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European Journal of Heart Failure 2006 8(1):46-53; doi:10.1016/j.ejheart.2005.05.007
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© 2005 European Society of Cardiology

Neuro-hormonal activation predicts ventilatory response to exercise and functional capacity in patients with heart failure

Claudio Passino*, Roberta Poletti, Francesca Bramanti, Concetta Prontera, Aldo Clerico and Michele Emdin

CNR Institute of Clinical Physiology National Research Council, Via Moruzzi 1, 56124 Pisa, Italy

* Corresponding author. Tel.: +39 50 3152191; fax: +39 50 3152109. E-mail address: passino{at}ifc.cnr.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Heart failure (HF) is characterised by reduced tolerance to effort, associated with progressive fatigue and dyspnoea. Neuro-hormonal activation is a hallmark of HF and influences its clinical evolution.

Aim: To evaluate the relationship between neuro-hormonal activation, exercise capacity and ventilatory efficiency.

Methods and results: 154 HF patients (127 males, 62±1 years) underwent cardiopulmonary exercise testing and resting blood sampling for assay of plasma brain natriuretic peptide (BNP), NT-proBNP, norepinephrine, epinephrine, aldosterone and plasma renin activity (PRA). BNP and NT-proBNP levels correlated with peak oxygen consumption (VO2) (both R=–0.53, p<0.001), VE/VCO2 slope (R=0.56; p<0.001 and R=0.58; p<0.001, respectively) and maximum workload (R=–0.49; p<0.001 and R=–0.47; p<0.001, respectively). Norepinephrine correlated slightly less with peak VO2 (R=–0.38, p<0.001), VE/VCO2 (R=0.45; p<0.001) and maximum workload (R=–0.35; p<0.001). There was a significant inverse correlation between left ventricular ejection fraction and BNP (R=–0.48, p<0.001), NT-proBNP (R=–0.42; p<0.001) and norepinephrine (R=–0.43; p<0.001). Weaker correlations were found for PRA, exercise parameters and ejection fraction. ROC curves showed that BNP was able to identify patients with peak VO2<14 ml/min/kg (cut-off 98 pg/ml, AUC 0.775) and a VE/VCO2>35 (cut-off 183 pg/ml, AUC 0.797), as well as NT-proBNP (cut-off 537 pg/ml, AUC 0.799 and cut-off 1010 pg/ml, AUC 0.768, respectively) and norepinephrine (cut-off 454 pg/ml, AUC 0.716 and cut-off 575 pg/ml, AUC 0.783, respectively).

Conclusion: Haemodynamic impairment (as indicated by BNP and NT-proBNP plasma values) and sympathetic activation predict exercise capacity and ventilatory efficiency in HF patients.

Key Words: Neuro-hormones • Heart failure • Ventilation • Oxygen consumption • Functional capacity

Received October 11, 2004; Revised January 12, 2005; Accepted May 12, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Heart failure (HF) is characterised by reduced tolerance to effort, associated with progressive fatigue and dyspnoea. Peak oxygen uptake (VO2) and ventilatory response to exercise, measured by the slope of the increase in ventilation with respect to CO2 output (VE/VCO2 slope), are indices of exercise capacity and ventilatory efficiency, respectively, and have prognostic significance in patients with HF [1-4].

Neuro-hormonal activation is a hallmark of HF, with a predominance of the vasoconstrictor/sodium-retentive system (in particular adrenergic, renin-angiotensin-aldosterone, endothelin, and vasopressin systems) over the vasodilator/natriuretic system (namely cardiac natriuretic hormones) [5,6]. In particular, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are produced in response to increased wall stretch as well as to neuro-hormonal activation [6-8]. Plasma levels of BNP and NT-proBNP (the amino-terminal inactive peptide derived from cleavage of the pro-hormone proBNP and secreted in the blood in equimolar amounts) have a negative correlation with left ventricular systolic function, and have been proposed as a diagnostic tool and prognostic marker in HF patients [9,10]. The diagnostic accuracy of BNP (or NT-proBNP) is better than ANP and other neuro-hormonal assays in predicting the severity of systolic dysfunction and functional status [6,9].

