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European Journal of Heart Failure 2008 10(8):793-795; doi:10.1016/j.ejheart.2008.06.008
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© 2008 European Society of Cardiology

Exercise-induced biphasic increase in circulating NT-proBNP levels in patients with chronic heart failure

Viviane M.A. Conraadsa,*,1, Cathérine De Maeyera, Paul Beckersa, Nadine Possemiersa, Manuella Martinb, Viviane Van Hoofc and Christiaan J. Vrintsa

a Department of Cardiology, Antwerp University Hospital Belgium
b Laboratory of Hormones, Antwerp University Hospital Belgium
c Laboratory of Biochemistry, Antwerp University Hospital Belgium

* Corresponding author. Department of Cardiology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel.: +32 3 821 46 72; fax: +32 3 821 39 74. E-mail address: Viviane.Conraads{at}uza.be (V.M.A. Conraads).


   Abstract
Top
 Notes
 Abstract
1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusions
 References
 
Background: Exercise increases natriuretic peptide levels in chronic heart failure (CHF) patients, but the effect is considered minor. We assessed acute and short-term release (<24 h) of NT-proBNP in CHF patients after a maximal cardiopulmonary exercise test (CPET) and 2 different submaximal training sessions.

Methods and results: 102 CHF patients either performed CPET (Group 1), a 1 h endurance (Group 2) or a combined endurance–resistance training session (Group 3). NT-proBNP concentration was determined before, at exercise cessation and after 18–22 h (Protocol A). In 20 patients, samples were obtained before, at exercise cessation, after 15, 30, 45, 60, 90 min, 2, 3, 4, 5, 6, 12, 22 h (Protocol B).

Protocol A: At peak exercise, a 15%, 11% and 17% relative increase (p<0.001 vs baseline, all 3 groups) was seen, with a return to baseline after 18–22 h. The increase correlated with indicators of more advanced heart failure.

Protocol B: A biphasic pattern was derived with a first peak within 1 h of exercise termination and a second peak (39%, 31% and 33% higher than baseline; p<0.05, all 3 groups) after 4–12 h.

Conclusions: The observed biphasic release of B-type natriuretic peptides supports standardization of sampling, taking recent exercise into account.

Key Words: Natriuretic peptides • Chronic heart failure • Exercise

Received April 1, 2008; Revised May 21, 2008; Accepted June 10, 2008


   1. Background
Top
 Notes
 Abstract
 1. Background
2. Aims
 3. Methods
 4. Results
 5. Conclusions
 References
 
Natriuretic peptides provide incremental benefit in establishing the diagnosis of congestive heart failure [1,2]. In addition, they allow prognostic discrimination [3,4] and may help to guide treatment [5,6]. Despite good analytical performance of these biomarkers, biological variation of both BNP and NT-proBNP, secondary to obesity, gender, age and renal dysfunction, is of concern [7,8]. A maximal exercise bout in chronic heart failure (CHF) patients has been shown to acutely increase circulating levels of B-type natriuretic peptides [9-12]. The prolonged effect of peak exercise and the influence of extended submaximal exercise sessions is unknown.


   2. Aims
Top
 Notes
 Abstract
 1. Background
 2. Aims
3. Methods
 4. Results
 5. Conclusions
 References
 
To test the effect of 3 modes of exercise on the acute and short-term release (<24 h) of NT-proBNP in patients with CHF. The 3 modes of exercise were: a maximal symptom-limited cardiopulmonary exercise test (CPET), an endurance training session and a combined endurance-resistance training session.


