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(Circulation. 1997;96:2586-2594.)
© 1997 American Heart Association, Inc.

Articles

Augmented Peripheral Chemosensitivity as a Potential Input to Baroreflex Impairment and Autonomic Imbalance in Chronic Heart Failure

Piotr Ponikowski, MD; Tuan Peng Chua, MD, MRCP; Massimo Piepoli, MD, PhD; Daniela Ondusova, MD; Katharine Webb-Peploe, MRCP; Derek Harrington, MRCP; Stefan D. Anker, MD; Maurizio Volterrani, MD; Roberto Colombo, MD; Giorgio Mazzuero, MD; Amerigo Giordano, MD; ; Andrew J. S. Coats, DM, FRACP

From the Department of Cardiac Medicine (P.P., T.P.C., M.P., D.O., K.W.-P., D.H., S.D.A., A.J.S.C.), Imperial College School of Medicine, National Heart and Lung Institute, London, UK, and Centro Medico di Gussago (M.V., A.G.) and Centro Medico di Veruno (R.C., G.M.), Fondazione "Salvatore Maugeri," Italy.

Correspondence to Prof Andrew J.S. Coats, Department of Cardiac Medicine, National Heart and Lung Institute, Dovehouse St, London SW3 6LY, UK.

	Abstract

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Background The precise mechanisms responsible for the sympathetic overactivity and blunted baroreflex control in chronic heart failure (CHF) remain obscure. Augmented peripheral chemosensitivity has recently been demonstrated in CHF. We evaluated the relation between peripheral chemoreflex sensitivity and autonomic activity in patients with CHF.

Methods and Results We studied in 26 stable patients with CHF the peripheral chemosensitivity (ventilatory response to hypoxia using transient inhalations of pure nitrogen), autonomic balance (spectral analysis of heart rate variability [HRV]), and baroreflex sensitivity (bolus phenylephrine method and index). To determine whether transient inactivation of peripheral chemoreceptors might influence autonomic balance, 12 patients underwent a second study during which they breathed 100% O₂. Peripheral chemosensitivity correlated inversely with HRV power within the low-frequency band (0.04 to 0.15 Hz) (r=-.52, P=.006) and inversely with baroreflex sensitivity (r=-.60, P=.005). When the patients were divided into two groups according to the chemosensitivity of age-matched normal controls (above and below mean+2 SDs of chemosensitivity of control subjects), those above the normal range revealed more impaired autonomic balance, ie, lower baroreflex sensitivity (1.4±1.3 versus 5.0±1.5 ms/mm Hg, P<.0001) and depressed values of low-frequency power (2.5±1.8 versus 4.1±0.8 ln ms², P<.005) compared with those with normal chemosensitivity. Transient hyperoxia did not alter heart rate or systolic pressure but resulted in an increase in HRV and an improvement in baroreflex sensitivity.

Conclusions A link between increased peripheral chemosensitivity and impaired autonomic control, including baroreflex inhibition, is demonstrated. The clinical importance of this phenomenon warrants further investigation.

Key Words: heart failure • autonomic function • chemoreceptors • baroreceptors

	Introduction

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Impaired autonomic balance characterized by sympathetic overactivity and reduced vagal activity has been described in CHF and has been shown to be associated with progression of the disease and a poor prognosis.^{1 2 3} Although the precise mechanisms responsible for this phenomenon are not clearly established, the role of blunted baroreflex control seems to be of importance.⁴ It has been postulated that reduced baroreflex sensitivity in CHF may be due to a combination of reduced arterial compliance,⁵ impaired central reflex integration, and a decrease in end-organ responsiveness.⁴ Other less well studied mechanisms may be involved.

Recently, overactivity of muscle ergoreceptors and peripheral chemoreceptors has been linked to autonomic imbalance in CHF.^{2 6} We confirmed an increased chemosensitivity in CHF.⁷ The augmented peripheral chemosensitivity may contribute to the sympathetic overactivity via an increased excitatory input from the peripheral chemoreceptors to the sympathetic nervous system.² An antagonistic interaction between the peripheral chemoreflex and the baroreflex has been reported in animals and healthy subjects.^{8 9 10} The blunted baroreceptor response in CHF may result in a loss of this inhibitory interaction, leading to a further increase in excitatory activity of the peripheral chemoreceptors. There are, however, no data regarding the association between peripheral chemoreflex sensitivity and autonomic imbalance or baroreflex sensitivity in patients with CHF.

