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Published ahead of print on March 5, 2003, doi:10.1164/rccm.200208-793OC
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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 1534-1539, (2003)
© 2003 American Thoracic Society

Original Article

Influence of Cheyne-Stokes Respiration on Cardiovascular Oscillations in Heart Failure

Richard S. T. Leung, John S. Floras, Geraldo Lorenzi-Filho, Fiona Rankin, Peter Picton and T. Douglas Bradley

Sleep and Cardiovascular Physiology Research Laboratories of the Mount Sinai Hospital, Departments of Medicine of the Mount Sinai Hospital, and Toronto General Hospital/University Health Network, and the Center for Sleep Medicine and Circadian Biology, University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to T. Douglas Bradley, M.D., Toronto General Hospital/UHN, NU 9–112, 200 Elizabeth Street, Toronto ON, M5G 2C4, Canada. E-mail: douglas.bradley{at}utoronto.ca


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In patients with congestive heart failure, Cheyne-Stokes respiration is accompanied by oscillations in blood pressure and heart rate at a very low frequency. It is not known whether these cardiovascular oscillations are primarily related to oscillations in ventilation or oxyhemoglobin saturation. We hypothesized that abolition of the ventilatory oscillations of Cheyne-Stokes respiration by CO2 inhalation would eliminate accompanying oscillations in blood pressure and heart rate but that elimination of hypoxic dips by supplemental O2 would not. We studied 10 subjects with heart failure and Cheyne-Stokes respiration during sleep using frequency spectral analysis. During Cheyne-Stokes respiration, heart rate and blood pressure oscillated in association with respiratory oscillations at very low frequency. Inhalation of CO2 abolished Cheyne-Stokes respiration and associated oscillations in both blood pressure and heart rate. In contrast, inhalation of O2 sufficient to eliminate hypoxic dips had no significant effect on Cheyne-Stokes respiration, blood pressure (n = 6), or heart rate (n = 5). We conclude that ventilatory oscillations during Cheyne-Stokes respiration rather than oscillations in oxygenation per se powerfully induce heart rate and blood pressure oscillations. Cheyne-Stokes respiration is therefore one of the mechanisms that contributes to the very low-frequency oscillations in heart rate and blood pressure observed in patients with heart failure.

Key Words: central sleep apnea • heart rate variability • blood pressure variability

Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) is a form of periodic breathing in which apneas and hypopneas alternate with ventilatory periods having a crescendo–decrescendo pattern of tidal volume. CSR-CSA is common among patients with congestive heart failure, being present in 30–40% of the two largest reported series (1, 2). Growing evidence indicates that CSR-CSA is part of a vicious pathophysiologic cycle involving the cardiovascular, pulmonary, and autonomic nervous systems, and it ultimately contributes to increased mortality among patients with heart failure (3–5). One possible mechanism linking CSR-CSA with poor prognosis is through intermittent surges in blood pressure (BP) and heart rate (HR), occurring in association with oscillations in ventilation. Such surges can be precipitated by cyclic increases in sympathetic nervous activity targeting the heart and peripheral vasculature (6, 7).

Several mechanisms have been proposed to account for cyclic oscillations in BP and HR during CSR-CSA. These include chemostimulation by apnea-related hypoxia and arousals from sleep. However, others have demonstrated that induction of respiratory oscillations by boluses of inhaled CO2 during sleep in healthy humans induced respiratory-related oscillations in HR (8). In addition, we previously demonstrated, during both voluntary periodic breathing under normoxic conditions in healthy subjects and spontaneous Cheyne-Stokes respiration during wakefulness in patients with heart failure, that periodic breathing generated periodic oscillations in BP and HR (7, 9). Therefore, neither hypoxia nor arousals from sleep are necessary for inducing periodic oscillations in these hemodynamic variables. However, it is not known whether this is true for spontaneous CSR-CSA in patients with heart failure during sleep. The possibility remains that oscillations in BP and HR accompanying CSR-CSA may arise from oscillations in ventilation itself, possibly through coactivation of respiratory and cardiovascular sympathetic neurons in the brainstem (10).

