Key words: circulatory delay; congestive heart failure; obstructive sleep apnea; periodic breathing

Periodicity of Obstructive Sleep Apnea in Patients With and Without Heart Failure* Clodagh M. Ryan, MB; and T. Douglas Bradley, MD Study objective: To determine whether the duration of the apnea-hyperpnea cycle is longer in patients with congestive heart failure (CHF) and obstructive sleep apnea (OSA) than in patients with OSA alone, and whether this is related to prolonged circulation time. Design: Retrospective study. Setting: Sleep laboratory of a university teaching hospital. Patients and intervention: Male patients with OSA and CHF (n 22) or without CHF (n 18) underwent overnight polysomnography. Measurements and results: Hyperpnea duration, time to peak tidal volume (VT), and lung-to-ear circulation time (LECT) were measured in all patients. Compared to the non-chf patients, those with CHF had significantly longer hyperpneas (25.7 7.8 s vs 17.6 5.6 s, p < 0.001) and LECT (14.9 3.4 s vs 9.0 1.8 s, p < 0.001) [mean SD]. There was also a significant relationship between LECT and hyperpnea duration (r 0.67, p < 0.001). Conclusion: In patients with CHF, prolonged lung-to-chemoreceptor circulation time influences the cycling characteristics of OSA such that it prolongs hyperpnea and sculpts a pattern resembling Cheyne-Stokes respiration. These findings further suggest that the increased tendency to periodic breathing in CHF may predispose to, or alter the physiologic manifestations of OSA. (CHEST 2005; 127:536 542) Key words: circulatory delay; congestive heart failure; obstructive sleep apnea; periodic breathing Abbreviations: AHI apnea-hypopnea index; CHF congestive heart failure; CPAP continuous positive airway pressure; CSA central sleep apnea; LECT lung-to-ear circulation time; OSA obstructive sleep apnea; Ptcco 2 transcutaneous Pco 2 ;Sao 2 arterial oxygen saturation; Vt tidal volume Obstructive sleep apnea (OSA) commonly occurs in patients with congestive heart failure (CHF). 1 Long-term relief of OSA in patients with CHF by continuous positive airway pressure (CPAP) causes significant improvements in cardiac function. 2 4 Therefore, it is important to determine what factors are involved in the pathophysiology of OSA in the *From the Sleep Research Laboratory of the Toronto Rehabilitation Institute, and the University of Toronto Centre for Sleep Medicine and Circadian Biology, Toronto, ON, Canada. Supported by a grant from the Canadian Institutes of Health Research (MOP 11607). Dr. Ryan is supported by unrestricted Research Fellowships from Respironics Inc. and The Toronto Rehabilitation Institute, and Dr. Bradley by a Senior Scientist Award from the Canadian Institutes of Health Research. Manuscript received May 21, 2004; revision accepted August 19, 2004. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org). Correspondence to: T. Douglas Bradley, MD, Toronto General Hospital/University Health Network, EC 6 248, 200 Elizabeth St, Toronto, ON, M5G 2C4, Canada; e-mail: douglas.bradley@ utoronto.ca setting of CHF. It has been hypothesized that a primary periodic breathing disorder may play a role in the pathophysiology of some cases of OSA. 5,6 According to this hypothesis, instability of the upper airway is a result rather than the cause of the periodic breathing. If periodicity of breathing contributes to upper airway occlusion, then evidence for this is likely to be found in subjects predisposed to periodic breathing during sleep, such as those with CHF. Patients with CHF frequently suffer from a form of periodic breathing known as Cheyne-Stokes respiration. 7 Cheyne-Stokes respiration is characterized by apneas alternating with prolonged hyperpneas, during which there is a slowly waxing and waning pattern of tidal volume (Vt). Although there have been a few reports of upper airway obstruction during Cheyne-Stokes respiration, there has been no systematic examination of a potential relationship between OSA and Cheyne-Stokes respiration in patients with CHF. 8 In patients with OSA and normal ventricular function, obstructive apneas are usually terminated 536 Clinical Investigations