This study was designed to investigate the relationship between chemoreflex sensitivity and autonomic nervous system activity assessed either on the basis of power spectral analysis of HRV or through baroreflex sensitivity testing.^{11 12} We also hypothesized that transient inactivation of the peripheral chemoreceptors by hyperoxia may result in partial restoration of autonomic balance in these patients.

	Methods

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Patients
Twenty-six patients with CHF (25 men; mean age, 60±8 years; NYHA class II or III; mean ejection fraction, 25.6±8.6%; peak O₂ consumption, 18.7±5.6 mL · kg^-1 · min^-1) were included in the study. The etiology of CHF was idiopathic dilated cardiomyopathy in 5 and ischemic heart disease in 21 patients. Patients remained clinically stable for 1 month preceding the study, and none were assessed within 6 months of an acute coronary event. All were in sinus rhythm. Exclusion criteria included pulmonary disease, significant renal dysfunction, diabetes mellitus, arterial hypertension, or autonomic neuropathy. All patients had remained stable with their medication remaining unchanged for the month before the study. No patient was being treated with ß-blockers. The individual clinical data are given in Table 1. The study protocol was approved by the local ethics committee, and all patients gave informed consent.

View this table: [in this window] [in a new window]   Table 1. Individual Clinical Data of the 26 Study Patients With CHF

Protocol
Patients were always studied in the morning (9:00 AM to 12:00 noon) and were asked not to smoke or drink caffeine on the study day. In each subject after a 20-minute period of supine rest in a quiet room, a 30-minute recording was obtained of heart rate (ECG, lead ensuring a prominent R wave), noninvasive blood pressure (Finapres; Ohmeda), and a respiratory signal using an impedance method (mercury-in-Silastic strain-gauge plethysmograph; Hokanson) positioned over the lower part of the chest and calibrated electronically before each test. Subjects breathed spontaneously and were asked to relax but not fall asleep.

Data Acquisition
RR interval, blood pressure, and respiratory signals sampled at 1000 Hz were acquired with the use of a computer program, described in detail previously.¹³ Data were stored on computer hard disk and on back-up floppy disks and subsequently processed off-line (as described later).

HRV and Blood Pressure Variability Analysis
In all patients, a stationary 20-minute period of recording was selected and subjected to spectral analysis. Premature beats were identified and corrected by linear interpolation with the previous and following beats. Power spectral analysis was applied to the RR interval and systolic blood pressure data through the use of an autoregressive algorithm with 15 as a model order.¹³ After decomposition, the following spectral bands were found: VLF (<0.04 Hz), LF (0.04 to 0.15 Hz), and HF (0.15 to 0.40 Hz). To distinguish between signal and noise, only components above 5% of total variability were considered for analysis. The areas below each peak as well as the TP (0 to 0.5 Hz) were calculated and expressed in ms² and mm Hg² for HRV and blood pressure variability, respectively. The LF and HF powers of the HRV were also computed after natural logarithm transformations (ln ms²) because preliminary tests had shown a skewed distribution. To estimate the relative predominance of each component, the relative power of each component was computed as normalized units (LFnu, HFnu) calculated as the percentages of the total power within the LF and HF bands, respectively, after subtraction of the VLF component.¹¹

The harmonic oscillations of HRV and blood pressure variability are reliable indices of autonomic balance within the cardiovascular system.^{11 12} The powers within the LF band of RR interval are modulated by both sympathetic and parasympathetic activities, whereas the fluctuations at the frequency of respiration (HF) are considered to reflect vagal tone.¹¹ However, it is assumed that LF bands of the HRV and blood pressure variability are predominately index of sympathetic activities, whereas the HF rhythm of HRV index of vagal tone.^{11 12} An important role of the arterial baroreceptors in the genesis of the RR interval fluctuations has been proposed¹⁴ The normalization of LF and HF powers has been recommended as a more reliable marker providing a quantitative estimate of autonomic balance, especially in conditions with marked sympathetic overactivity like CHF.¹¹ Although the mechanisms influencing the VLF band remain obscure,^{15 16} we have recently found a relationship between these slow oscillations in heart rate and peripheral chemoreceptor activity in patients with CHF.¹⁷ Therefore, in the present study, we included VLF in the analysis to further investigate this phenomenon.