Inhalation of CO2 acutely eliminates CSR-CSA, whereas O2 inhalation sufficient to abolish hypoxic dips does not (11). Therefore, to determine whether BP and HR oscillations are mainly related to ventilatory oscillations or recurrent dips in SaO2, we administered CO2 and O2 by inhalation to heart failure patients with CSR-CSA during overnight polysomnography. Our primary hypothesis was that abolition of CSR-CSA by administration of a CO2-enriched gas would eliminate oscillations in BP and HR. Our secondary hypothesis was that administration of supplemental O2 sufficient to eliminate hypoxic dips would not. Some of the results of these studies have been previously reported in the form of an abstract (12).


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
For further details of our methods, see the online supplement.

Subjects
We studied 10 consecutive patients with heart failure of at least 6 months in duration, due to ischemic cardiomyopathy, referred for polysomnography because of a suspicion of sleep apnea during which CSR-CSA was identified. They had a resting left ventricular ejection fraction of 35% or less and exertional dyspnea despite optimal medical therapy. Cardiac medications included ß-blockers in 4 subjects, digoxin in 6, amiodarone in 2, angiotensin-converting enzyme inhibitors in 10, calcium channel blockers in 3, diuretics in 9, and nitrates in 3. CSR-CSA was diagnosed when there were at least 15 apneas and hypopneas per hour of sleep, of which at least 80% were central. This protocol was approved by University of Toronto Human Subjects Review Committee. Written informed consent was obtained from all subjects. Data from 9 of the 10 subjects on the effects of CO2 and O2 on CSR-CSA, derived from the same overnight sleep studies as those described herein, have been previously published (11).

Experimental Setup
Polysomnography was performed using standard techniques described for our laboratory (13), including sleep staging (14), thoracoabdominal movements, SaO2, transcutaneous PCO2, fraction of inspired CO2, finger-arterial BP, and HR via an electrocardiogram. Central apneas and hypopneas were scored as previously described (11). All signals were displayed online to allow identification of Stage 2 sleep for experimental interventions.

Protocol
During polysomnography, each subject wore a facemask with a three-way stopcock, initially breathing room air as previously described (11). Once Stage 2 sleep with CSR-CSA became established, the subject was switched to a CO2-enriched gas containing 21% O2. The fraction of inspired CO2 was slowly increased until central apneas and hypopneas disappeared. Subsequently, after a return to breathing room air, O2 was administered at a concentration that was sufficient to increase SaO2 to the same level as during CO2 inhalation. Thus, recordings were taken during three breathing conditions: room air, CO2, and O2, in that order.

Data Analysis
Data were acquired by a computerized polysomnographic program and were analyzed offline. All signals were sampled at 200 Hz, except for the electrocardiograph signal, which was sampled at 1,000 Hz. The HR (expressed as its inverse; R-wave to R-wave, or RR interval measured from the QRS complex of the electrocardiogram), mean BP, and ventilatory signals were then analyzed in the frequency domain using Fourier transforms. Data sets of at least 14 minutes under all experimental conditions were used to permit acceptable frequency resolution at the frequency of periodic breathing. Power spectra were obtained over the frequency range of 0.005 to 0.8 Hz.

With instantaneous lung volume derived from the tidal volume signal as the input variable, and BP and RR interval as the two output variables, spectral power, coherence, and phase angles were calculated at the frequency of CSR-CSA for each subject. Coherence is a measure (from 0 to 1) of the linear correlation between input and output signals. At a given frequency, we use the term negative phase angle to describe an interval between a peak in the input variable and a subsequent peak in the output variable, which is less than one half of a cycle length (15). However, a negative phase angle does not necessarily imply that input physiologically precedes output.

