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European Journal of Heart Failure 2005 7(7):1105-1111; doi:10.1016/j.ejheart.2004.12.005
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© 2005 European Society of Cardiology

Exercise hyperventilation in chronic heart failure is not caused by systemic lactic acidosis

Roland Wensela,b,*, Darrel P. Francisa, Panagiota Georgiadoua, Adam Scotta, Sabine Genth-Zotza,c, Stefan D. Ankera,d, Andrew J.S. Coatse and Massimo F. Piepolia

a National Heart and Lung Institute, Imperial College of Science, Technology and Medicine London, UK
b Medizinische Klinik II, Klinikum der Universität Regensburg Franz-Josef-Strauß-Allee 11, 93042, Regensburg, Germany
c Medizinische Klinik II, Johannes Gutenberg Universität Mainz Germany
d Universitätsklinik (Charité, Campus Virchow) der Humboldt-Universität zu Berlin Germany
e Faculty of Medicine, University of Sydney Australia

* Corresponding author. Medizinische Klinik II, Klinikum der Universität Regensburg, Franz-Josef-Strauß-Allee 11, 93042, Regensburg, Germany. Tel.: +49 941 9447264; fax: +49 941 9447213. E-mail address: roland.wensel{at}klinik.uni-regensburg.de


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: Patients with heart failure have an abnormally high ventilatory response to exercise associated with gas exchange defects and reduced arterial pCO2.

Aims: We examined the possibility of lactic acidosis as the stimulus to this increased ventilation that abnormally depresses pCO2 during exercise in heart failure.

Method and results: We studied 18 patients with chronic heart failure. We measured VE/VCO2 slope during exercise, arterial blood gases and lactate concentrations during cardiopulmonary exercise testing (rest, peak exercise and one minute after the end of exercise). Neither VE/VCO2 slope nor arterial pCO2 were related to arterial lactate concentrations at peak exercise (r=–0.16, p=0.65 and r=–0.15, p=0.6). During early recovery, patients with a high VE/VCO2 slope had a particularly pronounced rise in arterial lactate and hydrogen ion concentrations (r=0.57, p<0.05 and r=0.84, p<0.0001) and yet their arterial pCO2 rose rather than fell (r=0.79, p<0.001). The rise in arterial pCO2 correlated with the increase in arterial hydrogen concentration (r=0.78, p<0.001) and with arterial pCO2 at peak exercise (r=–0.76, p<0.001).

Conclusions: In heart failure VE/VCO2 slope and low arterial pCO2 at peak exercise are not related to the degree of systemic lactic acidosis. Lactic acidosis is therefore not a plausible mechanism of exercise induced hyperventilation.

Key Words: Heart failure • Exercise • Ventilation

Received July 29, 2004; Revised September 24, 2004; Accepted December 20, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
In chronic heart failure, ventilation (VE) rises abnormally during exercise [1–3]. Part of this is necessary to compensate for impaired efficiency of pulmonary gas exchange [4,5], but part of this is in excess of that required to maintain a steady arterial partial pressure of carbon dioxide (pCO2) [2,6,7,8]. This latter excess component of ventilation, which can be properly called "Hyperventilation", causes arterial carbon dioxide to fall below its normal value during exercise. This "hyperventilation" component cannot be caused by CO2, since by definition it drives the CO2 level below normal. Its stimulus is not yet clearly defined.

The conventional explanation for the hyperventilation is that in heart failure, lactic acidosis develops early during exercise and this systemic metabolic acidosis is the trigger to early and excessive hyperventilation, thus explaining the fall in arterial pCO2 to below levels seen in normals [9,10]. However, this explanation is contradicted by the direct observation that systemic lactic acidosis at peak exercise is less severe, rather than more, in patients with heart failure than in normals [11]. Furthermore, systemic lactate concentration has never been shown to be clearly associated with arterial pCO2.

An alternative explanation for the exercise hyperventilation in heart failure is that there are abnormally active triggers elsewhere, for which there are an unlimited number of potential candidates. Increased pulmonary capillary wedge pressure [12], increased chemo [13,14]—and ergoreceptorsensitivity [15–19], altered central nervous signal processing [20] and neuroendocrine [21] changes are proposed mechanisms. In healthy controls, hyperventilation increases concomitantly with the increase in systemic lactate concentration and metabolic acidosis in early recovery implying that systemic acidosis is the key trigger for hyperventilation [22].

In heart failure, the disproportionate severity of hyperventilation in relation to the level of systemic acidosis suggests that there could be a significant additional trigger. The post-exercise changes of arterial pCO2 in relation to lactate concentration and metabolic acidosis have not been investigated so far.