Coherence Analysis
Coherence analysis was used to assess the correlation among oscillations in RR interval, respiration, and systolic blood pressure. The squared coherence function is a mathematical bivariant spectral method used to evaluate the phase stability of pairs of oscillations with the same frequency, present in two signals. It is similar to the coefficient of correlation and may span between 0 (no relationship) and 1 (complete coherence). High squared coherence values between variations in systolic blood pressure and heart rate in the LF band reflect an intact baroreceptor control of the cardiovascular system.^{11 12} In this case, the simultaneous analysis of RR interval and systolic blood pressure variabilities allows us to derive an index, calculated as the square root of the ratio of the RR interval power to the corresponding systolic blood pressure power within the LF band. It provides a measure of the overall gain of the baroreflex control of the sinoatrial node^{11 18} and has been widely used in the noninvasive assessment of arterial baroreflex mechanisms.^{11 12 18 19}

Baroreflex Sensitivity
In addition to the index described above, baroreflex sensitivity was assessed through the use of the bolus phenylephrine method.²⁰ Patients received intravenous injections of phenylephrine HCl with an initial dose of 150 µg, which was subsequently increased by 50 to 100 µg at a time, up to a maximum dose of 500 µg, to obtain an increase in systolic blood pressure of <15 mm Hg. The test was repeated at least three times with the optimal dose of phenylephrine. The baroreflex sensitivity was calculated as the slope of the regression line relating changes in RR interval to changes in systolic blood pressure, and only regression lines with a correlation coefficient of >.80 were used.^{20 21} In each patient, baroreflex sensitivity was calculated as the average of all valid regression slopes and expressed in ms/mm Hg.

Peripheral Chemosensitivity Evaluation
In this study, peripheral chemosensitivity was assessed using the transient hypoxic method described in detail elsewhere.^{7 22} Briefly, the test was performed while subjects were seated and after a period of quiet breathing. Minute ventilation was measured on a breath-by-breath basis with a heated pneumotachograph, and continuous monitoring of O₂ and CO₂ concentrations was done using mass spectrometry (inert gas dilution technique, Amis 2000; Innovision), calibrated before each test.^{22 23} This method has been extensively validated.²⁴ SaO₂ was measured using a pulse oximeter (model N-200E; Nellcor) set at fast mode with a response time of 2 to 3 seconds and a lightweight ear probe attached to the subject's right earlobe.²⁵ Each patient, who was unaware of the timing of the test, repeatedly breathed pure nitrogen for two to eight breaths. The number of breaths of nitrogen inhalation was kept low to prevent excessive hypoxemia and respiratory depression. This was repeated 10 to 15 times to provide a wide range of SaO₂, from 75% to 100%, with 2-minute intervals of air breathing between exposures to allow SaO₂ and end-tidal CO₂ to return to the subject's baseline levels. The fall in end-tidal CO₂ is due to hyperventilation caused by the hypoxic stimulus. The average of the two largest consecutive breaths that gave the highest ventilation after the hypoxic stimulus was used to calculate maximal ventilation. This value was plotted against the lowest SaO₂ reached for that period of nitrogen inhalation. The transient peripheral chemosensitivity was expressed as the slope of the regression line relating ventilation to SaO₂, calculated by least-squares linear regression analysis and measured in L · min^-1 · %SaO₂^-1.^{7 22} The reproducibility of the peripheral chemoreflex test using the transient hypoxic method in our laboratory has been described elsewhere,⁷ and there was good agreement between two repeated measures (r=.93, P<.05) with the mean coefficient of variation of 21.4%, which was comparable to other studies.^{26 27}

To characterize patients with CHF with elevated peripheral chemoreflex activity, we used a reference value of 0.293±0.217 L · min^-1 · %SaO₂^-1 obtained in our laboratory in a group of 15 healthy subjects (11 men; mean age, 55 years).⁷ An abnormally augmented peripheral chemosensitivity in patients with CHF was accordingly defined as a value greater than the mean+2 SDs of the peripheral chemoreflex in the control group, which corresponded to a value of 0.727 L · min^-1 · %SaO₂^-1.