It has recently been suggested that plasma BNP levels are related to VO2 at peak of exercise [11], and are a predictor of impaired exercise capacity in patients with HF [12]. Moreover, a combination of plasma BNP levels and peak VO2 improves risk stratification of patients with stable HF [13]. However, the role of adrenergic activation and the blood levels of these hormones (indices of haemodynamic change) in the origin of increased ventilatory drive and exercise intolerance has not been well evaluated in HF.

The aim of the present study was therefore to evaluate the relationship between functional capacity and ventilatory response to exercise, and neuro-hormonal activation, as assessed by BNP, NT-proBNP, norepinephrine, epinephrine, plasma renin activity (PRA) and aldosterone measurement in patients with HF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
We prospectively enrolled 154 consecutive patients with a diagnosis of cardiomyopathy, referred to our Institution from September 2002 to January 2004. Characteristics of the patients are summarised in Table 1. Inclusion criteria were: a significantly depressed (<45%) left ventricular ejection fraction (EF) and impairment of exercise capacity (peak VO2<25 ml/min/kg). Exclusion criteria were: acute myocardial infarction or unstable angina within the previous 6 months, exercise-limiting diseases, such as peripheral vascular disease, joint disease, significant primitive pulmonary disease, renal failure (defined as a creatinine value above 1.5 mg/dl) and significant anaemia (defined as haemoglobin concentration below 12 g/dl). HF severity was clinically evaluated according to the New York Heart Association (NYHA) classification.


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  		Table 1 Characteristics of the patients

 
All patients were treated with restriction of water-sodium intake (using a personalised, well-controlled diet with a sodium intake of 100-140 mmol/day) and were on stable (i.e.>1 month) optimal medical treatment, which was continued at the time of the study, for obvious ethical reasons. The study was approved by the ethical committee of our institution and informed consent was obtained from all patients. The investigation conforms with the principles outlined in the Declaration of Helsinki.

2.1. Plasma assays
Blood samples were withdrawn at 8 A.M. from an antecubital vein, after a 20-min supine rest. Samples for NT-proBNP and BNP analysis were put into ice-chilled polypropylene tubes containing EDTA and aprotinin (1 mg and 500 KIU/ml blood, respectively). Serum was rapidly separated by centrifugation and assayed immediately. NT-proBNP was measured by a fully automated electrochemiluminescence "sandwich" immunoassay on Elecsys 2010 analyser (Roche diagnostics, Germany; reference value: <155 pg/ml). BNP was measured with two-site immunoradiometric assay (IRMA, Shionogi, Osaka, Japan; reference value: <40 pg/ml).

Blood samples for catecholamine assay were drawn into pre-cooled plastic tubes containing EGTA (0.2 ml of solution at 9% W/V) as anticoagulant and glutathione (0.012 g) as antioxidant. The plasma was then separated from the blood cells within 30 min by centrifugation (3000xg) at 4 °C for 10 min, aliquoted and stored at –70 °C. The measurement of catecholamines in plasma was carried out automatically by HLC 725 (Eurogenetics-Tosoh, Turin, Italy) by purification, derivatisation of catecholamines and fluorescence detection at 480 nm with an excitation wavelength at 340 nm (reference value: norepinephrine<500 pg/ml; epinephrine<80 pg/ml).

Plasma renin activity (PRA) and aldosterone were measured by RIA (DiaSorin S.r.l., Saluggia, Italy); all assays were performed following the procedures specified by the manufacturers (reference value: PRA 0.2-2.8 ng/ml/h; aldosterone 20-180 pg/ml).

2.2. Cardiopulmonary exercise test (CPT and echocardiographic measurements)
On the same morning as the neuro-hormonal blood testing, echocardiography and a maximal CPT were performed. Exercise capacity was tested using an upright bicycle ergometer: exercise began with 10 W after a 4-min baseline recording and 1-min warm-up, followed by a ramp protocol with increments of 10 W/min to exhaustion. VO2, CO2 production, and minute ventilation were measured using a breath-to-breath gas analysis (Vmax, Sensormedics, USA). A 12-lead electrocardiogram was monitored continuously. Blood pressure was recorded every minute using a cuff sphygmomanometer. Peak VO2 was determined as the highest value in the terminal phase of the exercise. Ventilatory efficiency during exercise was defined as the slope of the ventilation versus VCO2 relation in its linear part (VE/VCO2 slope). The physician who performed and analysed the CPT was blinded to the results of the blood tests.

