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(Chest. 2003;123:366-371.)
© 2003 American College of Chest Physicians

Nasal Oxygen and Muscle Sympathetic Nerve Activity in Heart Failure*

Stefan Andreas, MD; Christian Bingeli, MD; Paul Mohacsi, MD; Thomas F. Lüscher, MD and Georg Noll, MD

* From the Department of Cardiology and Pneumology (Dr. Andreas), Georg-August-University, Göttingen, Germany; the Cardiology and Cardiovascular Research Division (Drs. Bingeli, Lüscher, and Noll), University Hospital, Zürich, Switzerland; and the Department of Cardiology (Dr. Mohacsi), Inselspital, Bern, Switzerland.

Correspondence to: Stefan Andreas, MD, Department of Cardiology and Pneumology, Robert-Koch-Str 40, 37075 Göttingen, Germany; e-mail: Sandreas{at}med.uni-goettingen.de


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Aims: To evaluate the effects of mild hyperoxia on sympathetic activity during quiet breathing in patients with chronic heart failure (CHF) and, hence, to investigate whether tonic activation of excitatory chemoreceptor afferents contributes to the elevated sympathetic activity in these patients. Sympathetic activation in patients with CHF may result in part from increased chemoreflex sensitivity. Previous studies using microneurography did not demonstrate deactivation of the chemoreceptors while the patients were breathing 100% O2. However, 100% O2 may decrease cardiac output, thereby offsetting the effects on the chemoreflexes.

Setting: University hospital.

Patients and interventions: Ten patients with moderate-to-severe CHF (mean [±SD] age, 53.9 ± 9.2 years; mean ejection fraction, 21.3 ± 4.7%) were assigned to breathing 20 min of O2 as well as room air (3 L/min) applied by nasal prongs. Muscle sympathetic nerve activity (MSNA) was evaluated by microneurography of the peroneal nerve.

Results: The application of O2 resulted in an increase of arterial O2 saturation but no significant change in MSNA during resting ventilation. Although voluntary apneas were no longer with O2 (25.3 ± 5.8 vs 32.6 ± 8.6 s, respectively; p = 0.014), MSNA during the last 10 s of voluntary apnea was lower while breathing O2 (63.5 ± 15.0 vs 59.9 ± 13.9 bursts per minute, respectively; p = 0.02).

Conclusions: The increased MSNA in the patients studied could not be reduced by mild hyperoxia, suggesting that the tonic activation of chemoreflex afferents is unlikely to contribute to the elevated sympathetic activity. That nasal O2 reduces MSNA during apnea may explain the beneficial effects of nocturnal O2 therapy in CHF patients with Cheyne-Stokes respiration.

Key Words: autonomic nervous system • heart failure • oxygen


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Sympathetic nervous system activation has come to be recognized as an important aspect in the pathophysiology of chronic heart failure (CHF). Baroreflex impairment has been documented in patients with CHF.1 Baroreflexes exert an inhibitory influence on the chemoreflexes2 and could therefore result in increased chemoreflex sensitivity in CHF patients. However, it has been found3 4 that breathing 100% O2 does not decrease postganglionic sympathetic nerve activity to muscle blood vessels (ie, muscle sympathetic nerve activity [MSNA]) in patients with CHF. But, the detrimental hemodynamic effects of breathing 100% O2, as a decrease in cardiac output or an increase in systemic vascular resistance,4 5 might have offset any decrease in sympathetic nerve activity secondary to chemoreflex inhibition by O2. The hemodynamic effects of O2 are dose-dependent in CHF patients with minor alterations at low inspiratory O2 concentrations.4 Aortic and carotid chemoreceptors exhibit a hyperbolic response to O2 with only minimal further depression of afferent activity while the partial pressure of O2 exceeds about 100 mm Hg.6 Mildly elevated inspiratory O2 concentrations therefore have the potential of depressing chemoreceptor afferents without major changes in hemodynamics.

Sympathetic activity is accurately quantified by microneurography.2 7 8 Previous investigations9 have demonstrated that MSNA reflects short-term changes in sympathetic activity, is highly reproducible, and correlates closely with cardiac norepinephrine spillover.