Respiration was considered to exert a significant influence on HR (RR intervals) and BP when the coherence between the two signals exceeded the 95% confidence interval for coherence across the frequency range from 0.005 to 0.8 Hz (16). The peak powers within the very low-frequency band were logarithmically transformed and then compared between air, CO2, and O2 inhalations by repeated-measures analysis of variance with Tukey's test. A p value of less than 0.05 was considered statistically significant.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
All 10 subjects were men. Their demographic and baseline sleep study data are presented in Table 1 . All were administered CO2 during the study night. Because of sleep disruption and time constraints imposed by our protocol during the study night, only six subjects were administered O2. The single patient with a paced rhythm was excluded from HRV analysis.


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  		TABLE 1. Baseline clinical and sleep characteristics of patients*

 
The presence and severity of CSR-CSA when subjects breathed room air were relatively constant during S2 sleep throughout the night. CSR-CSA was accompanied by oscillations in SaO2 and transcutaneous CO2 and by oscillations in HR and BP, in which peaks in HR (i.e., troughs in RR interval) and BP occurred during hyperpnea and troughs during apnea (Figure 1) . When viewed in the frequency domain, these oscillations corresponded to large peaks in power spectral density in the very low-frequency band (Figure 2) . Indeed, these power spectral peaks in RR interval and BP dominated the very low-frequency band and occurred at precisely the same frequency as the peak in respiration. Furthermore, there was significant coherence between respiration and RR interval (0.94 ± 0.01) in every subject (except the subject with a paced rhythm) and respiration and BP (0.79 ± 0.06) in 9 of the 10 subjects. The peak fluctuations in HR and BP followed corresponding cycles in breathing (mean cycle length of 86.7 ± 18.8 seconds) by phase angles of -40.5 ± 9.1 and -37.2 ± 27.6 degrees, respectively. These indicate that changes in respiration preceded changes in HR and BP by approximately 10 seconds (10.1 ± 3.1 seconds for HR and 9.6 ± 8.9 seconds for BP) and that HR and BP oscillations were practically synchronous.



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  		Figure 1. Time domain recordings from a representative patient during air, CO2, and O2 inhalation. While breathing room air, the patient displays spontaneous CSR-CSA consisting of the classic crescendo–decrescendo pattern of hyperpnea alternating with periods of apnea. As expected, SaO2 and transcutaneous CO2 vary in phase with respiration. Although oscillations in transcutaneous PCO2 were detected, their magnitude was damped because of the relatively long (50-second) time constant of the transcutaneous capnograph. Oscillations in HR and BP are also clearly associated with the ventilatory oscillations, such that peaks in HR (i.e., troughs in RR interval) and BP occur during the hyperpnea and troughs in HR and BP during the apnea. Inhalation of CO2 sufficient to raise PaCO2 above the apneic threshold abolishes CSR-CSA and oscillations in SaO2, transcutaneous CO2, HR, and BP. Inhalation of O2 eliminates SaO2 desaturations but does not eliminate CSR-CSA. Moreover, oscillations in HR and BP continue despite steady normoxia. ILV = instantaneous lung volume; PtcCO2 = transcutaneous CO2.

 


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  		Figure 2. Power spectral densities from the same recording as shown in Figure 1. Oscillations in respiration, SaO2, transcutaneous CO2 (PtcCO2), and HR and BP are seen as peaks in power spectral density occurring at very low frequency. Peaks in all five variables accompany CSR-CSA while breathing room air. The peaks in HR and BP occur at precisely the same frequency and with high coherence to respiration. All five peaks disappear during inhalation of CO2 when CSR-CSA is abolished. Inhalation of O2 causes only the disappearance of the peak in SaO2; CSR-CSA persists, as do the associated oscillations in transcutaneous PCO2, HR, and BP. ILV = instantaneous lung volume.

 
A particularly interesting observation was made in one patient with a fixed HR due to cardiac pacing. In this patient, BP oscillated synchronously with ventilatory oscillations in the presence of fixed HR, indicating that respiration-associated BP oscillations can occur independently of changes in HR (Figure 3) .