Effect of Transient Hyperoxic Deactivation of Peripheral Chemoreceptors on Autonomic Balance
To assess the effect of transient hyperoxic deactivation of peripheral chemoreflex input on autonomic balance, 12 patients underwent a two-phase protocol (20-minute phases) during which they breathed air (air phase) or 100% O₂ delivered via mask (oxygen phase). The phases were performed in a random order with controlled respiration (12 breaths/min), and patients were not aware of the gas they breathed. During the protocol, simultaneous recordings of ECG, blood pressure, and respiration were performed, and stable 15-minute periods at the end of each phase were selected and subjected to spectral analysis (as described above).

Statistical Analysis
Data are given as mean±SD. The simple linear regression method, paired and unpaired Student's t test, or Mann-Whitney U test was used where appropriate. Values of P<.05 were considered significant.

	Results

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HRV Indices and Baroreflex Sensitivity in Patients With CHF
Power spectral analysis of HRV and blood pressure variability was performed in all patients. The value of the -index in the LF band could not be calculated in 3 patients due to lack of coherence between heart rate and blood pressure within this band. The mean value of the index in the remaining 23 patients was 3.74±2.86 ms/mm Hg (for individual data, see Table 2).

View this table: [in this window] [in a new window]   Table 2. Individual Values of Peripheral Chemosensitivity and Autonomic Indices in 26 Patients With CHF

Baroreflex sensitivity using the bolus phenylephrine method was assessed in 21 patients (Table 2). In two patients, we were not able to calculate the baroreflex sensitivity because of frequent ventricular or supraventricular beats. In the remaining 19 patients, the mean value of baroreflex sensitivity by this method was 3.45±2.22 ms/mm Hg. In 16 patients who had baroreflex sensitivity assessed by both methods, we found a moderate correlation between the -index and baroreflex sensitivity using the phenylephrine method (r=.54, P=.03).

Peripheral Chemosensitivity in CHF Patients
The evaluation of the peripheral chemoreflex using the ventilatory responses to transient hypoxia was performed in all 26 patients, and the results are individually presented in Table 2. None of the patients were hypoxemic at baseline, with SaO₂ values ranging from 96% to 100%. As mentioned in "Methods," with increasing breaths of nitrogen, there was an inevitable fall in end-tidal CO₂ due to increased ventilation caused by the hypoxic stimulus (mean end-tidal CO₂ concentration at the end of two breaths of nitrogen inhalation was 5.5±0.8% compared with 5.2±0.8% at the end of eight breaths, with a fall in end-tidal CO₂ fractional concentration of 0.3%). To reduce the effects of the fall in end-tidal CO₂ on respiration, adequate time intervals were given to allow the end-tidal CO₂ concentration to return to baseline before the next nitrogen inhalation.

Patients showed a higher mean peripheral chemosensitivity (mean value, 0.72±0.36 L · min^-1 · %SaO₂^-1) compared with an age-matched group of healthy control subjects (0.29±0.21 L · min^-1 · %SaO₂^-1) in our laboratory (P<.01).⁷

Peripheral Chemosensitivity and Autonomic Imbalance in Patients With CHF
A group of 11 patients (42%) with peripheral chemoreflex values of >0.729 L · min^-1 · %SaO₂^-1 (ie, >mean+2 SDs in control subjects) were considered to have an abnormally augmented peripheral chemosensitivity. There was no difference in these patients' clinical characteristics (age, CHF etiology, NYHA functional class, ejection fraction, peak O₂ consumption) compared with the patients with normal chemoreflex sensitivity (Table 3). However, the patients with high chemosensitivity revealed a different HRV profile characterized by depressed LF power (expressed in absolute or normalized units) and a higher power of HRV within the VLF band (expressed as the percentage of TP). Moreover, in this group, depressed values of baroreflex sensitivity were found when calculated with the phenylephrine method or as the index (Table 2). Of interest, there was no significant difference between the two groups in baseline values of heart rate, blood pressure, phenylephrine dose, or magnitude of the blood pressure response to phenylephrine (Table 2).