Cheyne-Stokes respiration during sleep is common in CHF patients, induces repetitive apneas with concomitant O2 desaturations, and impairs sleep.10 This breathing disorder is related to sympathetic activation11 and increased mortality.12 An improvement in exercise capacity and a reduction of urinary norepinephrine excretion following the successful treatment of Cheyne-Stokes respiration with nasal O2 in CHF patients was demonstrated.13 14 15

We therefore examined the effects of mild hyperoxia during quiet breathing and voluntary apnea on MSNA in patients with CHF.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Subjects
All patients with CHF admitted to the department of cardiology of the Inselspital Bern were candidates for the study. Patients < 75 years of age were eligible if they met the following criteria: at least one episode of cardiac decompensation; left ventricular ejection fraction of <= 35%; and stable condition while receiving cardiac medication. Exclusion criteria were as follows: myocardial infarction within 1 year of study entry; significant obstructive lung disease, as defined by an FEV1/FVC ratio of < 60%; primary valvular heart disease; rales on auscultation; or tibial edema. Left ventricular end-diastolic and left atrial diameter were evaluated by echocardiography from a left parasternal view. Left ventricular ejection fraction at rest was determined by 99mTC-gated blood pool scintigraphy. Ten healthy subjects without significant obstructive lung disease (as defined above) who were matched for gender, age, and body mass index, served as a control group to document that sympathetic nerve activity was elevated in CHF subjects. The study was approved by the local ethics committee. Written informed consent was obtained from all participants.

Protocol
The subjects were studied in the morning after a light breakfast. After micturition, to avoid any increase in sympathetic nerve activity through bladder distention, subjects were asked to resume the supine position. The nondominant leg was fixed by a vacuum cushion, and ECG leads and a BP cuff were attached. Respiration was evaluated by a thoracic strain gauge. O2 saturation was measured transcutaneously on the tip of the index finger by pulse oximetry (Micro span, model 3040 G; Biochem Int; Wanheshea, WI) that was set on a fast-response rate. The subjects were asked to breathe through the nose. To accustom the subjects to the procedure, they were asked to breathe room air first for 20 min (baseline). Then O2 and thereafter room air were applied by nasal prongs with a flow rate of 3 L/min for 20 min each. O2 administration by nasal prongs with a flow of 3 L/min will lead to an inspiratory O2 concentration of approximately 30%.16 O2 and room air were applied by nasal prongs with a flow of 3 L/min, since nasal airflow may have an effect on respiration17 and, thereby, potentially on MSNA. BP was measured noninvasively (Dinamap XL Monitor, model 9302; Johnson & Johnson Medical; Arlington, TX) every 3 min.

At the end of the period of breathing O2 and room air, the patients were asked to hold their breath as long as possible after a normal expiration. The completion of this voluntary apnea was evaluated by a strain gauge. The short-term changes in BP during apnea were evaluated by Finapres (Ohmeda 2300; BOC Health Care; Louisville, KY). The increase in MSNA during the apneas was calculated as follows: MSNA averaged over the last 10 s of apnea minus MSNA averaged over 1 min preceding the apnea. The control subjects did not receive supplemental O2 and did not perform a voluntary apnea.

Microneurography
Multifiber recordings of MSNA were obtained from the peroneal nerve posterior to the fibular head with tungsten microelectrodes (200-µm shaft diameter, 1 to 5 µm uninsulated tip; Medical Instruments; University of Iowa; Iowa City, IA) as described before.18 19 A reference electrode was inserted subcutaneously. Electrodes were connected to a preamplifier (gain, 1,000) and amplifier (variable gain, 10 to 50). Neural activity was fed through a band-pass filter (bandwidth, 700 to 2,000 Hz) and then a resistance-capacitance integrating network (time constant, 0.1 s) to obtain a mean voltage neurogram. The signal was displayed on an oscilloscope and was registered on a thermocoupled printer at a paper speed of 5 mm/s. In addition, the analog signal was digitized by use of an analog-digital board (MIO-16 L; National Instruments; Austin, TX) and the appropriate software (Lab View; National Instruments) with a sampling rate of 500 Hz. Digitized data were used to assess MSNA in the mean voltage neurogram by appropriate software (MatLab; MathWorks; Natick, MA). Three criteria for acceptance of the MSNA recording were required, as follows: (1) electrical stimulation (0.1 to 1.0 V, 0.2 ms, and 12 Hz) through the electrode in the peroneal nerve elicited involuntary muscle contractions in the muscle innervated by the peroneal nerve but without paresthesia; (2) tapping or stretching the innervated muscle region elicited afferent mechanoreceptor discharges, whereas stroking the skin did not; and (3) the neurogram revealed spontaneous, intermittent, pulse-synchronous sympathetic bursts that increased during apnea. Neurograms with cutaneous sympathetic activity or mixed cutaneous-sympathetic and muscle-sympathetic nerve activity were not accepted. If there was any evidence of a dislocation of the electrode position during the study, the experiment was excluded.