by a hyperpnea with an abrupt rise and rapid decline in Vt prior to the onset of the next apnea. In contrast, if OSA occurred in the setting of CHF, and was related to an underlying periodic breathing disorder, rises and falls in Vt during hyperpnea might be more gradual owing to increased lung to chemoreceptor circulation time. 9,10 This pattern of hyperpnea would resemble the waxing and waning pattern of Vt associated with Cheyne-Stokes respiration and central sleep apnea (CSA). To test this hypothesis, we compared hyperpnea duration, lungto-chemoreceptor circulation time, and time-to-peak Vt in patients with OSA either with or without CHF. Subjects Materials and Methods Patients with CHF due to either ischemic cardiomyopathy or nonischemic dilated cardiomyopathy were referred for overnight sleep studies because of a history suggestive of OSA, including loud snoring plus at least one of the following: restless sleep, excessive daytime sleepiness, morning headaches, or witnessed apneas. The diagnosis of CHF was based on a history of at least one episode of pulmonary edema with exertional dyspnea accompanied by left ventricular dysfunction, defined by a left ventricular ejection fraction 45% by equilibrium radionuclide angiography or two-dimensional echocardiography. Patients had to have exertional dyspnea (New York Heart Association functional class II or III) despite clinical stability and optimal medical therapy for at least 1 month prior to entry. Patients without CHF referred to the sleep laboratory and subsequently found to have OSA were recruited as control subjects. All CHF and control subjects were free of neurologic and respiratory disease, and the control subjects were free of cardiovascular disease as assessed by history and physical examination. The diagnosis of OSA in both groups was based on the presence of at least 10 apneas and hypopneas per hour of sleep observed on an overnight polysomnogram, of which at least 85% had to be obstructive in nature. The Human Subjects Review Committee of the University of Toronto approved the protocol, and all subjects provided written informed consent prior to participation in the study. Polysomnography Overnight polysomnography was performed in all patients according to standard techniques previously described for our laboratory. 10 Sleep stages were scored using standard criteria. 11 A respiratory inductance plethysmograph (Respitrace; Ambulatory Monitoring; White Plains, NY) calibrated for Vt against a spirometer was used to measure thoracoabdominal movements. 12 Arterial oxygen, saturation (Sao 2 ) was measured continuously using a pulse oximeter (Nellcor N200; Tyco International Healthcare; Pleasanton, CA) placed on the ear. Transcutaneous Pco 2 (Ptcco 2 ) was measured continuously with a transcutaneous capnograph (Kontron Medical, Hoffman LaRoche; Basel, Switzerland), previously validated against arterial Pco 2. 10 Mean Ptcco 2 and mean Sao 2 were estimated by averaging the highest and lowest values every 30 s throughout sleep. Obstructive apneas were defined as a reduction in Vt to 100 ml for at least 10 s associated with out-of phase thoracoabdominal movements. 13 Obstructive hypopneas were defined as a 50% reduction in Vt from baseline (but Vt 100 ml), lasting for at least 10 s accompanied by out-of phase thoracoabdominal movements. 13,14 The number of apneas and hypopneas per hour of sleep was defined as the apnea-hypopnea index (AHI). We confined our data analysis to stage 2 non-rapid eye movement sleep for several reasons. First, this was the dominant stage in all subjects. Second, apnea-hyperpnea cycles were most commonly present during this stage. Third, the cardiovascular and respiratory systems are under predominantly metabolic regulation during this stage, and therefore are not subject to behavioral influences. Finally, by analyzing all data from a single sleep state, we were able to control for the potential effects of sleep state on apnea-hyperpnea characteristics. During episodes of recurrent obstructive apneas in stage 2 sleep, the respiratory cycle was divided into two phases: the apneic phase and the hyperpneic phase. The apnea duration