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European Journal of Heart Failure 2001 3(6):679-684; doi:10.1016/S1388-9842(01)00189-1
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© 2001 European Society of Cardiology

Chemoreflexsensitivity in chronic heart failure patients

Marcus G. Hennersdorf*, Stefanie Hillebrand, Christian Perings and Bodo-E. Strauer

Department of Cardiology, Pneumology and Angiology, Medical clinic and policlinic B, Heinrich-Heine-University Moorenstr. 5, D-40225 Duesseldorf, Germany

* Corresponding author. Tel.: +49-211-81-18800; fax: +49-211-81-9520. E-mail address: hennersdorf{at}med.uni-duesseldorf.de (M.G. Hennersdorf).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims: Patients with heart failure are characterised by a disturbed sympathovagal balance, as could be shown by analyses of heart rate variability and baroreflexsensitivity. Furthermore, the modulation of ventilation is disturbed in those patients with an increased ventilation volume following the inhalation of hypoxic gas. This study should evaluate, whether heart failure patients have a decreased hyperoxic chemoreflexsensitivity associated with an increased rate of ventricular arrhythmias.

Methods and results: Into this study, 49 consecutive patients were enrolled. Of these, 23 suffered from heart failure; the remaining had no evidence of heart failure and a normal left ventricular ejection fraction. All patients were investigated by analysing the reduction of heart rate following inhalation of pure oxygen. The difference of RR-interval divided by the difference of the venous oxygen partial pressure both before and after oxygen inhalation resulted in the chemoreflexsensitivity. Patients with heart failure showed a significantly decreased chemoreflexsensitivity compared to those without (2.62±1.85 vs. 5.80±6.37 ms/mmHg, P<0.05). Of patients with heart failure, 69.6% had a decreased chemoreflexsensitivity below 3 ms/mmHg, in contrast to only 38.5% of the control group. Patients with decreased chemoreflexsensitivity showed significantly more non-sustained ventricular tachycardias (46 vs. 4%, P<0.05) during Holter ECG.

Conclusion: Patients with heart failure show a significantly decreased hyperoxic chemoreflexsensitivity. A decreased chemoreflexsensitivity is associated with an increased rate of non-sustained ventricular tachycardias. This may be related to an increased sympathetic tone in these patients. The chemoreflexsensitivity may be important in arrhythmic risk stratification of patients with heart failure.

Key Words: Heart failure • Chemoreflexsensitivity • Arrhythmia

Received November 13, 2000; Revised February 26, 2001; Accepted May 9, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Chronic heart failure is associated with a decreased vagal tone. This can be evaluated by analysis of heart rate variability [1] or baroreflexsensitivity [2]. A disturbed sympathovagal balance is closely correlated with an increased risk of cardiac and arrhythmic mortality [3].

Autonomic dysfunction can lead to a disturbed chemoreflex function. This can be shown by an enhanced increase of minute ventilation or heart rate during hypoxia [4,5]. A disturbed function of the chemoreflex following hypoxia has been demonstrated in chronic heart failure patients. Those patients often show an increased ventilatory response to exercise [6] and, as a consequence, an augmented peripheral chemoreflex as an expression of a disturbed control of ventilation. In patients with heart failure, an augmented increase of minute ventilation after inhalation of pure nitrogen has been detected [5].

On the other hand it is well known, that oxygen inhalation leads to a decrease of the heart rate. In patients with heart failure, this decrease seems to be reduced [7].

Furthermore it has been shown, that patients with an increased arrhythmic risk are characterised by a decreased hyperoxic chemoreflexsensitivity, as measured by analysis of the decrease of heart rate as a consequence to the inhalation of pure oxygen [8]. This has been evaluated in patients who survived myocardial infarction (relative risk for ventricular arrhythmias 7.6 in patients with decreased chemoreflexsensitivity) [9] and in patients with dilated cardiomyopathy [10].