View this table: [in this window] [in a new window]   Table 3. Clinical Data and Autonomic Measures in Patients With CHF and Augmented Peripheral Chemosensitivity (>Mean+2 SDs in Healthy Control Subjects) Compared With Patients With Lower Values of Peripheral Chemosensitivity (Below These Values)

We correlated the values of chemoreflex sensitivity with the following spectral measures of HRV: power within VLF, LF, and HF bands expressed in absolute values or as a percentage of TP (for VLF) or normalized units (for LF and HF). There was a modest but significant inverse correlation between chemosensitivity and power within the LF band (r=-.52, P=.006) and between chemosensitivity and VLF power calculated as a percentage of TP (r=.48, P=.011). We also observed a strong trend toward an inverse relationship between chemosensitivity and LF power expressed in normalized units (r=-.38, P=.055). When baroreflex sensitivity was correlated with hypoxic chemosensitivity, we found a significant inverse correlation for both methods—stronger for phenylephrine (r=-.78, P<.0001) but still significant for the -index method (r=-.66, P=.0006) (Figure). There was, in contrast, no significant relationship between chemoreflex sensitivity and ejection fraction or peak O₂ consumption.

View larger version (11K): [in this window] [in a new window]   Figure 1. Correlation between chemosensitivity (expressed in L · min-1 · %SaO2-1, horizontal axis) and the baroreflex sensitivity calculated from a phenylephrine method (expressed ms/mm Hg, vertical axis) (left) in 19 patients or baroreflex sensitivity calculated as an index in the LF band (expressed in ms/mm Hg, vertical axis) (right) in 23 patients with CHF.

Effect of Transient Hyperoxic Deactivation of Peripheral Chemoreceptors on Autonomic Measures
In 12 patients who were acutely exposed to hyperoxia, there was no difference in the mean RR interval and systolic blood pressure between the two phases (air versus oxygen). However, hyperoxic conditions resulted in an increase in LF and HF power of HRV (3.11±1.78 versus 4.31±1.48 ln ms² and 3.41±1.34 versus 3.95±1.40 ln ms² for air versus oxygen phase, respectively; P<.05), and an improvement in baroreflex sensitivity calculated as the index (3.61±3.17 versus 5.86±4.33 ms/mm Hg for air versus oxygen phase, respectively; P=.03). The phenylephrine method was not performed in this part of the study.

	Discussion

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The main finding of this study was that increased peripheral chemosensitivity observed in patients with CHF was associated with impaired cardiac autonomic activity expressed as either an abnormal profile of HRV or a depressed arterial baroreflex sensitivity.

Recent studies have shown that neurohormonal activation may occur even at mild stages of CHF and may be involved in the progression of the disease.^{2 28 29} Several investigators have shown impaired sympathovagal balance, characterized by sympathetic overactivity and parasympathetic withdrawal, to be an important part of neuroendocrine activation in CHF.^{15 30 31 32 33 34} Unfortunately, the precise mechanisms responsible have never been adequately established, despite extensive studies. The impaired arterial baroreflex control of the circulation and blunted reflex influences from the cardiopulmonary receptors are be possible contributing factors.⁴ In fact, these are two important reflexogenic areas with inhibitory influences on the sympathetic nervous system.^{2 4} Therefore, decreased reflex responses from either arterial baroreceptors or cardiopulmonary receptors, already present in mild stages of CHF,^{4 30} may result in a loss of reflex sympathetic inhibition and vagal stimulation. An important role of baroreflex dysfunction in the generation of sympathoexcitation in CHF has been suggested by Middlekauff et al,³⁵ who demonstrated nonuniform sympathetic activation in patients with CHF, in whom only tissues under baroreflex control demonstrated excessive sympathetic nerve activity.

Another intriguing possible explanation could be a relative overactivity of excitatory inputs to the sympathetic nervous system.² Two of the major sympathetic excitatory reflex inputs are those from muscle ergoreceptors and arterial chemoreceptors.² We recently demonstrated an exaggerated ergoreflex activity⁶ and an increased peripheral chemoreceptor sensitivity⁷ in patients with CHF. In addition, an antagonistic interaction between the peripheral chemoreceptors and arterial baroreceptors has been demonstrated in animals and healthy subjects.^{7 8 9} It could therefore be postulated that an increased chemoreceptor drive in CHF contributes to either sympathetic overactivity or the blunted baroreflex sensitivity. To test this hypothesis, we investigated the relation between the peripheral chemosensitivity assessed by the ventilatory response to transient hypoxia with indices of autonomic activity, including spectral measures of HRV and baroreflex sensitivity.