was defined as the time between the end of inspiration of the breath preceding the onset of apnea and the onset of inspiration during the breath that terminated the apnea. The hyperpnea duration was defined as the time between the onset of inspiration of the first breath terminating the apnea and the end of the inspiration of the breath preceding the next apnea. Cycle duration was calculated as the sum of the apnea and the hyperpnea durations. Time to peak Vt was defined as the interval from the onset of the breath terminating the apnea to the largest Vt. 9 Lung-to-ear circulation time (LECT) was used as an estimate of lung-to-carotid chemoreceptor circulation time. We have previously validated this technique against cardiac output as a measure of circulation time in patients with sleep apnea, with and without CHF. 9 LECT was taken as the interval from the onset of the first breath terminating the obstructive apnea to the nadir of the subsequent dip in Sao 2 measured at the ear. Ten consecutive apnea-hyperpnea cycles during the first episode of stage 2 sleep were analyzed in each subject. Statistical Analyses Data are expressed as mean SD. Statistical analyses were performed using SigmaStat 2.03 (SPSS; Chicago, IL). Continuous variables were compared using two-tailed, unpaired t tests for variables with normally distributed data, and Mann-Whitney rank-sum test for variables with nonnormally distributed data. Relationships among variables were analyzed using least-squares linear regression where appropriate; p 0.05 was considered statistically significant. Results Subject Characteristics Eighteen men with OSA alone were matched for age (47.3 11 years vs 54.3 11 years) and body mass index (31.5 7 vs 31.5 7 kg/m 2 )to22men with OSA and CHF. The cause of CHF was coronary artery disease in 12 subjects and idiopathic dilated cardiomyopathy in 10 subjects. In patients with CHF, severe left ventricular dysfunction was evidenced by a mean left ventricular ejection fraction of 26.8 9.7%. Medical therapy for heart failure in the CHF and OSA group consisted of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in 21 patients, -blockers in 15 patients, diuretics in 16 patients, and digoxin in 12 patients. www.chestjournal.org CHEST / 127 / 2/ FEBRUARY, 2005 537

Data for the entire sleep period appear in Table 1. Subjects had moderately severe OSA as indicated by their AHI. The two groups were well matched for AHI, sleep efficiency, sleep-stage distribution, frequency of arousals, mean and minimum Sao 2, and mean Ptcco 2. Respiratory Data From Stage 2 Sleep Figures 1, 2 are representative polysomnographic recordings during stage 2 sleep from patients with OSA alone and patients with CHF and OSA, respectively. They demonstrate that LECT, hyperpnea duration, and total cycle duration are greater in the patient with CHF and OSA than in the patient with OSA. Following apnea termination in the patient with OSA, there was an abrupt rise and rapid decline in Vt. In contrast, in the patient with CHF and OSA, there was a gradual rise and slow decline in Vt similar to the waxing and waning pattern of Vt typically seen during Cheyne-Stokes respiration in CHF patients with CSA. As shown in Table 2, the LECT, hyperpnea, and cycle duration were all significantly greater in the CHF and OSA group than in the OSA group. The number of breaths per hyperpnea was also significantly greater in the subjects with OSA and CHF, although the respiratory rate during hyperpnea was similar in both groups. Apnea duration was similar in the two groups. There were no significant differences in mean or minimum Sao 2 and mean Ptcco 2 between the groups. LECT correlated significantly with hyperpnea duration, breaths per hyperpnea, and time to peak Vt (Fig 3). However, LECT was not related to apnea duration (r 0.06, p 0.70). Figure 1. Typical polysomnographic recording from a patient with OSA but without CHF. Out-of-phase ribcage and abdominal movements during apneas indicate obstruction. Hyperpnea duration (B to D) is 17.7 s, cycle duration (A to D) is 43.1 s, and LECT from the end of apnea (B) to the maximum dip in Sao 2 (C) is 9.9 s. LECT is