   3. Methods
Top
 Notes
 Abstract
 1. Background
 2. Aims
 3. Methods
4. Results
 5. Conclusions
 References
 
Stable, optimally treated outpatiens with CHF (left ventricular ejection fraction (LVEF) <40%, ischemic or dilated cardiomyopathy) were included. Patients with recent revascularisation/acute coronary syndrome (<6 weeks), acute peri-myocarditis and creatinine>2.5 mg/dl were excluded. Approval by the Institutions' local Ethics Committee and written informed consent were obtained. Group 1 (n=29, 58±2 y, 23 males, LVEF 28±2%, baseline NT-proBNP 1970±511 pg/ml) performed a symptom-limited bicycle CPET; Group 2 (n=36, 62±2 y, 26 males, LVEF 34±2%, baseline NT-proBNP 3213±656 pg/ml) participated in a 1 h endurance exercise session; Group 3 (n=37, 63±2 y, 25 males, LVEF 34±2%, baseline NT-proBNP 2698±610 pg/ml) attended a 1 h combined endurance-resistance exercise session, as previously described [13]. Blood was collected into EDTA tubes. Plasma was separated by centrifugation and stored at –20 °C. NT-proBNP was determined with a sandwich immunoassay (Roche diagnostics). For Protocol A, blood was sampled before, immediately after exercise cessation and after 18 to 22 h. Consecutive patients who agreed to participate in Protocol A were asked to stay overnight in order to be enrolled in Protocol B. Protocol B consisted of 14 blood samples taken before, immediately after exercise cessation, and after 15, 30, 45, 60, 90 min, 2, 3, 4, 5, 6, 12, and 22 h. Non-parametric tests were used as appropriate. (SPSS, version 15.0 SPSS Inc., Chicago, Illinois). P-values<0.05 were considered significant.


   4. Results
Top
 Notes
 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
5. Conclusions
 References
 
Resting NT-proBNP correlated with functional parameters (LVEF: r=–0.4, p<0.001; maximal workload: r=–0.05, p<0.001; VO2peak: r=–0.5, p<0.001, with creatinine (r=0.4, p<0.001) and BMI (r=–0.4, p<0.001).

4.1. Protocol A
At peak exercise, the relative increase compared to baseline was 15%, 11% and 17% (all p<0.001) for groups 1, 2 and 3, respectively. After 18-22 h, NT-proBNP levels had returned to baseline (all p>0.1). NT-proBNP increase at exercise cessation correlated with disease severity (LVEF: r=–0.3: p=0.001; maximal workload: r=–0.3, p=0.01; VO2 peak: r=–0.3, p=0.03, resting NT-proBNP: r=0.7, p<0.001).

4.2. Protocol B
Out of the 3 groups, 20 patients (Group 1; n=7, Group 2: n=6, Group 3; n=7) agreed to participate in protocol B (14 blood samples). In these patients, a common pattern was discernable; there was an initial peak in NT-proBNP concentration within 1 h after exercise, a second peak between 4 and 12 h post exercise and a return to baseline levels after 18 to 22 h. Fig. 1 clearly illustrates that, compared to the first peak, the second peak attained even higher values for all 3 groups. NT-proBNP levels measured at the second peak were 39% (p=0.02), 31% (p<0.05) and 33% (p=0.04) higher than at baseline for groups 1, 2 and 3, respectively.


Figure 01
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  		Fig. 1 Percentage increase compared to baseline NT-proBNP levels (ProtocolB) for CHF-groups.

 

   5. Conclusions
Top
 Notes
 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusions
References
 
CPET, as well as 2 different modes of sustained submaximal exercise elicited a biphasic NT-proBNP increase in CHF patients. The second peak outreached the immediate rise following exercise cessation. In vitro experiments [14] and in vivo models of acute heart failure [15] support the assertion that an early ventricular storage release due to wall stress is followed by activated transcription and sustained de novo production. Although speculative, two considerations should be taken into account. Firstly, the observed NT-proBNP concentration curves might result from prolonged diastolic dysfunction. Morikawa et al. [16] demonstrated that peak exercise in patients with dilated cardiomyopathy induced prolonged decreased early left ventricular diastolic filling velocity and a sustained prolongation of diastolic filling deceleration time. On the other hand, neuromodulatory effects resulting in lower levels of circulating natriuretic peptides have been demonstrated as a result of both endurance [17] and combined endurance-resistance training [13]. One might hypothesize that repetitive bursts of prolonged natriuretic peptide release in response to regular physical exercise would eventually aid in reversing disturbed haemodynamics and left ventricular remodelling.

The present results should be interpreted with caution since the sample size for protocol B was small and the biphasic pattern needs confirmation with the use of BNP measurements. In addition, biological variability of NT-proBNP in a non-exercising control CHF group is lacking.

This study proposes a hitherto unrecognized biphasic increase of significant magnitude (second peaks that attained 130 to 140% of resting values) in CHF patients following exercise. In order to minimize intra-individual variability, information on recent physical exercise at the time of blood sampling for NT-proBNP evaluation might be of interest.


   Notes
Top
 Notes
Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusions
 References
 
1 Viviane Conraads is a Senior Clinical Investigator of the Fund for Scientific Research (FWO)-Flanders (Belgium). Back


   References
Top
 Notes
 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusions
 References
 

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