Left atrial and ventricular diameters, as well as posterior wall and septum thickness and left ventricular mass and EF, were measured by echocardiography in all patients according to the recommendations of the American Society of Echocardiography [14]. All echos were recorded on tapes or stored digitally and evaluated by expert echocardiographers who were unaware of the study aims and results.

2.3. Statistics
Statistical analysis was carried out using SPSS 12.0 (SPSS Inc., Chicago, IL, USA). Because BNP, NT-proBNP, norepinephrine, PRA and aldosterone values are not normally distributed, natural logarithmic transformation of data was used for statistical analysis when needed. Differences among independent groups were analysed by ANOVA. Linear regression analysis was performed to assess the relationship between neuro-hormones and other variables. The independent predictors of peak VO2 and VE/VCO2 slope were assessed by a multivariate linear regression, performed on the covariates found to be statistically significant at univariate linear regression. The predictive power of a variable was quantified in terms of the area under the receiver operating characteristic (ROC) curve. A difference in the Area Under the Curve (AUC) defined the increment in predictive power between different models. The statistical significance of difference of AUC from that of the line of "no information" and between different curves was evaluated by Mann-Whitney U-statistics. The results are expressed as mean±SEM and P value was considered significant when <0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Neuro-hormones and functional capacity
NT-proBNP, BNP and plasma norepinephrine concentrations were found to be significantly elevated in the more severe NYHA classes (Table 2). Aldosterone and PRA were slightly increased, compared to reference values. On average, the peak VO2 was depressed while the ventilatory drive to exercise, as expressed by the VE/VCO2 slope, was pathologically elevated.


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  		Table 2 Results from neuro-hormonal characterisation and cardiopulmonary testing

 
3.2. Relationship between neuro-hormones, cardiac function and functional capacity
NT-proBNP and BNP were significantly related to EF (R=–0.42, p<0.001 and R=–0.48, p<0.001, respectively) and to exercise parameters: peak VO2, VE/VCO2 slope and maximum workload (R=–0.47, p<0.001 and R=–0.49, p<0.001, respectively) (Fig. 1 and Table 3). Compared to NT-proBNP and BNP, norepinephrine correlated slightly less with peak VO2, VE/VCO2 slope and maximum workload (R=–0.35, p<0.001) and with EF (R=–0.34, p<0.001) (Fig. 2 and Table 3). Weaker correlations were found for PRA and peak VO2, VE/VCO2 slope and maximum workload (R=–0.17, p=0.043) and with EF (R=–0.23, p=0.004) (Table 3). No correlation was found between epinephrine or aldosterone and EF, as well as exercise variables. As compared to NT-proBNP or BNP, the correlations of EF with exercise variables were much weaker (Table 3).


Figure 1
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  		Fig. 1 Linear regression for NT-proBNP, exercise variables (peak VO2/kg, VE/VCO2 slope and maximum workload) and left ventricular function (ejection fraction). Dotted lines represent 95% confidence limits for slope of regression line.

 


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  		Table 3 Results from uni- and multivariate analysis, considering peak VO2 and VE/VCO2 as dependent variables

 


Figure 2
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  		Fig. 2 Linear regression for norepinephrine, exercise variables (peak VO2/kg, VE/VCO2 slope and maximum workload) and left ventricular function (ejection fraction). Dotted lines represent 95% confidence limits for slope of regression line.

 
There was no difference in EF (30.3±1.0 vs. 30.0±0.8%, p=ns) or in neuro-hormone concentration for patients with idiopathic or ischaemic cardiomyopathy, however, plasma norepinephrine levels were higher in the ischaemic population (670±38 vs. 560±41 pg/ml, p=0.012). Conversely, patients with ischaemic cardiomyopathy showed a significantly lower peak VO2 (11.9±0.4 vs. 13.8±0.5 ml/min/kg, p=0.005) and maximum workload (75±3 vs. 89±3 watts, p=0.004), as well as a reduction in ventilatory efficiency, as indicated by a steeper VE/VCO2 slope (40±1 vs. 35±1, p=0.003).

