Tonic Chemoreflex Activation Does Not Contribute to Elevated Muscle Sympathetic Nerve Activity in Heart Failure
Background Sympathetic activation in heart failure may be due to an increase in sympathetic excitatory influences or to a decrease in inhibitory signals to the brain stem. Chemoreflex sensitivity may be increased in patients with heart failure. The present study tested the hypothesis that tonic activation of excitatory chemoreceptor afferents contributes to the elevated sympathetic activity in heart failure.
Methods and Results We recorded sympathetic nerve activity to muscle circulation from the peroneal nerve of 12 chronic heart failure patients while the patients were breathing room air and during deactivation of the chemoreceptors while the patients were breathing a 100% O2 gas mixture. All patients except 2 were in class III of the New York Heart Association functional classification. Left ventricular ejection fraction defined by radionuclide ventriculography was 24±2% (mean±SE). We also obtained measurements of resting sympathetic nerve activity in 9 healthy control subjects to document that sympathetic nerve activity was elevated in heart failure subjects. Resting sympathetic nerve activity was 59±5 bursts/min in heart failure patients versus 36±4 bursts/min in control subjects (P<.01). In heart failure patients, oxygen administration increased oxygen saturation from 94±0.9% to 99±0.3% (P<.0001). This increase in oxygen saturation did not affect resting muscle sympathetic nerve activity (798±122 U/min while patients breathed room air and 824±35 U/min during 100% O2 breathing) or blood pressure.
Conclusions Increased efferent sympathetic activity to muscle circulation in patients with heart failure is not explained by tonic activation of excitatory chemoreflex afferents.
Activation of the sympathetic nerves is a key component of the pathophysiology of chronic heart failure. The cause of the heightened sympathetic drive is not known.1 In normal humans, sympathetic activity is regulated by baroreflex, chemoreflex, and somatic reflex mechanisms.2 3 4 5 6 Activation of central sympathetic outflow in heart failure may be due to an increase in excitatory influences or to a decrease in inhibitory signals to the brain stem.1
Chemoreflex activation by hypoxia is an excitatory influence that results in increased sympathetic outflow and blood pressure.4 5 In normal humans, hyperoxia results in a reduction in sympathetic nerve activity.7 Spontaneously hypertensive rats have an increased chemoreflex drive, even during normoxic conditions.8 Thus, there is a precedent for the postulation that chemoreflexes could contribute to resting sympathetic activation in pathological states, even in the absence of hypoxia.
The baroreflexes exert an inhibitory influence on the chemoreflexes.9 10 Baroreflex impairment, which has been documented in patients with heart failure,1 11 could result in the potentiation of chemoreflex sensitivity. Preliminary data suggest that chemoreflex sensitivity is increased in patients with heart failure.12 We hypothesized that increased chemoreflex sensitivity might explain in part the increased sympathetic outflow in heart failure patients. We therefore examined the effects of chemoreflex deactivation, using 100% inspired oxygen,7 8 13 14 on sympathetic activity and hemodynamics in patients with heart failure.
We studied 12 stable patients with chronic heart failure (9 men, 3 women, aged 57±9 years). All had clinical, radiographic, and echocardiographic evidence of impaired ventricular function. All patients had heart failure for a duration of more than 60 days. The cause of heart failure was ischemic heart disease (n=7) or was idiopathic in nature (n=5). Resting radionuclide ventriculograms showed an average left ventricular ejection fraction of 24±2% (mean±SE). Ten patients were in class III of the NYHA functional classification. The 2 remaining patients were in NYHA functional class II. All patients were on various combinations of diuretics, nitrates, converting enzyme inhibitors, and digitalis. None received amiodarone or β-blockers. Medications were withheld the morning of the study.
We also recorded resting muscle sympathetic nerve activity over a 10-minute period in nine age- and sex-matched healthy control subjects (mean age, 57±9 years; 6 men, 3 women). Control subjects were not taking any medication. Our objective in including studies of resting muscle sympathetic nerve activity in control subjects was to demonstrate that the patients with heart failure in the present study had elevated levels of muscle sympathetic nerve activity. We did not study the effects of 100% oxygen in the normal subjects because this was not essential to the goals of our study, which were to confirm that resting sympathetic activity was elevated in our heart failure patients and to determine whether 100% oxygen lowered the elevated resting muscle sympathetic nerve activity in the heart failure patients.