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  		Figure 3. Time domain recording from a subject with a paced cardiac rhythm. As expected, the HR is fixed. However, respiratory-associated oscillation of BP occurs nonetheless, indicating that BP oscillations do not occur secondarily to changes in HR. ILV = instantaneous lung volume.

 
Effect of CO2 Inhalation
Inhalation of CO2 (the mean fraction of inspired CO2 was 1.9 ± 0.6%) raised transcutaneous CO2 (from 37.2 ± 4.3 to 38.9 ± 4.8 mm Hg, p < 0.002), completely abolished apneas and hypopneas, and restored regular breathing, as previously reported (11). Apnea-related dips in SaO2 were also eliminated such that the mean low SaO2 increased from 93.1 ± 2.9% to 95.4 ± 2.1% (p < 0.002). Periodic RR interval and BP oscillations were eliminated along with the periodic breathing pattern (Figure 1). In the frequency domain, CO2 inhalation abolished the CSR-CSA–related very low-frequency peaks in RR interval and BP spectral power (Figure 2). Accordingly, CO2 decreased both peak very low-frequency power (Figure 4) and very low-frequency band power as a proportion of total power (Figure 5) for the variables of interest.



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  		Figure 4. Comparison of effects of air, CO2, and O2 inhalation on HR (upper panel) and BP (lower panel) peak spectral power at very low frequency (VLF). Elimination of CSR-CSA by CO2 inhalation causes a highly significant, almost complete abolition of very low-frequency peak spectral power of HR (from 5.23 ± 0.83 to 4.37 ± 0.81, p < 0.001) and BP (from 3.09 ± 0.30 to 2.13 ± 0.25, p < 0.001). In contrast, inhalation of O2 had no effect on peak very low frequency power of any of the variables (HR 5.20 ± 0.71 and BP 3.06 ± 0.33), indicating that respiratory-associated oscillations in HR and BP persist.

 


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  		Figure 5. Comparison of effects of air, CO2, and O2 inhalation on HR (upper panel) and BP (lower panel) spectral power in the very low-frequency (VLF) band, expressed as a proportion of total power in all bands. Elimination of CSR-CSA by CO2 inhalation causes a halving of very low frequency peak spectral power of HR (from 0.540 ± 0.24 to 0.260 ± 0.16, p < 0.003) and BP (from 0.575 ± 0.15 to 0.30 ± 0.55, p < 0.004). In contrast, inhalation of O2 had no effect on total very low-frequency power of any of the variables (HR 0.539 ± 0.219, BP 0.548 ± 0.202).

 
Effect of O2 Inhalation
Six subjects received supplemental O2 at doses sufficient to eliminate O2 desaturation completely (mean low SaO2 increased from 91.9 ± 3.1% to 95.4 ± 2.6%, p < 0.05) to a level not significantly different from that during CO2 inhalation (94.5 ± 2.6, p = NS). Transcutaneous PCO2 did not increase significantly (from 35.7 ± 4.7 to 36.2 ± 4.0 mm Hg, p = NS), and apnea–hypopnea index remained unchanged compared with room air, as previously described (11). CSR-CSA and its associated oscillations in HR and BP persisted in all subjects. An example is shown in Figure 1. In the frequency domain (Figure 2), peaks in RR interval and BP power spectral density at the frequency of CSR-CSA in the very low-frequency band were unchanged compared with room air breathing but were greater than during CO2 inhalation (Figure 4). Coherence between the respiratory and RR interval oscillations and between respiration and BP spectral power remained significant in all subjects studied during O2 inhalation (0.82 ± 0.05 and 0.76 ± 0.07, respectively). Phase angles between respiration and HR (-27 ± 18°) and respiration and BP (-27 ± 23°) were not significantly different than those observed during room air breathing. HR and BP oscillations were synchronous.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We have demonstrated that CSR-CSA induces HR and BP oscillations in patients with heart failure at the frequency of periodic breathing. Because elimination of CSR-CSA by CO2 inhalation abolished very low-frequency oscillations of HR and BP whereas alleviation of apnea-related dips in SaO2 by O2 inhalation did not, these phenomena are more tightly linked to oscillations in ventilation than to fluctuations in SaO2.