We found that in patients with higher peripheral chemosensitivity, the power within the LF band decreases and the power of RR interval variability shifts toward the VLF band. It was confirmed by the finding that patients with CHF with significantly augmented chemosensitivity (values above mean+2 SDs in normal control subjects) revealed significantly lower values of LF power (calculated in either absolute or normalized units) and respectively higher relative power within VLF band (expressed as percentage of total RR variability).

Several authors have applied power spectral analysis of HRV to investigate the abnormal autonomic control of the circulation in CHF.^{15 32 33 34 36} The variability in RR intervals is significantly depressed in patients with CHF, and changes in HRV occurring in CHF correlate with the severity of the disease. At a mild stage of CHF, the pattern of HRV is characterized by a predominant LF component with a reduction in the power within the HF band, and it seems to mirror augmentation of sympathetic activity and withdrawal of vagal tone.^{33 34} In moderate-to-severe CHF, the sympathoexcitation with accompanying deterioration in baroreceptor function abolishes the ability of the cardiovascular system to modulate heart rate or blood pressure, which results not only in a further reduction of HF power but also in a significant decrease in the power within the LF band, in some cases falling to zero.³⁶ Such an HRV pattern can also be found at peak strenuous exercise in normal subjects, suggesting that it may be associated with extreme sympathetic overactivity.³⁷

The inverse correlation between LF power and chemosensitivity found in our study confirms the relation between high sympathetic tone and chemoreflex drive in CHF. Interestingly, 4 of our patients with undetectable power within the LF band revealed very high chemosensitivity, with a mean value of 1.13 L · min^-1 · %SaO₂^-1 (versus 0.67 L · min^-1 · %SaO₂^-1 in the remaining patients). Because in this study the chemosensitivity also correlated with the VLF power calculated as percentage of the TP, we may conclude that in patients with CHF, high chemoreceptor drive occurs together with a progressive loss of power within the LF band and is associated with an increase in the power of the VLF component and that these changes reflect severe autonomic imbalance. This finding supports our previous observation that the presence of VLF oscillations in the RR interval spectrum did not correlate with the clinical severity of CHF but rather with profound abnormalities in sympathovagal balance and enhancement of peripheral chemoreceptor drive.¹⁷

We demonstrated a strong inverse relationship between baroreflex sensitivity and chemoreceptor drive. Such an inverse interaction has already been reported in animals and healthy subjects,^{8 9 10} but we are not aware of any previous report in patients with CHF. Grassi et al³⁰ reported recently an impairment of baroreflex sensitivity in patients with milder forms of CHF and concluded that it did not depend on a generalized alteration of autonomic cardiovascular control but rather on factors affecting specifically the central and/or afferent portion of the reflex arc. Among possible central factors, these authors suggested the role of angiotensin II in blunting the baroreflex sensitivity by crossing the blood-brain barrier.³⁰ On the basis of our results, it could be hypothesized that chemoreceptor drive may be such a central factor because neurophysiological studies have demonstrated that carotid baroreceptors and chemoreceptor neurons are distributed in close proximity to each other in the solitary and paramedian reticular nuclei in the medulla and that interneuronal connections might facilitate inhibitory interaction between these two reflexes.³⁸

We also tested whether modulation of the hypoxic chemoreflex drive would result in any acute changes in autonomic activity. To address this question, we subjected 12 patients to transient hyperoxia, which is known to inactivate peripheral chemoreceptor activity.³⁹ Hyperoxia did not significantly change heart rate or blood pressure, but resulted in an increase in LF and HF powers and in baroreflex sensitivity. In consideration of the previously characterized HRV pattern in CHF, such changes could be considered favorable. We are not able to draw any definite conclusions from this observation based on the rather small group of patients with CHF, but we believe it deserves further comment. First, even in patients with profoundly impaired autonomic balance, a transient decrease in chemoreceptor drive was able to partially restore autonomic balance and especially to improve baroreflex sensitivity. In this protocol, we computed the index, which has been found to be a reliable index of the overall gain of the influence of baroreflex mechanisms on heart rate.^{18 19} The concept of the index is based on closed-loop models in an attempt to characterize the complexity of baroreflex control: it potentially offers advantages over the bolus phenylephrine method, which is a simplified open-loop linear model of blood pressurexheart rate interactions.^{12 19}