short in keeping with normal cardiac function. Note that during hyperpnea, there is an abrupt rise and rapid decline in Vt. related to differences in circulation time. The pattern in patients with CHF is characterized by a longer hyperpnea with more breaths, and a more gradual rise and fall in Vt than in patients without CHF. As a result, the periodic breathing cycle is longer in patients with CHF. We also found that hyperpnea duration was directly proportional to lung-to-chemoreceptor circulation time as estimated Discussion This study demonstrates that the pattern of OSA differs in patients with and without CHF, and is Table 1 Polysomnographic Data From Total Sleep Time* Variables OSA (n 18) CHF and OSA (n 22) AHI, /h 37.9 17 36.8 20 Total sleep time, h 4.5 1.6 5.2 1.1 Sleep efficiency, % 73.6 21.7 77.2 11.5 Arousals, /h 32.5 16.2 33.2 15.2 Stage 1, % 10.6 9.2 10.6 8.5 Stage 2, % 67.7 12.7 67.7 9.9 Slow wave sleep, % 7.4 7.4 9.6 7.6 Rapid eye movement, % 11.7 5.3 14.3 8.4 Mean Sao 2,% 94.5 2.2 94.2 2.2 Minimum Sao 2,% 80.0 9.0 78.0 8.9 Mean Ptcco 2,mmHg 44.7 6.7 44.5 5.1 *Data are presented as mean SD. There were no significant differences between the groups for any variable. Figure 2. Typical polysomnographic recording from a patient with CHF and OSA. Out-of-phase ribcage and abdominal movements during apnea indicate obstruction. Compared to the patient without CHF in Figure 1, hyperpnea duration (B to D, 40 s), cycle duration (A to D, 56.9 s), and LECT (B to C, 13.5 s) are substantially longer. In contrast to Figure 1, Vt gradually rises to a peak during hyperpnea and gradually declines to apnea. 538 Clinical Investigations

Table 2 Respiratory Data From Stage 2 Sleep* Variables OSA (n 18) CHF and OSA (n 22) p Value Apnea duration, s 20.9 7.6 22.6 7.8 NS Hyperpnea duration, s 17.6 5.6 25.7 7.8 0.001 Breaths/hyperpnea, No. 4.0 0.8 6.3 1.4 0.001 Time to peak Vt, s 3.9 0.8 6.2 1.5 0.001 Cycle duration, s 38.5 9.7 48.7 11.4 0.005 LECT, s 9.0 1.8 14.9 3.4 0.001 Respiratory rate during hyperpnea, breaths/min 17.0 2.8 18.6 3.5 NS Mean Sao 2,% 94.5 2.2 94.3 2.1 NS Minimum Sao 2,% 82.8 9.5 83.4 6.7 NS Sao 2,% 4.8 2.9 4.8 2.2 NS Mean Ptcco 2,mmHg 44.3 6.6 44.4 5.1 NS *Data are presented as mean SD. NS not significant; Sao 2 difference between peak and nadir oxygen saturation during cycle duration. by LECT. These findings are analogous to those of a previous study 9 in which we compared the pattern of periodic breathing in CHF patients with CSA to that in patients with idiopathic CSA who did not have CHF. We also found that patients with CHF had longer hyperpnea and periodic breathing cycles than did those without CHF. In that study, differences in the character of periodic breathing were related to differences in cardiac function. Patients with CHF had longer hyperpneas and periodic breathing cycles than those without CHF, and hyperpnea duration was directly proportional to LECT. Furthermore, Figure 3. Linear regression plots demonstrating a significant relationship between LECT and hyperpnea duration (top left, A), breaths/hyperpnea (top right, B), and time to peak Vt (bottom, C) in patients with OSA alone, and in patients with both CHF (F) and OSA (E). www.chestjournal.org CHEST / 127 / 2/ FEBRUARY, 2005 539

LECT was inversely proportional to cardiac output so that the longer LECT in the patients with CHF was related to their lower cardiac output. Thus, lower cardiac output influenced hyperpnea and periodic breathing cycle durations through prolongation of lung to chemoreceptor circulation time. The present data extend those of the previous study by demonstrating that prolonged lung to chemoreceptor circulation time also influences the pattern of periodic breathing in patients with OSA. Thus in both instances, prolonged circulation time related to CHF sculpts a more gradual, waxing-waning pattern of hyperpnea that is the hallmark of Cheyne-Stokes respiration. The Cheyne-Stokes pattern of hyperpnea in the patients with CHF and OSA was characterized objectively by a longer time to peak Vt and a greater number of breaths per hyperpnea than in the non- CHF group. These data indicate that once apneainduced