We therefore set out to determine whether systemic acidosis is a plausible trigger of exercise hyperventilation in heart failure by examining the relationship between the systemic lactate and hydrogen ion concentrations, and the ventilatory response to exercise and the degree of hyperventilation. More specifically, we related the change in systemic lactate concentration from peak exercise to early recovery to the corresponding change in arterial pCO2.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Patients
We studied 18 patients (age: 62±11, left ventricular ejection fraction: 30±15%, 17 male) with chronic heart failure due to ischemic heart disease (n=13) or idiopathic dilated cardiomyopathy (n=5). New York Heart Association functional classification showed two patients in class I, 8 in class II and 8 in class III. Medication included angiotensin converting-enzyme inhibitors (n=16), angiotensin II receptor antagonists (n=2), beta-blockers (n=12), amiodarone (n=2), loop diuretics (n=15), spironolactone (n=9), aspirin (n=10), digitalis (n=5), Hydroxymethylglutaryl coenzyme A-reductase inhibitors ("statins", n=11), nitrates (n=5) and warfarin (n=8). Medication had been constant and clinical status stable for at least 6 weeks prior to our study.

The study was performed according to the Declaration of Helsinki, and the procedures have been approved by the local ethics committee. All patients gave written informed consent.

2.2. Exercise testing
After 5 min of standing at rest, a symptom-limited treadmill cardiopulmonary exercise test was performed on all patients. We used the modified Naughton protocol. Pulmonary gas exchange was analysed breath-by-breath using a metabolic cart consisting of a flowmeter and a mass spectrometer (AMIS 2000, Innovision, Denmark). Patients breathed through a mouthpiece (volume 35 ml). Peak oxygen uptake (peak VO2) was defined as the highest 30-s average of oxygen uptake in the last minute of exercise. The anaerobic threshold was calculated using the V-slope method [23]. Ventilation to CO2 production (VE/VCO2) ratio was calculated at rest, at the anaerobic threshold and at peak exercise. The ventilatory response to exercise was measured as the slope of the linear regression relating VE to VCO2 (VE/VCO2 slope) during exercise.

2.3. Measurement of blood gases and dead space ventilation
A 20-gauge arterial catheter (Leader; Vygon) was inserted into the radial artery. Arterial blood samples were obtained at rest and during the second minute of each stage of the exercise and 1 minute after the end of exercise. Arterial blood gases, lactate and hydrogen ion concentrations were measured with electrodes by standard methods and physiological dead space (VD) was calculated from gas exchange and arterial pCO2.

2.4. Statistics
All data are expressed as mean±standard deviation. Changes in VE/VCO2, arterial pCO2 and arterial lactate and hydrogen ion concentrations during the exercise test were analysed with a repeated measures ANOVA. All-pairwise comparison was performed using the Dunn's procedure. The relationship between two variables was tested with the Pearson correlation and simple linear regression analysis. A p-value of <0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
The results of the exercise tests are given in Table 1.


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  		Table 1 Results of cardiopulmonary exercise testing

 
There was an increase in arterial lactate and hydrogen ion concentrations during the exercise test with the highest concentrations occurring at recovery (Table 2). Similarly, arterial pCO2 fell from pre-test baseline to peak exercise, but no difference between peak exercise and recovery levels was observed (p=0.9)


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  		Table 2 Arterial blood gases and lactic acid concentrations

 
3.1. Contribution of hyperventilation to inefficient gas exchange during exercise
The VE/VCO2 slope correlated negatively with the arterial pCO2 at peak exercise (r=–0.72, p<0.001, Fig. 1a) and positively with the physiological dead space to tidal volume ratio (VD/VT) at peak exercise (r=0.80, p<0.0001, Fig. 1b). This showed that both impaired gas exchange efficiency and hyperventilation were present and contributing to the increased ventilation.


Figure 1
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  		Fig. 1 Relationship between the VE/VCO2 slope during exercise and (a) the arterial pCO2 at peak exercise, and (b) the physiological dead space to tidal volume ratio (VD/VT) at peak exercise.

 
3.2. Is systemic lactic acidosis a plausible mediator of the hyperventilation?
Arterial lactate concentrations at peak exercise correlated neither with arterial pCO2 at peak exercise (r=–0.15, p=0.6, Fig. 2a) nor with the VE/VCO2 slope (r=–0.16, p=0.65, Fig. 2b). Instead, hydrogen ion concentrations did show correlation at peak exercise with arterial pCO2 (r=0.50, p<0.05, Fig. 2c) and VE/VCO2 slope (r=–0.55, p<0.05, Fig. 2d).


