have the opposite effect [20,21]. The fact that patients in our study were only permitted diuretics makes our study interesting since it indicates that renin activation in CHF is not only due to effects of ACE-inhibitors, angiotensin II receptor antagonists or beta-blockers. Whether the increase in renin levels in our study was solely due to diuretic treatment is impossible to tell, since most of the CHF patients received diuretics. Renin is synthesized in the kidneys and released from the juxtaglomerular cells. Its main hemodynamic action in CHF is mediated via angiotensin II, which is a potent vasoconstrictor and increases release of aldosterone. The increased levels of ET-1, a strong vasoconstrictor, found in our study is in concordance with several previous studies [22–27].

However, the normal levels of A and NA found in our CHF patients is in contrast to other studies, in which increased levels of NA have been shown [8,9,20,28–30]. One explanation for this discrepancy could be the previously demonstrated close relationship between activation of NA and the degree of hemodynamic abnormalities [19] as our patients might have been less decompensated. Another explanation could be that our patients were all newly diagnosed CHF patients and that the time course of activation of the different systems are not identical. The fact that N-terminal ANP and BNP are known to be activated early in the course of the disease namely in asymptomatic CHF [31] lends support to this theory. If this is true, our data suggest that A and NA are not useful for diagnosing early stage CHF. An alternative explanation could be the rather high age of our study groups, since it has been demonstrated that NA levels increase with age [32]. Furthermore, it is possible that differences in diuretic treatment could also explain these differences [21].

Exercise induced an increase in levels of ANP, A and NA in both groups and of BNP in the CHF group but not in AVP, PRA and ET-1. Using the same relative and submaximal workload, there were no significant differences in the relative hormone response to exercise between the CHF and control groups, except for BNP. To our knowledge, no previous studies have used a protocol similar to ours, making a direct comparison with previous results difficult.

Previous studies, using maximal exercise protocols, have found that ANP levels during exercise increased significantly in patients with CHF but not in the control groups [33,34]. In contrast, other studies have found no difference in the absolute levels of ANP at peak exercise [35,36] or in increase of ANP [37]. An important factor for neuroendocrine activation is the possible interference with medical treatment, e.g. the recently shown direct effect of beta-blockers on ANP and BNP levels [38]. In our study, only diuretics were allowed, which could be the reason for the lack of any difference. In support of this idea, another study of untreated CHF patients showed no difference in ANP increase between normal subjects and CHF patients. [37]. In one previous study, ANP secretion was indexed relative to oxygen uptake at maximal exercise, in this study it was found that the ANP-exercise ratio was higher in CHF patients than in normal subjects [39]. In our study, the ANP response to exercise peaked earlier in the CHF group than in the control group. This indicates some kind of ‘exhaustion’ of the rapid atrial release of ANP in contrast to the control group. The explanation could be a depletion of the ANP stores in the CHF patients, where higher basal levels of ANP have to be maintained.

The effect of maximal exercise on BNP has previously been studied and absolute levels were found to be higher in CHF patients than in normal subjects [40]. The increase was only significant in the CHF group [33] and the BNP-exercise ratio (i.e. change in BNP normalized with change in oxygen consumption) was higher in CHF patients [40]. In accordance with this, we found that the increases in absolute BNP levels were only significant in the CHF group and that the levels of BNP were higher in this group. When converted to relative values, an increase was only observed in the CHF group. However, in contrast, the relative levels at the single time points were not statistically different. There seems to be a trend towards higher relative levels of BNP during exercise in the CHF group compared to normal subjects and we cannot totally rule out the fact that the lack of difference may have been due to a type II error in our study. Differences in pharmacological treatment could also explain some of the discrepancies. However, direct comparison between our data and the study that used BNP-exercise ratio (40) is not possible. Firstly, the latter study did not take into account the different absolute level of hormones in the two groups (i.e. relative increase). Secondly, it did not take into account differences in maximal oxygen uptake.

Both in controls and CHF patients A and NA increased during exercise, which is in agreement with several previous studies [41–43]. In general the relative increment or secretory reserve were similar in the two groups. However, since basal levels were increased in CHF patients in some studies, higher peak levels were obtained in the CHF groups compared to normal subjects. One study, using an approach almost similar to ours (subjects exercised at 50% of maximum voluntary exercise capacity), demonstrated a similar relative increase in NE [41]. Unfortunately, this study was rather small (six patients and nine healthy volunteers). However, in line with previous data, our study demonstrates that the ability to increase catecholamines is unchanged in CHF patients.

ET-1 levels were unchanged throughout exercise both in CHF patients and in controls. For CHF patients this in agreement with most previous studies [24,44–46]. Two of these studies included controls and found, as we did, that no change in ET-1 was induced by exercise [24,46].

In summary, we found that in newly diagnosed CHF patients, baseline levels of ANP, BNP, AVP, PRA and ET-1 were elevated compared to healthy subjects. Exercise induced an increase in ANP, A and NA in both in CHF patients and in normal subjects and of BNP in CHF patients but not in normal subjects. Increments in ANP, A and NA were similar in healthy subjects compared to CHF patients at the same relative, submaximal workload, whereas BNP only increased in the CHF group.


   Acknowledgements
 
We thank Anne-Mette Hviid, Lisbeth Skibdal Sørensen, Elsa Larsen and Jytte Oxbøl for skilled technical assistance.


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

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