Informed written consent was obtained from all subjects. The study was approved by the Institutional Human Subjects Review Committee.
Measurements, Protocol, and Interventions
Blood pressure was measured each minute with a Physio-Control Lifestat 200 sphygmomanometer. ECG, respiration (pneumograph), and oxygen saturation (Nellcor N-100C pulse oximeter) were recorded on a Gould 2800S recorder. One hundred percent oxygen was administered via a mask (see-through adult nonrebreathing oxygen mask, mask No. 1060, Hudson Respiratory Supply Co) in 8 patients and via a mouthpiece in 4 patients. In these 4 patients, a nose clip ensured exclusive mouth breathing. Sympathetic nerve activity to muscle was recorded continuously through multiunit recordings of postganglionic sympathetic activity to muscle circulation, measured from a nerve fascicle in the peroneal nerve posterior to the fibular head, as described previously.3 6 15 Electrical activity in the nerve fascicle was measured by use of tungsten microelectrodes (200-μm shaft diameter, tapering to an uninsulated tip of 1 to 5 μm). A subcutaneous reference electrode was first inserted 2 to 3 cm away from the recording electrode, which was itself inserted into the nerve fascicle. The neural signals were amplified, filtered, rectified, and integrated to obtain a voltage display of sympathetic nerve activity.
Measurements were taken both in normal control subjects and in patients with heart failure during a 10-minute baseline period while subjects were breathing room air. One hundred percent oxygen was then administered to patients with heart failure and measurements were repeated over a period of approximately 8 minutes. We also obtained control studies in eight heart failure patients, in which free breathing of room air was compared with breathing room air through a mask (n=4) or mouthpiece (n=4) for 5 minutes.
Comparisons are between measurements taken during breathing of room air and measurements averaged over 8 minutes of hyperoxia. Sympathetic bursts were identified by a careful inspection of the voltage neurogram. The amplitude of each burst was determined, and sympathetic activity was calculated as bursts/min multiplied by mean burst amplitude and expressed as U/min. Measurements of nerve activity when subjects were breathing room air (baseline) are expressed as 100%. Measurements were made by a single observer (P. van de B.). The intraobserver and interobserver variabilities in our laboratory have been reported to be 4.3±0.3%6 and 5.4±0.5%,16 respectively. Results are expressed as mean±SE. Statistical analysis was performed by use of Student's paired t test (two-tailed), and the level of significance was defined as P<.05.
Oxygen administration increased oxygen saturation from 94±0.9% to 99±0.3% (P<.0001, Figs 1⇓ and 2). This increase in oxygen saturation did not affect blood pressure but was accompanied by a small reduction in heart rate (88±5 to 86±6 beats per minute [bpm]; P<.03). Mean blood pressure was 86±5 mm Hg on room air and 86±5 mm Hg on 100% oxygen. Baseline muscle sympathetic nerve activity was markedly elevated in the heart failure patients compared with the age-matched control subjects (59±5 versus 36±4 bursts/min; P<.01). Muscle sympathetic nerve activity did not change during oxygen administration in the heart failure patients (Figs 1 and 2⇓⇓). Sympathetic nerve activity averaged 798±122 U/min (100%) while patients breathed room air and 824±35 U/min (112±9%) during breathing of 100% oxygen. Blood pressure did not change and sympathetic nerve activity did not decrease (808±90 U/min; 111±11%) even during the last minute of breathing 100% oxygen. Qualitative assessment of minute ventilation by use of the pneumograph showed no evidence of a fall in minute ventilation during administration of 100% oxygen. Breathing room air through a mask or mouthpiece did not change any measurements compared with free breathing of room air.
This study indicates that chemoreflex deactivation with hyperoxia does not elicit a reduction in muscle sympathetic nerve activity in patients with heart failure. Thus, elevated sympathetic nerve activity to muscle in patients with heart failure is not explained by tonic activation of excitatory chemoreflex afferents even in heart failure patients with mild arterial hypoxemia.