chemical and mechanical stimuli cause arousal from sleep and restoration of pharyngeal patency, the slower rate at which blood courses through the lungs plus the prolonged lung-to-chemoreceptor circulation time in the patients with CHF and OSA causes a more gradual fall in Sao 2 and, therefore, a more gradual rise in chemoreceptor stimulation and Vt than in the non-chf group. However, LECT appears not to influence apnea duration, just as in the case of CSA. 9 These data indicate that obstructive apnea duration must be determined by other factors such as upper airway properties, and the degrees of apnea-related asphyxia and inspiratory effort. 15 This raises the question as to the underlying pathophysiology of the upper airway occlusion in patients with CHF and OSA. These patients shared the same predisposing features of OSA with the non-chf group, including obesity, habitual snoring, male gender, and middle age. 16 They also suffered from symptoms typical of OSA, including restless sleep. Therefore, the patients with CHF and OSA may simply have acquired OSA on the basis of these typical features and upper airway narrowing alone. However, other factors may be at play, such as fluid shifts in the neck related to CHF and volume overload. Shepard et al 17 showed that alteration in fluid volume in the neck and thorax can affect pharyngeal function and anatomy. In supine subjects, fluid was shifted from the legs to the neck and thorax by elevating the legs. This increased the collapsibility of the pharynx. They speculated that edema of the neck and upper airway could narrow the pharyngeal lumen and predispose to pharyngeal collapse. Since patients with CHF frequently suffer from fluid overload, congestion of the neck by jugular venous distension or pharyngeal mucosal edema might contribute to the development of upper airway narrowing and instability in these patients when recumbent during sleep. Although we have no data directly related to this possibility, the potential role of engorgement of the neck and pharyngeal edema in narrowing the upper airway and facilitating collapse warrants further investigation in patients with CHF. Upper airway narrowing and increased compliance are crucial predisposing factors for upper airway collapse in most cases of OSA. 18 Here, a primary collapse of the pharynx at the onset of sleep is thought to induce periodic obstructive apneas and hyperpneas. The role of a primary periodic breathing disorder related to respiratory control system instability in OSA is less certain. 1 In one study, Alex et al 8 observed upper airway occlusion at the beginning and end of mixed apneas during Cheyne-Stokes respiration in patients with CHF. They hypothesized that upper airway occlusion could be entrained by an underlying periodic breathing disorder. Support for this theory has also been provided by Badr et al, 19 who demonstrated progressive pharyngeal narrowing during induced hypocapnic central apnea. Furthermore, in some patients with CHF, the type of sleep apnea can change overnight from predominantly OSA to predominantly CSA in association with a decrease in Pco 2. 20 These data suggest that in some patients with CHF and OSA, there is an underlying periodic breathing disorder that could induce upper airway collapse during the waning portion of the ventilatory cycle due to withdrawal of inspiratory drive to the pharyngeal dilator muscles. Most mathematical models of periodic breathing are based on the respiratory control system instability hypothesis. This hypothesis explains periodic breathing as reflecting abnormalities of the negative feedback system in which the time required for the chemoreceptors to sense a change in the feedback signal (ie, Paco 2 and Pao 2 ) is prolonged. This temporal dissociation between alterations in the feedback signals and their sensing at the chemoreceptors is one of the factors, along with increased chemosensitivity, that destabilizes the respiratory control system and predisposes to periodic breathing. The magnitude of these feedback delays and the sensitivity of the chemoreceptors provides a measure of susceptibility to periodic breathing. 21 Thus, on the basis of this theory, prolonged lung-to-chemoreceptor circulation time, as observed in our patients with CHF and OSA, would predispose to respiratory control system instability, and thus to periodic breathing. However, chemosensitivity in patients with CHF and OSA has been shown not to be elevated. 22 Furthermore, mean Sao 2 and Ptcco 2 during sleep were within normal limits and did not 540 Clinical Investigations