Hitherto, the hyperoxic chemoreflexsensitivity in patients with heart failure has not been studied. The objectives of this study were to analyse the chemoreflexsensitivity in those patients and correlate it to spontaneously occurring ventricular arrhythmias showing the correlation of disturbed chemoreflexsensitivity and increased arrhythmic risk in patients with chronic heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
Forty-nine consecutive patients were recruited into this study. Of these 23 suffered from heart failure. The other 26 showed a normal left ventricular function, had no evidence of heart failure and served as a control group. Heart failure was diagnosed by clinical variables (dyspnoea on exertion or paroxysmal nocturnal) and determination of the left ventricular ejection fraction by invasive biplane angiography. None of the patients had a myocardial infarction or coronary revascularization within the last 6 months before study enrolment.

All patients underwent invasive coronary and left ventricular angiography due to their clinical symptoms. The determination of the ejection fraction was performed by analysis of biplane ventriculographies using the Dodge formula [11]. Coronary artery disease was found in 39 patients. The remaining suffered from dilated cardiomyopathy or hypertensive heart disease (Table 1).


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  		Table 1 Demographic data of patients with heart failure and controls

 
Patients with a known history of pulmonary disease were excluded from the study. All heart failure patients were treated with angiotensin-converting enzyme inhibitors, digitalis and diuretics. None of the patients were treated with betablockers during the time of the investigation. Two of these patients were in NYHA class I, 10 in NYHA class II and 11 in NYHA class III. None of the patients was in NYHA class IV.

All patients were in sinus rhythm. Patients with atrial fibrillation or atrial flutter were excluded from the study. To assess the prevalence of ventricular arrhythmias, 24-h Holter monitoring was performed (Reynolds Medical, USA). Non-sustained ventricular tachycardias were defined as at least three consecutive premature ventricular beats with a frequency of at least 120/min and a duration of up to 30 s. Ventricular tachycardias with a duration of more than 30 s were defined as sustained ventricular tachycardias.

2.1. Measurement of chemoreflexsensitivity
The patients were recumbent for a period of 10 min. After this phase, a blood sample was taken from a cubital vein and the partial oxygen pressure was determined using a standardised blood gas analyser (Radiometer Copenhagen). Additionally, the mean RR-interval out of 10 consecutive RR-intervals was calculated using a standardised 12-channel electrocardiogram (Siemens). Then, the patients inhaled 100% pure oxygen (5 l/min) via a face mask. No conversation was allowed during this period for minimisation of mental influences. After a period of 5 min, the venous partial oxygen pressure and the mean RR-interval out of 10 consecutive RR-intervals were determined again. The difference between the mean RR-interval before and after oxygen inhalation divided by the difference between venous partial oxygen pressure before and after oxygen inhalation gave the chemoreflexsensitivity (ChRS) (ms/mmHg).

According to previous papers a chemoreflexsensitivity below 3.0 ms/mmHg (representing the median value) was considered as pathologically decreased [9].

All patients gave written informed consent. There were no objections from an ethical point of view.

2.2. Statistical analysis
The results are presented as means±S.D. After testing for normal distribution the Mann–Whitney U-test or Students t-test were used for analysis of independent variables. Categorical data were analysed by chi-square test with Fisher's exact test. For categorical data with more than three variables the Kruskal–Wallis ANOVA test was used. Statistical significance was reached if the P-level was <0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Chemoreflexsensitivity
Significant increases in the partial oxygen pressure and the RR-intervals occurred during oxygen inhalation in the patient group as a whole. The oxygen pressure increased from 38.9±9.6 to 49.5±14.9 mmHg (P<0.0001). The RR-interval was 844.3±179.6 ms before and 867.6±179.9 ms after oxygen inhalation (P<0.0001). The chemoreflexsensitivity of the whole group amounted to 4.28±4.99 ms/mmHg.

In all patients with heart failure the partial oxygen pressure and the RR-interval rose significantly during oxygen inhalation (Table 2). The resulting chemoreflexsensitivity amounted to 2.62±1.85 ms/mmHg. Compared to the patients with a normal left ventricular function (5.80±6.37 ms/mmHg, P<0.05), this value was significantly decreased (Fig. 1). The baseline values of partial oxygen pressure and RR-interval of both groups were not different (Table 2).


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  		Table 2 Baseline values and increase of RR-interval and PO2 during oxygen inhalation in patients with and without heart failure

 


Figure 1
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  		Fig. 1 Significantly decreased chemoreflexsensitivity in patients with compared to those without heart failure (HF). The dotted line represents the cut-off value of 3 ms/mmHg.