Statistical Analysis
The data were averaged over each 20-min interval of baseline, breathing room air or O2, respectively. The results are expressed as the mean ± SD. The patients and the control subjects were compared using the unpaired Student t test. The results for apnea while breathing O2 and room air were compared using the paired Student t test (two-tailed tests). For the effect of O2 during resting ventilation, repeated-measures analysis of variance with inclusion of the baseline values was used. Statistical analyses were performed on a personal computer using appropriate software (StatView; Abacus Inc; Berkeley, CA). A p value of < 0.05 was considered to be statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Subject Characteristics
The patients had moderate-to-severe CHF with slightly restrictive lung function tests (Table 1 ). One patient was a woman. The control subjects were comparable in age and body mass index. Eight patients had coronary artery disease, and two patients had idiopathic dilated cardiomyopathy. Four patients were classified as New York Heart Association class II, and six patients were classified as class III. Two patients exhibited atrial fibrillation. Medication consisted of a diuretic and an angiotensin-converting enzyme inhibitor in all patients, ß-acetyldigoxin in five patients, amiodarone in three patients, and a ß-blocker in one patient. Arterial blood gas analysis performed a day before the experiment showed a PO2 of 75.1 ± 12.0 mm Hg, a PCO2 of 33.4 ± 4.4, and a pH of 7.40 ± 0.18.


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  		Table 1. Characteristics of the Patients*

 
Quiet Breathing
MSNA was higher in the patients compared to the control subjects (61.2 ± 15.4 vs 28.5 ± 17.1 bursts/min, respectively [p < 0.002]; 66.9 ± 29.7 vs 43.1 ± 19.8 bursts per 100 heart beats, respectively [p < 0.05]). The patients had a lower systolic BP (99.6 ± 8.2 vs 129.0 ± 15.2 mm Hg, respectively; p = 0.0001) and a lower diastolic BP (66.1 ± 9.5 vs 78.3 ± 9.1 mm Hg, respectively; p = 0.008) compared to the control subjects.

While receiving O2 during quiet breathing, there was a significant increase in O2 saturation, but no change in heart rate, BP, or MSNA in the patients (Table 2 ). There was no significant difference between baseline values and values while breathing room air for all variables.


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  		Table 2. Effects of O2 on MSNA During Resting Ventilation*

 
Apnea
There was an increase in MSNA during voluntary apnea (Fig 1 ). Despite the voluntary apneas being significantly longer while breathing O2 (apnea duration, 25.3 ± 5.8 vs 32.6 ± 8.6 s, respectively; p = 0.014), MSNA (expressed as bursts per minute) was lower while breathing O2 compared to breathing room air during the last 10 s of voluntary apnea (Table 3 ). There was a trend toward lower systolic BP while breathing O2. The increase in MSNA during apnea was reduced with supplemental O2 compared to breathing room air (1.6 ± 11.2 vs 7.1 ± 10.0 bursts/min, respectively; p = 0.02) as was the increase in MSNA total activity (8.1 ± 16.0 vs 15.4 ± 20.1 arbitrary units, respectively; p = 0.04). There was a greater desaturation in the apnea following the period of breathing room air (1.0 ± 1.1 vs 2.1 ± 1.4%, respectively; p = 0.07). The nadir in O2 saturation while breathing room air appeared 42 ± 23 s after the cessation of the apnea. While breathing O2, a distinct nadir was not present in most patients. There was no significant effect of O2 on MSNA or on any other parameter during the time following the apnea (data not shown).



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  		Figure 1. Voluntary apnea in a patient with CHF. Tracings for (from the top) ECG, BP (by Finapres), respiration, and MSNA are shown. The time period of the tracings is exactly 2 min.

 

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  		Table 3. Effects of O2 During the last 10 s of Voluntary Apnea*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
The present study indicates for the first time that chemoreflex deactivation with mild hyperoxia during resting ventilation does not elicit a reduction in MSNA in patients with CHF and thus confirms the results of a study3 using an inspiratory O2 concentration of 100%. This study, however, was criticized on the grounds that hemodynamic effects4 5 or the Haldane effect20 might have offset any decrease in sympathetic nerve activity secondary to chemoreflex inhibition by breathing pure O2.21 The inspiratory O2 concentration used in our study (about 30%) does not lead to significant hemodynamic effects in CHF patients.4 CHF patients given O2 by nasal prongs, as was the case in the present study, showed only a small increase in PaCO2 and were still hypocapnic.22 An inspiratory O2 concentration of about 30% will, however, still exhibit a distinct effect on aortic and carotid chemoreceptors, due to the hyperbolic response curve, with only minimal further depression of afferent activity, while the PaO2 exceeds about 100 mm Hg.6 As in our CHF patients, hyperoxia has no consistent effect on sympathetic activity in healthy humans.23 24 25