Although total spectral power of HR is attenuated in heart failure compared with normal subjects, there is a relative increase in spectral power of HR variability in the very low-frequency band. This increase in spectral power at a very low frequency has been associated with periodic breathing (17). However, there has not been definitive evidence that the HR and BP oscillations are caused by periodic breathing. A number of older studies described oscillations in HR and BP in association with Cheyne-Stokes respiration, but their findings are of questionable validity and relevance to the present study. For example, in 1971, a review of the older literature by Dowell and colleagues (18) asserted that HR and BP increase during the apneic phase of Cheyne-Stokes respiration, a finding at odds with both these results and those of other recent studies (7, 17, 19). Moreover, frequency spectral analyses were not used in those older studies to examine the interactions of respiration, HR, and BP during CSR-CSA. A number of more recent studies examining the relationship between cycles of CSR-CSA on the one hand and HR and BP oscillations on the other have applied either voluntary periodic breathing or voluntary cessation of periodic breathing during wakefulness (17, 20, 21). However, it has been shown that voluntary generation of altered breathing patterns may independently influence indices of autonomic tone (22). Moreover, because CSR-CSA is a disorder that is modulated by the respiratory metabolic control system, it occurs far more frequently during sleep than wakefulness. Therefore, experimental findings from either voluntarily induced or spontaneous periodic breathing obtained during wakefulness, where behavioral factors may influence both respiratory and cardiovascular variables, may not be generalizable to sleep, where these variables are almost exclusively under metabolic and autonomic control (23). Thus, our observations in patients with heart failure who have spontaneous CSR-CSA during sleep are representative of the physiologic milieu in which CSR-CSA most frequently occurs.

The precise mechanism linking CSR-CSA with BP and HR oscillations remains to be determined. However, our data shed new light on this issue. First, they demonstrate that periodic oscillations in BP and HR are not dependent on episodic hypoxia. When intermittent hypoxia was eliminated by O2 inhalation, oscillations in HR and BP remained associated with oscillations in ventilation. These findings are qualitatively similar to those during voluntary periodic breathing (9). They are also consistent with the report of Franklin and colleagues (19), who found that HR and BP oscillations during CSR-CSA were unaffected by inhalation of supplemental O2. However, it is possible that inhalation of a high concentration of O2 sufficient to induce hyperoxia with an SaO2 higher than in our experiments would attenuate CSR-CSA (24–26) and thereby reduce the associated oscillations in HR and BP, possibly by secondarily raising PaCO2. Nonetheless, these findings indicate that HR and BP oscillations at a very low frequency are dependent primarily on periodic oscillations in ventilation, rather than episodic hypoxia. Because fluctuations of PaCO2 above and below the apneic threshold (13) are necessary for the perpetuation of CSR-CSA, cardiovascular oscillations might also be linked to oscillations in PaCO2.

Oscillations in HR and BP can be generated by spontaneous CSR-CSA under the primary influence of the chemical–metabolic control system or by voluntary periodic breathing under the primary influence of the behavioral control system (7, 9). Accordingly, these oscillations may be primarily related to oscillations in central respiratory drive, whether of metabolic or behavioral origin.

The peak fluctuations in HR and BP were practically synchronous and followed corresponding cycles in breathing by approximately 10 seconds. Thus, there appears to be a relatively long time constant between the generation of central respiratory drive and the subsequent cardiovascular responses. This 10-second delay is more in keeping with the behavior of the sympathetic than the parasympathetic nervous system. Under normal circumstances, cardiac vagal parasympathetic activity modulates HR responses at high frequencies, whereas the sympathetic nervous system is more slowly adapting and is thus incapable of causing cardiovascular effects at frequencies greater than 0.15 Hz (27–29). Indeed, it is for this reason that respiratory-related changes in sympathetic outflow to the heart are not an important determinant of respiratory sinus arrhythmia (30). Accordingly, patients with heart failure, who have greatly diminished parasympathetic activity (31), display little or no high-frequency spectral power (32). Conversely, it seems unlikely that the observed very low-frequency oscillations in HR and BP accompanying CSR-CSA are primarily the result of parasympathetic influences. However, the possibility that oscillations in parasympathetic activity contribute to oscillations in HR and BP associated with CSR-CSA cannot be entirely excluded.