 
A chemoreflexsensitivity below 3 ms/mmHg was found in 69.6% of the patients with heart failure, compared to only 38.5% of the control group (P<0.05).

The left ventricular ejection fraction was significantly different between patients with and without decreased chemoreflexsensitivity (40.94±16.47 vs. 52.20±17.24%, P<0.05) (Fig. 2).


Figure 2
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  		Fig. 2 Characteristics of patients with decreased and normal chemoreflexsensitivity. EF=left ventricular ejection fraction (mean, %); nSVT=non-sustained ventricular tachycardia (%); NYHA III=percentage of patients with NYHA class III.

 
3.2. Correlation with NYHA classification
The chemoreflexsensitivity and the NYHA classification were closely correlated. As Fig. 3 shows, the chemoreflexsensitivity decreased significantly with increasing NYHA class. On the other hand, patients with decreased chemoreflexsensitivity were more frequent in a NYHA class III compared to those with a normal chemoreflexsensitivity (Fig. 2).


Figure 3
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  		Fig. 3 Association between NYHA classification and chemoreflexsensitivity.

 
3.3. Correlation with 24-h electrocardiography
Patients with decreased chemoreflexsensitivity showed more ventricular premature beats compared to those with a normal chemoreflexsensitivity, but without reaching the level of significance (1803.9±4326.3 vs. 755.6±1474.8). However, non-sustained ventricular tachycardias were significantly more frequent in the group with decreased chemoreflexsensitivity (46%) in contrast to only 4% in the group with a chemoreflexsensitivity >3.0 ms/mmHg (P<0.01). Patients with a normal chemoreflexsensitivity showed sustained ventricular tachycardias in 4%, compared to 12% in the group of patients with a decreased chemoreflexsensitivity.

Subgroup analysis showed (Table 3), that those patients with heart failure, who were characterised by decreased chemoreflexsensitivity, had more ventricular premature beats, more ventricular couplets and a significantly higher degree of non-sustained ventricular tachycardias compared to patients with normal chemoreflexsensitivity. But also the three patients of the control group with non-sustained ventricular tachycardias had a decreased chemoreflexsensitivity.


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  		Table 3 24-h Holter results in patients with decreased and normal chemoreflexsensitivity

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Heart failure is characterised by neurohormonal activation and a disturbed sympathovagal balance. In these patients the values for heart rate variability and baroreflexsensitivity are decreased as well [1,2,12]. If the vagal tone is altered, the patients have a higher risk for cardiac and arrhythmogenic mortality. Data from the Studies of Left Ventricular Dysfunction trial (SOLVD) indicate that the sympathetic and humoral activation precedes the onset of clinically recognised heart failure [13].

4.1. Reactions to hypoxia
The peripheral chemoreflex is disturbed in heart failure and shows augmented sympathetically mediated changes in ventilation control [14]. Chua et al. [5] investigated 50 patients with heart failure and 12 healthy controls, and showed that this reflex leads to a sympathetically mediated increase of minute ventilation as a result of inhalation of pure nitrogen. This increase was significantly more pronounced, if the left ventricular function was reduced. Of the patients, 61% with augmented peripheral chemoreflex had evidence of non-sustained ventricular tachycardia, in contrast to only 21% of the group with normal peripheral chemoreflex. In another study, Ponikowski et al. [7] could show, that an augmented peripheral chemoreflex is well correlated with decreased heart rate variability and a decreased baroreflexsensitivity.

4.2. Reactions to hyperoxia
It is well known, that oxygen administration leads to a decrease of heart rate in normal subjects [15]. In the study of Ponikowski [7], the inhalation of pure oxygen did not result in a relevant decrease in heart rate, but lead to an improvement of heart rate variability and baroreflexsensitivity. This can be an expression of increased vagal tone as a result of the deactivation of peripheral chemoreceptors induced by oxygen. It can be postulated that these patients did not show a decrease of the heart rate, because they suffered from heart failure with the consequence of a decreased hyperoxic chemoreflexsensitivity as shown in our study. Moreover, in the study of Haque et al. [16], patients with congestive heart failure had only little alterations of their heart rate during oxygen inhalation. Only van de Borne et al. [17] found a small, but significant decrease of heart rate during oxygen inhalation in heart failure patients.