The absence of baseline hypoxemia raises the subject of stimulus of the increased activity of peripheral chemoreceptors in CHF. At present, we are only able to speculate on this important matter. Absolute hypoxemia as measured in the periphery may not be the only stimulus to chemoreceptors. Blood flow is impaired in patients with CHF, and this may lead to ischemic hypoxia of the carotid bodies, a potential stimulus to increased chemosensitivity. Increased sympathetic drive may also be a stimulus to increased chemosensitivity. This is a postulated mechanism of the increased chemosensitivity gain during exercise.⁴⁰ Although the issue of whether augmented chemosensitivity is the cause or effect of increased sympathetic activity remains unresolved, in CHF the deleterious interactions between them may contribute to further autonomic imbalance.

The augmentation of the chemoreflex in CHF may be a compensatory mechanism. There is a pivotal role for arterial blood pressure in the syndrome of CHF, with the body engendering responses directed toward the maintenance of adequate blood pressure.⁴¹ In normal subjects, abrupt inactivation of arterial chemoreceptors through administration of concentrated O₂ induces a transient fall in arterial blood pressure, with a simultaneous decrease in sympathetic activity.³⁹ In the process of regulation of blood pressure, maintenance of optimal tissue oxygen tension may be as important as optimal blood flow. Chemoreceptors may function as oxygen sensors, initiating integrated autonomic nervous system changes in the respiratory system and circulation in attempt to prevent tissue hypoxia.

In light of our findings, it is interesting to note the recent results of van de Borne et al,⁴² who observed that chemoreflex deactivation with 10 minutes of hyperoxia did not alter MSNA in patients with CHF. The authors⁴² concluded that tonic chemoreflex activation was unlikely to contribute to the elevated resting muscle sympathetic nerve activity, postulating the role of chemoreceptor-independent mechanisms. However, it should be remembered that not all patients with CHF have increased peripheral chemoreflex sensitivity. As documented in our study group, 11 of the 26 patients (42%) demonstrated abnormal values of chemosensitivity, a finding we have confirmed in a much larger CHF population (T.P. Chua, P. Ponikowski, A.J.S. Coats, unpublished observations). It is therefore not known whether the lack of suppression in the microneurographic peroneal sympathetic activity by continuous hyperoxia was due to the fact that most of the patients studied by van de Borne et al⁴² may have had a normal baseline chemoreflex, which was not assessed in this study. Alternatively, the high resting MSNA values in the study by van de Borne et al⁴² may not have been corrected by a relatively short (10-minute) period of hyperoxia, or the hyperoxic effects on baroreflex and HRV may be more rapid than MSNA effects. Clearly, this area requires more detailed evaluation.

Recently, Haque et al⁴³ demonstrated the detrimental effects of transient O₂ supplementation on hemodynamic parameters and systemic vascular resistance on a patient population with recently unstable and edematous heart failure. We cannot exclude that O₂ supplementation may have different effects on CHF populations with more severe heart failure with respect to our population. However, these authors⁴³ did not observe a significant influence of O₂ on sympathetic activity, and they postulated non-neural, noncardiac effects of O₂; therefore, these results do not seem to be contradictory to our findings. We obviously could not exclude the possibility of minor hemodynamic changes during our patients' exposure to transient hyperoxia, but because heart rate and blood pressure remained stable throughout the study, a significant influence of such changes on autonomic balance seems unlikely.