To investigate the independent predictors of peak VO2 and VE/VCO2 slope, multivariate linear regression analysis was used, which included all variables found to be statistically significant at univariate linear regression. Among these variables, age and NT-proBNP were both independent predictors of peak VO2 (p<0.001), whereas only NT-proBNP was an independent predictor of VE/VCO2 slope.

ROC curves indicate a good power of NT-proBNP and BNP in identifying patients with peak VO2 below 14 ml/min/kg (AUC 0.799, 95% CI 0.719-0.879 and AUC 0.775, 95% CI 0.696-0.855, respectively), or with VE/VCO2 slope higher than 35 (AUC 0.768, 95% CI 0.692-0.844 and AUC 0.797, 95% CI 0.725-0.869, respectively) (Fig. 3 and Table 4). Norepinephrine showed slightly less power in identifying patients with peak VO2 below 14 ml/min/kg (AUC 0.716, 95% CI 0.629-0.804), and a slightly better power in predicting VE/VCO2 slope higher than 35 (AUC 0.783, 95% CI 0.710-0.857) (Fig. 4). The threshold value for norepinephrine to predict a peak VO2 below 14 ml/min/kg was 454 pg/ml with a sensitivity of 77% and a specificity of 62%; a VE/VCO2 slope steeper than 35 was predicted with threshold value of 575 pg/ml with a sensitivity of 69% and a specificity of 77%. PRA, aldosterone and plasma epinephrine values were not able to discriminate patients with different functional capacity.


Figure 3
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  		Fig. 3 Receiver operating characteristic curve of NT-proBNP for the determination of peak VO2<14 ml/min/kg (left graph) and VE/VCO2 slope >35 (right graph). AUC: area under the curve.

 


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  		Table 4 Results from ROC analysis

 


Figure 4
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  		Fig. 4 Receiver operating characteristic curve of norepinephrine for the determination of peak VO2<14 ml/min/kg (left graph) and VE/VCO2 slope >35 (right graph). AUC: area under the curve.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Dysfunction of the neuro-hormonal control of circulation is recognised as a major determinant of the clinical evolution of heart failure [15]. This provides the rationale for the dramatic improvement observed with neuro-endocrine drugs, which counteract activation of the renin-angiotensin-aldosterone system and adrenergic overactivity [16-19]. An increase in cardiac natriuretic peptides, namely BNP, is a consistent finding in decompensated HF patients: the main stimulus is increased myocardial wall stretch [7,8]. However, the increased secretion of this natriuretic/vasodilator hormone is also aimed at counteracting the increased activity of sodioretentive-vasoconstrictor systems, namely the adrenergic, renin-angiotensin-aldosterone and endothelin systems [6]. For these reasons, BNP levels are elevated in patients with HF and mirror the severity of left ventricular dysfunction and the degree of neuro-hormonal activation [6,9,10].

NT-proBNP is the amino-terminal inactive peptide derived from cleavage of the pro-hormone, proBNP. NT-proBNP and BNP are secreted in the blood in equimolar amounts and have a similar diagnostic and prognostic power [10]. However, NT-proBNP has some characteristics that permit a more accurate determination. In particular, NT-proBNP has a higher molecular weight and shows a lower in vivo and in vitro degradation than BNP, resulting in a better reproducibility and functional sensitivity [20].

Reduction in exercise tolerance is a common feature of HF. Due to the poor correlation between indices of resting left ventricular systolic function and exercise tolerance [21], other indices have been sought to characterise patients with HF. In particular, exercise testing with metabolic gas exchange analysis has been shown to be clinically useful in the diagnosis and risk stratification of patients with HF. Poor exercise capacity, measured by low peak VO2, predicts an unfavourable outcome independently of other clinical and haemodynamic indices and is widely accepted as a prognostic marker in patients with HF [1,4,22,23]. Moreover, an enhanced ventilatory response to exercise, as expressed by the VE/VCO2 slope (related to poor haemodynamic status and pulmonary interstitial oedema), predicts poor prognosis in patients with HF [2,24].