4.3. Hyperoxic chemoreflexsensitivity
The possibility of analysing autonomic dysfunction by hyperoxic chemoreflexsensitivity was shown in previous studies. If the hyperoxic chemoreflexsensitivity is decreased, patients are at risk of ventricular arrhythmias. This could be demonstrated from our own group in patients with different cardiac diseases. In patients with survived sudden cardiac death [8], myocardial infarction [9] and in dilative cardiomyopathy [10], a decreased chemoreflexsensitivity was associated to a high risk of ventricular arrhythmias.

The present study showed clearly, that patients with congestive heart failure are characterised by a decreased hyperoxic chemoreflexsensitivity. These patients had a significantly lower chemoreflexsensitivity compared to patients with a normal left ventricular ejection fraction (2.62±1.85 vs. 5.80±6.37 ms/mmHg). Almost 70% of the heart failure patients had a reduction below 3 ms/mmHg, in contrast to only 38.5% of the control group. Patients with lower values of chemoreflexsensitivity also suffered from an increased rate of ventricular extrasystoles, as significantly more frequent non-sustained ventricular tachycardias. However, the patient selection could include a bias, because the control group consisted of patients without heart failure, but with underlying heart disease. Healthy individuals certainly should have a higher chemoreflexsensitivity resulting in an even more pronounced differentiation.

4.4. Underlying mechanisms
The underlying mechanism responsible for this phenomenon is unknown. Oxygen leads to a deactivation of peripheral chemoreceptors, that produces a vagal activation with the consequence of reduction of the heart rate [18]. Ponikowski et al. [7] showed, that oxygen administration can produce an increase in heart rate variability and baroreflexsensitivity as an expression of enhanced vagal activity. This could be confirmed by the study of Bartels et al. [19], who found significant increases of heart rate variability and baroreflexsensitivity in COPD patients receiving pure oxygen. But the effect of vagal mediated lowering of the heart rate seems to be reduced in patients with heart failure [7]. Those patients show an impaired baroreflex that interacts with central chemoreflex integration [20]. Plasma catecholamines are increased in heart failure [21] and can potentiate the chemosensitivity of oxygen [22]. Furthermore, a reduced peripheral blood flow can play a role in patients with depressed left ventricular function [23] with the consequence of a blood flow diminuation of the central nervous system and consequently of the medulla oblongata or the chemoreceptor itself [24]. Other possibilities are shown by experimental studies and can be linked to a depression of nitric oxide [25] production in the carotid body affecting afferent sensitivity, and an elevation of central angiotensin II [26] affecting central integration of chemoreceptor input. Furthermore, the inhalation of oxygen produces a reduction of minute ventilation [14]. This leads to a reduced activation of the pulmonary stretch receptors resulting in an increased vagal tone itself. It is possible, that this phenomenon contributes to the decrease in heart rate following oxygen supplementation.

The method of hyperoxic testing of the chemoreflexsensitivity can be performed easily and without any harm for the patients. To test the hypoxic chemoreflexsensitivity pure nitrogen is needed, whereas pure oxygen for the analysis of hyperoxic chemoreflexsensitivity is available everywhere in a hospital. Furthermore, the evaluation of the hypoxic chemoreflexsensitivity potentially can lead to an increased risk of arrhythmias due to the elevated sympathetic tone during the investigation. A disadvantage of the method could be, that the hyperoxic chemoreflexsensitivity reflects not only the dysfunction of one reflex arch, but the interaction of several mechanisms (peripheral chemoreceptors, diminuation of the minute ventilation, pulmonary stretch receptors). This could potentially narrow the impact and accuracy of the method.

In conclusion, this study shows, that patients with heart failure have a disturbed sympathovagal balance, that can be measured by deactivation of the carotid chemoreceptors following the inhalation of pure oxygen. This hyperoxic chemoreflexsensitivity is decreased in comparison to a control population without heart failure. Heart failure patients are at increased risk of ventricular arrhythmias, if they show a decreased chemoreflexsensitivity.


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

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