Supplemental O₂ therapy has been shown to be effective in some patients with CHF, especially those with a Cheyne-Stokes pattern of respiration.⁴⁴ It is possible that at least some of these patients could have a periodic breathing pattern related to increased peripheral chemosensitivity. Preliminary data from our laboratory suggest that in advanced CHF, increased chemoreflex drive may cause slow periodic oscillations in heart rate, blood pressure, and respiration. In some patients, however, we found that slow periodic oscillations in respiration coincide with periodic hyperventilation and may significantly influence the VLF oscillations in RR intervals and blood pressure. It is also possible that in some patients, VLF rhythms (perhaps at a different frequency) may be carried by alternative chemoreceptors (eg, central CO₂ sensitivity). These concur with previous observations suggesting the role of hypocapnia-related hyperventilation in the genesis of Cheyne-Stokes breathing and central sleep apneas in patients with CHF.⁴⁵ The association among Cheyne-Stokes respiration, episodes of O₂ desaturation, and potential arrhythmogenesis in moderate-to-severe CHF has been documented.⁴⁶ Naughton et al⁴⁷ reported that Cheyne-Stokes respiration in CHF is associated with elevated sympathoadrenal activity: the urinary norepinephrine concentration correlated with the degree of arterial O₂ desaturation during sleep. Since increased sympathetic activity is known as an independent risk factor in CHF,³ these findings may help to relate the higher mortality in patients with CHF with Cheyne-Stokes respiration, only recently confirmed by Hanly et al.⁴⁸

In an attempt to find any relation between increased chemosensitivity and the likelihood of cardiac events, we followed our patients for 1 to 18 months (median follow-up, 10 months). We found that in the group with augmented chemosensitivity, there were three serious cardiac events (one cardiac death and two transplantations) (22%) but none in the group with lower chemosensitivity. Whether there could be a link among high peripheral chemoreceptor sensitivity, severely impaired autonomic balance, and prognosis in patients with CHF requires further evaluation.

Study Limitations
We deliberately selected the analysis of HRV and blood pressure variability as well as the assessment of baroreflex activity as measures of autonomic function. We are, however, aware that these methods provide only indirect information about the integrated mechanisms of autonomic control within the cardiovascular system, but unfortunately, no gold standard measure of sympathovagal balance exists.⁴⁹ For more appropriate use of power spectral analysis of HRV, we calculated the power within each band in absolute units as well as normalized units; this is a recommended approach for the assessment of sympathovagal balance in CHF.¹¹

There are three principal methods of assessing hypoxic chemosensitivity through the use of steady state,⁵⁰ progressive,⁵¹ and transient²⁶ hypoxia. Although the absolute values obtained from each method are different, they reflect the same indexes of chemosensitivity.^{27 52} The transient hypoxic ventilatory test was chosen in our study in preference to the other two methods to avoid prolonged hypoxia in patients with CHF. Prolonged hypoxia is also known to cause depression of the central respiratory drive. Although hyperventilation induced by the hypoxic stimulus causes hypocapnia, which may in turn reduce the hypoxic ventilatory response, we ensured in our tests that SaO₂ and end-tidal CO₂ levels had returned to baseline before the next exposure to nitrogen. Indeed, with other tests of peripheral chemosensitivity (ie, steady state and progressive methods), the prospects of central respiratory depression by prolonged hypoxia are greater.

All our patients were receiving diuretics, ACE inhibitors, digoxin, and nitrates as standard therapy for CHF, but none were taking ß-blockers. The effects of ACE inhibitors and digoxin on chemosensitivity are not known, but these drugs may potentially influence HRV and baroreflex sensitivity.^{53 54} In any case, we have now found that in our study in 50 patients with CHF, the medication of those who had augmented chemosensitivity did not differ significantly from the medication of those with normal chemosensitivity (T.P. Chua and A.J.S. Coats, unpublished observations). We therefore believe that the findings in this study were not significantly affected by patient medications.

In summary, the results of this study suggest a relationship between the increased peripheral chemosensitivity and impaired autonomic balance in patients with CHF. The clinical importance of this observation, and especially a possible link with prognosis, warrants further investigation.

	Selected Abbreviations and Acronyms

 

CHF = chronic heart failure HF = high frequency HRV = heart rate variability LF = low frequency MSNA = muscle sympathetic nerve activity NYHA = New York Heart Association SaO2 = oxygen saturation TP = total power VLF = very low frequency

Received November 27, 1996; revision received May 5, 1997; accepted May 15, 1997.

	References

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