Figure 2
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  		Fig. 2 Relationship between (a) the arterial pCO2 at peak exercise and (b) the VE/VCO2 slope during exercise and arterial lactic acid concentrations at peak exercise; and the relationship between (c) the arterial pCO2 at peak exercise and (d) the VE/VCO2 slope during exercise and arterial hydrogen ion concentrations at peak exercise.

 
3.3. Effects of washout of muscle metabolites after peak exercise
By one minute after peak exercise, arterial pCO2 no longer correlated significantly with VE/VCO2 slope (r=–0.43, p=0.08). There was now a trend towards a higher arterial lactate concentration in patients with a high VE/VCO2 slope (r=0.29, p=0.24). Arterial hydrogen ion concentration at one minute of recovery had also lost its correlation with VE/VCO2 slope (r=–0.03, p=0.9).

Metabolites released from the recently exercising muscle continued to wash out into the circulation, however, with arterial lactate concentration rising by 1.2 mmol/L (p<0.001) and arterial hydrogen concentration rising by 2.2 nmol/L (p<0.01) from peak exercise to 1 min of recovery (Table 2). The size of these changes was clearly related to the VE/VCO2 slope during exercise. In fact, VE/VCO2 slope correlated significantly with the rise in arterial lactate concentration (r=0.57, p<0.05, Fig. 3a), with rise in hydrogen ion concentration (r=0.84, p<0.0001, Fig. 3b) and with rise in arterial pCO2 (r=0.79, p<0.001, Fig. 3c). The rise in arterial pCO2 strongly correlated with the increase in arterial hydrogen concentration (r=0.78, p<0.001) and with arterial pCO2 at peak exercise (r=–0.76, p<0.001).


Figure 3
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  		Fig. 3 Relationship between the VE/VCO2 slope during exercise and the absolute difference (Delta=value at 1 min recovery—value at peak exercise) in (a) arterial lactic acid concentrations, (b) arterial hydrogen ion concentrations and (c) arterial pCO2.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
In this study we have shown that VE/VCO2 slope and arterial pCO2 during exercise in chronic heart failure are not correlated with systemic lactic acidosis at peak exercise (Fig. 2). Instead, VE/VCO2 slope and arterial pCO2 correlated with the rise in systemic acidosis in early recovery (Fig. 3). Secondly, heart failure patients fail to show the fall in arterial pCO2 in early recovery, signifying the lack of the increase in hyperventilation previously reported in normals [22]. On the contrary, heart failure patients with an increased ventilatory response to exercise have a rise in arterial pCO2, signifying a decline in hyperventilation. Thirdly, this decline in hyperventilation occurs despite a rise in systemic acidosis.

These findings strongly argue against the hypothesis of systemic lactic acidosis being the trigger of exercise induced hyperventilation in chronic heart failure.

In this manuscript we used the term hyperventilation only to mean excess ventilation above and beyond that increase in ventilation required to maintain arterial pCO2 in the face of exercise and abnormal pulmonary physiology. Thus hyperventilation in this manuscript is synonymous with a fall in arterial pCO2. Hyperventilation made a substantial contribution to the enhanced ventilatory response to exercise (i.e. a high VE/VCO2 slope) in our study of patients with heart failure. The development of systemic lactic acidosis cannot be the trigger of this hyperventilation since our data revealed no relationship between peak exercise arterial lactate levels and arterial pCO2 or VE/VCO2 slope. This is in agreement with previous studies that showed peak exercise arterial lactate levels to be lower in patients with heart failure compared to normal subjects [11]. Furthermore, systemic acidosis was actually more pronounced in the patients with a higher arterial pCO2 and a lower VE/VCO2 slope. This suggests the presence of a stimulus to ventilation other than systemic lactic acidosis to reduce arterial pCO2. Because this increase in ventilation does not relate to arterial lactate levels, hydrogen ion concentrations are lowest in the patients with the highest degree of hyperventilation. Patients with highest VE/VCO2 slope and lowest arterial pCO2 during exercise exhibited the highest rise in systemic lactic acidosis at one minute of recovery.

The observed alleviation in hyperventilation despite the overt increase of a systemic metabolic stimulus may therefore result from the reduction of an alternative stimulus to ventilation. There are numerous candidates for such a stimulus.

A high VE/VCO2 slope and low arterial pCO2 have been shown to be associated with poor hemodynamic status at rest and during exercise [12,24]. The recovery of the central hemodynamics after the end of exercise may reduce the potential ventilatory stimulus of increased pulmonary venous congestion. However, it seems unlikely to occur so rapidly to exert effects with the first minute of exercise recovery.