Direct intraneural recordings have shown that heart failure is indeed accompanied by increased efferent sympathetic nerve activity to skeletal muscle17 18 but not to skin.19 These prior studies evaluated heart failure patients who were not on therapy. Our data indicate that high levels of sympathetic traffic are present even in heart failure patients treated with diuretics, digitalis, and ACE inhibitors.
The mechanisms responsible for this increased sympathetic activation are unknown. Efferent sympathetic nerve activity is regulated by homeostatic mechanisms involving afferent input that arises from both inhibitory and excitatory sensory receptors.1 With respect to the inhibitory influences, abnormalities in baroreflex control mechanisms may play an important role in the development of sympathetic excitation in heart failure.1 Baroreflex activation inhibits sympathetic nerve activity.1 11 Impaired baroreflexes, a characteristic of heart failure,1 11 may result in decreased tonic inhibition of sympathetic nerve activity. The baroreflexes also exert a powerful restraining influence on the peripheral chemoreceptors,9 10 which respond to hypoxia by increasing sympathetic nerve activity and blood pressure. Thus, an impairment of the baroreflexes, with consequent loss of the inhibitory influence on the chemoreflexes, could result in potentiation of chemoreflex-mediated sympathetic activation in heart failure. Preliminary studies by other investigators suggest that chemoreflex sensitivity is increased in patients with heart failure.12 Our data, however, indicate that even in heart failure patients with mild arterial hypoxemia, tonic chemoreflex activation is unlikely to contribute significantly to the high levels of resting muscle sympathetic nerve activity. Thus, chemoreceptor-independent mechanisms might be responsible for the increased sympathetic nerve activity.
In studies in normal subjects, other investigators have demonstrated that 100% oxygen elicits reductions in both muscle sympathetic nerve activity7 and heart rate.7 20 21 A very recent study22 in five heart failure patients also did not detect any effect of 100% oxygen on muscle sympathetic nerve activity. Heart rate did not change. The findings in the present study that 100% oxygen administration decreased the heart rate of chronic heart failure patients in the absence of significant changes in muscle sympathetic nerve activity may be explained by a differential sympathetic response at the cardiac versus the muscle vascular level. It should be emphasized, however, that the decrease in heart rate, although significant, was small.
There are several potential limitations to our study. First, although 100% oxygen did not acutely decrease muscle sympathetic nerve activity, it is possible that chronic administration of supplemental oxygen might modulate the sympathetic activity. Second, supplemental oxygen might modulate sympathetic activation in patients with heart failure with more profound hypoxia and chemoreflex activation. Third, we did not measure chemoreflex sensitivity directly and cannot rule out the possibility that the chemoreceptors may be less sensitive to increased oxygen levels because of resetting as a result of mild chronic hypoxia. Last, we cannot exclude the possibility that detrimental hemodynamic effects of 100% oxygen in patients with heart failure22 elicited an increase in sympathetic nerve activity, which offset any decrease secondary to chemoreflex inhibition by 100% oxygen.
In conclusion, hyperoxia does not decrease muscle sympathetic nerve activity in patients with heart failure, which indicates that tonic activation of excitatory chemoreflex afferents is unlikely to contribute to the elevated resting muscle sympathetic nerve activity in heart failure patients.
Dr van de Borne is a visiting research scientist from the Hypertension Clinic, Department of Cardiology, Free University of Brussels, Belgium, and is a recipient of a 1994-1995 International Research John E. Fogarty Fellowship, NIH (No. 1F05 TW05181-01); a 1993 Dr Andre´ Loicq Foundation Travel and Research Award, Belgium; a 1994 Bekales Research Award, Belgium; and a 1994-1995 Michael J. Brody Fellowship from the University of Iowa, Iowa City. This study was also supported by a Grant-in-Aid from the American Heart Association, a University of Iowa CIFRE Grant, the Council for Tobacco Research, and grants HL-24962 and HL-14388 from the NIH. We thank Mary Clary, RN, and Diane Davison, RN, MA, for technical assistance and Linda Bang for expert typing of this manuscript.
- Received December 27, 1995.
- Revision received March 13, 1996.
- Accepted March 14, 1996.
- Copyright © 1996 by American Heart Association
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