HR and BP rose in synchrony, both peaking during the hyperpneic phase of CSR-CSA. This indicates that rises in HR were not baroreceptor mediated during this time. BP oscillations were also documented in one subject who had a pacemaker and fixed HR, indicating that periodic breathing can have a direct effect on BP independent of HR (Figure 3). One possible mechanism by which CSR-CSA could cause BP oscillations is through alterations in intrathoracic pressure and thereby preload. During the hyperpneic phase of CSR-CSA, mean intrathoracic pressure is more negative than during the apneic phase, resulting in enhanced preload. However, patients with heart failure and CSR-CSA are characterized by markedly elevated left ventricular filling pressures (33). Because cardiac output in such patients would be relatively insensitive to further increases in preload, it seems unlikely the BP oscillations are primarily caused by such a mechanism. A more likely explanation for the simultaneous increases in HR and BP is a parallel increase in sympathetic drive to the heart and peripheral vasculature (34). Because vagal tone is markedly impaired in heart failure (31), this sympathetically mediated rise in BP cannot be buffered by baroreflex-mediated parasympathetic withdrawal.

These observed increases in HR and BP during the hyperpneic phase of CSR-CSA may result from intermittent surges in central sympathetic outflow phase linked to oscillations in central respiratory drive (19, 35, 36). There is evidence for direct connections between respiratory and cardiovascular sympathetic neurons in the brainstem. Activation of the respiratory neurons can coactivate these sympathetic neurons (36). Therefore, several stimuli, including chemostimulation, arousals, or voluntary cortical influences, could contribute to linked cardiorespiratory outflow. However, arousals have been to shown have little effect on BP during CSR-CSA (7). Chemostimulation by hypoxia might also be expected to elicit sympathetic discharge, but our results indicate little role for hypoxia in generating HR and BP oscillations, possibly because of the mild degree of hypoxia in most patients with CSR-CSA. Excess respiratory drive in heart failure arises to a large degree not from hypoxia, but from nonchemical stimuli, especially vagal afferent stimulation from pulmonary congestion (33, 37), which also contributes to sympathetic nervous activation (38).

Synchronous activation and deactivation of respiratory and cardiovascular systems during CSR-CSA would optimize ventilation/perfusion matching (39). However, this interaction of the two systems might also lead to deleterious effects during CSR-CSA, such as excessive sympathetic activation. Indeed, CSR-CSA in patients with heart failure is associated with increased sympathetic activity (6, 35), which is in turn inversely related to survival (40, 41). Through this mechanism, periodic increases in sympathetic activity associated with CSR-CSA might contribute to the increased mortality associated with CSR-CSA among patients with heart failure (4, 5).

In conclusion, our data demonstrate that CSR-CSA in patients with heart failure powerfully induces oscillations in HR and BP at very low frequency. CSR-CSA is therefore one of the mechanisms that contributes to the very low-frequency power peaks in HR and BP that have been described in patients with heart failure and that are associated with poor prognosis (17, 21, 42). Our data also indicate that HR and BP oscillations associated with CSR-CSA are more tightly linked to oscillations in ventilation than to fluctuations in SaO2.


   FOOTNOTES
 
Supported by grant MOP-11607 from the Canadian Institutes of Health Research, a Canadian Institutes of Health Research Phase I Clinician Scientist Award (R.S.T.), a Heart and Stroke Foundation of Ontario Career Scientist Award (J.S.F.), and a Canadian Institutes of Health Research Senior Scientist Award (T.D.B.).

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Received in original form August 2, 2002; accepted in final form February 28, 2003


   REFERENCES
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 RESULTS
 DISCUSSION
 REFERENCES
 

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