Furthermore, our study confirms previous findings1 3 8 in that we demonstrated a higher MSNA in CHF patients who were receiving medical treatment compared to the MSNA of a control group. The mechanism responsible for sympathetic activation in CHF patients are not well understood. Central sympathoexcitation may result either from an increase in excitatory influences or from a decrease in inhibitory influences. A potential explanation for the increase in MSNA is a decrease of inhibitory influences exerted by a baroreflex mechanism.26 Impaired baroreflexes is characteristic of CHF patients.1 Baroreflex activation inhibits the MSNA response to peripheral chemoreceptors excitation by hypoxia and hypercapnia.2 Excitatory influences are known to be mediated by chemoreceptors2 and muscle metaboreceptors.27 28 The activation of chemoreceptors by hypoxia or hypercapnia2 is unlikely to play a major role, since hypoxemia or hypercapnia is rarely noticed in patients with CHF while awake in the present study or in previous studies.29

Our data indicate that in CHF patients, chemoreflex activation is unlikely to contribute significantly to the high levels of resting MSNA. Thus, chemoreceptors did not play a major role in the increased sympathetic activity in CHF patients. Chemosensitivity, as evaluated by hypoxic and hypercapnic ventilatory responses, has been described as being increased30 31 especially in CHF patients with Cheyne-Stokes respiration.32 This is not necessarily a contradiction to our findings and previous findings,3 since respiratory and cardiovascular control, albeit intimately linked in the brainstem, may well have distinct and different inputs besides chemoreceptor afferents.33

Apnea
The second novel finding of the present study is that nasal O2 reduces the increase in MSNA at the end of voluntary apnea in CHF patients. The progressive increase in MSNA during apnea is likely to be due to O2 desaturation and carbon dioxide retention. This sympathoexcitatory effect is further augmented by the absence of breathing, when sympathoinhibitory input from the intrathoracic receptors ceases.34 35 With the cessation of apnea and the resumption of breathing, there is an abrupt termination of MSNA.34 The reduced increase in MSNA with nasal O2 administration during voluntary apnea that was observed in the present study is likely due to the reduced O2 desaturation with the administration of supplemental O2 and must be viewed against the significant longer duration of apneas with oxygen. Since voluntary apnea itself is sympathoexcitatory, the lower MSNA while breathing O2 suggests a profound effect of O2.

As in our CHF patients, Morgan et al36 noticed an increase in MSNA during voluntary apnea that was attenuated with supplemental O2 in healthy humans. Therefore, the qualitative effects of apnea with and without O2 seem to be similar in CHF patients and healthy subjects. Since we have not submitted our control group to voluntary apnea, we cannot comment on the possible quantitative differences.

The reduced increase in MSNA with nasal O2 during voluntary apnea in our CHF patients has the potential to explain the improvement of exercise capacity and the reduction of urinary norepinephrine excretion that was observed following the successful treatment of Cheyne-Stokes respiration with nasal O2 therapy in CHF patients.13 14 15

Limitations
Since flow over the nasal prongs is constant, any change in tidal volume will cause an opposite change in the inspired O2 concentration. A face mask or a mouthpiece with an attached reservoir would have avoided this problem, but this would have influenced ventilation.37 However, the results of the present study cannot be explained by variable inspiratory O2 concentrations since all patients showed a clear increase in arterial O2 concentration with the administration of supplemental O2. Evaluating the MSNA response not only to hyperoxia but also to hypoxia might have given additional insight into chemoreflex activation. For reasons of patient safety, however, exposure to hypoxia was not regarded as being feasible. We investigated only stable CHF patients in New York Heart Association class II to III, but not those in stage IV, and, therefore, our results cannot be generalized to unstable or very severe CHF patients.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Nasal O2 therapy did not reduce increased sympathetic activity during resting ventilation in the CHF patients studied, suggesting that tonic activation of chemoreflex afferents is unlikely to contribute to the elevated sympathetic activity. However, nasal O2 reduces MSNA during voluntary apnea. This helps us to understand the improvement of exercise capacity and the reduction of urinary norepinephrine excretion following the successful treatment of Cheyne-Stokes respiration with nocturnal O2 therapy in CHF patients.


   Footnotes
 
Abbreviations: CHF = chronic heart failure; MSNA = muscle sympathetic nerve activity

Dr. Andreas received a grant from the Deutsche Forschungsgemeinschaft (No. An 260/1-2), and Dr. Noll received a grant from the Swiss National Foundation (No. 32-52690.97).

Received for publication December 10, 2001. Accepted for publication June 6, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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