differ between our patients with CHF and OSA or patients with OSA, indicating similar levels of chemostimulation. Instability of the chemical control system of respiration has been the subject of recent investigation by Younes et al. 23 Using proportional assist ventilation to assess ventilatory stability in the upper airways of subjects with severe OSA stabilized with CPAP, they have demonstrated a more unstable chemical control system in those patients with severe OSA, leading to periodic breathing with central apneas and hypopneas. They hypothesized that the greater susceptibility to periodic breathing in patients with severe OSA may be related to differences in upper airway resistance, which is dependent on the balance between the collapsing effect of increasing diaphragmatic efforts and the dilating effects of recruitment of upper airway dilators. Therefore, contrary to the respiratory control system instability hypothesis, they proposed that greater instability in chemical control may be a consequence rather than a cause of recurrent obstructive apneas. A final possibility, is that the patients with CHF and OSA had OSA prior to the development of CHF, following which the consequent increased circulatory delay and prolongation of chemical feedback signals to the chemoreceptor entrained the rhythm of their apnea-hyperpnea cycle by prolonging hyperpnea. The observation that short-term application of CPAP to patients with CHF and OSA immediately alleviates upper airway obstruction and OSA favors this hypothesis. 24 The present data do not allow us to distinguish the relative importance of each of these potential mechanisms in shaping the pattern of the obstructive apnea-hyperpnea cycle. It is likely that the relative contribution of each of these mechanisms varies from one individual to another. However, it is apparent that the presence of CHF, and associated increased lung-to-chemoreceptor circulatory delay, influences the pattern of OSA such that it prolongs hyperpnea and sculpts a pattern resembling Cheyne-Stokes respiration. Our findings lead us to conclude that the increased circulatory delay and tendency to periodic breathing in CHF may predispose to, or alter the physiologic manifestations of OSA. However, the potential roles of circulatory delay and periodic breathing in the pathophysiology of upper airway obstruction in patients with CHF and OSA remains unclear. Nevertheless, since long-term relief of upper airway obstruction by CPAP causes significant improvements in cardiac function in patients with CHF, 2 4 more research should be directed at determining the underlying pathophysiology of OSA in this setting. References 1 Sin DD, Fitzgerald F, Parker JD, et al. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. 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20 Tkacova R, Niroumand M, Lorenzi-Filho G, et al. Overnight shift from obstructive to central apneas in patients with heart failure: role of Pco 2 and circulatory delay. Circulation 2001; 103:238 243 21 Khoo MC, Gottschalk A, Pack AI. Sleep-induced periodic breathing and apnea: a theoretical study. J Appl Physiol 1991; 70:2014 2024 22 Solin P, Roebuck T, Johns DP, et al. Peripheral and central ventilatory responses in central sleep apnea with and without congestive heart failure. Am J Respir Crit Care Med 2000; 162:2194 2200 23 Younes M, Ostrowski M, Thompson W, et al. Chemical control stability in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2001; 163:1181 1190 24 Tkacova R, Rankin F, Fitzgerald FS, et al. Effects of continuous positive airway pressure on obstructive sleep apnea and left ventricular afterload in patients with heart failure. Circulation 1998; 98:2269 2275 542 Clinical Investigations