Increased chemoreflex-sensitivity gain is observed in heart failure and had been proposed to contribute to hyperventilation during exercise. The fall of arterial pCO2 during exercise, however, makes it unlikely that the trigger to ventilation is carbon dioxide itself, unless there was a shift in the carbon dioxide threshold rather than the chemoreflex gain during exercise.

Instead of triggering ventilation via central chemoreceptors, as described for normal subjects [25], lactate may exert its effects before entering the circulation. In analogy to previous studies [11] we can speculate that in our patients intramuscular lactate levels were markedly higher than the systemic levels. During the early recovery phase, lactate that was dynamically trapped in the muscle was washed out, causing the observed rise in arterial lactate. Hence, the increase of arterial pCO2 during early recovery would occur concomitantly with the fall in muscular lactate levels that, however, we did not measure in our study.

The muscular accumulation of metabolic products has been shown to increase the neurogenic input to ventilatory control via intramuscular ergoreceptors [26–34]. Recently, we showed that local muscular acidosis is a potent stimulus of skeletal muscle ergoreflex activation and hyperventilation in patients with chronic heart failure, whereas normals showed no ergoreflex activation at all at similar levels of acidosis [20].

Our finding that patients with an increased ventilatory response to exercise show a paradoxically blunted hyperventilation during early recovery could arise from such an increased sensitivity to intramuscular acidosis.

The clear correlation between the rise in arterial hydrogen ion and the increase in arterial pCO2 implies not simply the failure of one (the humoral) regulatory process but rather the emergence of a "paradoxical" (potentially ergoreflex-mediated) one that becomes dominant. We suggest that in patients with heart failure and an increased ventilatory response to exercise, the increased sensitivity of local muscle ergoreceptors makes lactate a more potent stimulus to excess ventilation while trapped within the muscle than after its escape and distribution in the circulating blood. This would explain why the rise in arterial pCO2 during early recovery is accompanied by (and correlates with) a rise in systemic acidosis.

This increase in arterial pCO2 after the end of exercise was higher in patients with a higher VE/VCO2 slope and more pronounced hyperventilation at peak exercise. Only in patients with a normal VE/VCO2 slope the "physiologic" fall in arterial pCO2 after the end of exercise was observed suggesting that there is continuous shift in ventilatory control from the physiologic respiratory compensation of systemic lactic acidosis to the stimulation of ventilation by local lactate accumulation in the course of heart failure.

The hypothesis of muscular acidosis being the trigger to exercise hyperventilation in heart failure is based on the measurements of systemic lactate and hydrogen levels. To substantiate this hypothesis, direct measurement of muscular acidosis during exercise and recovery is needed. Microdialysis [35], which can continuously measure muscle lactate but also many other metabolites, could provide the necessary data. By simultaneous monitoring of systemic and local muscular concentrations of lactate and hydrogen it would be possible to show the relationship between hyperventilation and local as well as systemic levels of these metabolites and whether the reduction in hyperventilation seen during early recovery coincides with the reduction in muscular lactate and hydrogen concentrations.

4.1. Study limitations
The study population was quite heterogeneous regarding disease aetiology and medical treatment. Because of the low patient number no firm statements with regard to potential effects of these factors on our results can be made. The majority of patients (n=13) had chronic heart failure due to ischemic cardiomyopathy and the observed relationships between hyperventilation, VE/VCO2 slope, lactate and hydrogen levels match those reported for the entire study population. Similarly, patients treated with Beta-blockers (n=12) and patients treated with statins (n=11) showed no different results compared to the entire study population. To gain conclusive results regarding this issue, however, a relatively large patient cohort would have to be investigated, which should be addressed by future studies.

We did not perform direct measurements of muscle acidosis in this study, because we thought systemic acidosis would well explain the ventilatory response, which was not the case. As discussed above such measurements will have to be performed in future studies to investigate the role of muscular acidosis in exercise ventilatory control.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
In patients with chronic heart failure the degree of hyperventilation during exercise is not determined by systemic lactic acidosis: the two (hyperventilation and systemic lactic acidosis) are not correlated and moreover during early recovery the former declines while the latter increases.

Greater hyperventilation and higher VE/VCO2 slope during exercise are associated with a larger increment in systemic lactate during early recovery, indicative of greater quantities of lactate "trapped" in exercising muscle of those patients. This suggests an important role for local skeletal muscle acidosis in the regulation of ventilation during anaerobic exercise in patients with chronic heart failure.


   Acknowledgement
 
Dr. Wensel is supported by the Ernst Schering Research Foundation and Dr. Piepoli by the Wellcome Trust Advanced Research Fellowship, Dr. Georgiadou by the Wellcome Trust and Prof. Coats by the Viscount Royston Trust.


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

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