In the present study, NT-proBNP and BNP were related to peak VO2 and to maximum workload, as well as to the VE/VCO2 slope. These results confirm those obtained by Kruger et al. [12] with BNP and by Williams et al. [11] with NT-proBNP. A similar, though slightly weaker relationship was also found for plasma norepinephrine levels and PRA, but not for aldosterone and epinephrine, and exercise variables. These data indicate a close relationship between exercise tolerance, ventilatory efficiency and neuro-hormonal activation. However, the absence of a relationship between aldosterone and epinephrine and functional capacity indicates that other factors may influence plasma levels of these hormones. Furthermore, it is known that plasma levels of epinephrine and aldosterone are not strictly related to clinical status in patients with HF [6].

Multivariate linear regression analysis indicates that NT-proBNP is an independent predictor of VO2 and VE/VCO2 slope. From ROC analysis, NT-proBNP, BNP and norepinephrine predict reduced functional capacity and impaired ventilatory efficiency: in particular, cut-off values of 537 pg/ml for NT-proBNP, 98 pg/ml for BNP and of 454 pg/ml for norepinephrine are able to discriminate patients with a peak VO2 higher than 14 ml/min/kg, which is an accepted cut-off value for clinical stability in patients with HF [22].

Independently of EF, patients with ischaemic cardiomyopathy have a worse clinical outcome compared to patients with idiopathic cardiomyopathy [25], possibly due to the coexistence of ischemia and left ventricular dysfunction, as factors limiting exercise tolerance. This is outlined in the present study, by a lower peak VO2 and a steeper VE/VCO2 slope and by higher norepinephrine plasma levels in patients with ischaemic cardiomyopathy, possibly favouring arrhythmic events.

It is remarkable that a simple assay, such as NT-proBNP or BNP, from blood sampled at rest, correlates well with markers of cardiac and ventilatory efficiency obtained during exercise. Exercise intolerance, manifested by symptoms of dyspnea and fatigue, has a multifactorial origin: cardiac dysfunction is a central phenomenon, but vascular (mal)adaptation, endothelial dysfunction, pulmonary function, and neuro-endocrine activation, triggered by abnormal baro-, chemo-, and ergoreceptor sensitivity, also play a significant role [21]. Both the secretion of natriuretic peptides by the ventricular cardiomyocytes, as measured by BNP/NT-proBNP plasma level, and cardio-pulmonary performance, as tested by CPT, are influenced by the haemodynamic status and the level of neuro-hormonal activation, thus they have complementary clinical and prognostic information [13]. Some studies [26] have suggested using BNP/NT-proBNP plasma assay to follow-up heart failure patients and that BNP may replace cardiopulmonary parameters. In our opinion, the information that can be obtained from a CPT is unique, is not an alternative to other tests and needs to be implemented in a multitask diagnostic work-up, including natriuretic peptides, for the optimal management of patients with heart failure.

4.1. Limitations of the study
Some drugs including ACE inhibitors, ARBs, diuretics and nitrates may reduce the circulating levels of cardiac natriuretic peptides, variable effects have been reported with beta-blockers [27-31]. Furthermore, pharmacological treatment may also affect other neuro-hormones measured in this study (mainly renin, epinephrine and norepinephrine). The possible effect of drugs on the plasma concentration of certain neuro-hormones might indirectly influence our findings, but without weakening or affecting the pathophysiological and clinical relevance of the observed relationships between BNP/NT-proBNP and functional capacity and ventilatory response to exercise in this cohort of patients in whom optimal medical treatment is able to reduce-without completely abolishing-cardiac natriuretic peptide and neuro-hormonal overexpression.

In conclusion, this study shows that neuro-hormonal activation, as illustrated by increased BNP/NT-proBNP and norepinephrine levels, is clearly associated with impairment of exercise capacity and ventilatory efficiency. NT-proBNP, BNP and norepinephrine are able to identify HF patients with greater impairment of exercise capacity or ventilatory efficiency. Indeed, NT-proBNP and BNP, reflect haemodynamic failure (which enhances adrenergic drive) and depressed exercise tolerance and ventilatory inefficiency, as shown by the correlation with VO2 and VE/VCO2 slope, better than EF.


   Acknowledgement
 
We are grateful to Luc Zyw for his helpful statistical advice.


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

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