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(Circulation. 2003;107:727.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Central Sleep Apnea in Left Ventricular Dysfunction

Prevalence and Implications for Arrhythmic Risk

Paola A. Lanfranchi, MD; Virend K. Somers, MD, PhD; Alberto Braghiroli, MD; Ugo Corra, MD; Ermanno Eleuteri, MD; Pantaleo Giannuzzi, MD

From the Divisions of Cardiology (P.A.L., U.C., E.E., P.G.) and Pulmonary Disease (A.B.), Fondazione Salvatore Maugeri IRCCS, Veruno, Italy, and the Divisions of Cardiovascular Diseases and Hypertension, Mayo Clinic, Rochester, Minn (P.A.L., V.K.S.).

Correspondence to Paola A. Lanfranchi, Research Center Hôpital Sacré-Coeur, 5400 Boulevard Gouin West, Montréal QC H4J-1C5, Canada. E-mail paola-lanfranchi{at}CRHSC.umontreal.ca

	Abstract

Top Abstract Introduction Methods Results Discussion Conclusions References

 
Background— The prevalence and characteristics of sleep-disordered breathing in patients with asymptomatic left ventricular (LV) dysfunction are unknown. Therefore, we evaluated the prevalence of sleep-disordered breathing in patients with LV dysfunction without overt heart failure and tested the hypothesis that sleep-disordered breathing is linked to greater hemodynamic and autonomic impairment.

Methods and Results— We studied 47 patients with LV ejection fractions 40% without any history of heart failure. Central sleep apnea (CSA), as defined by an apnea-hypopnea index 15/h, was present in 26 patients (55%), 17 (36%) of whom had severe CSA (apnea-hypopnea index 30/h). Obstructive sleep apnea was evident in 5 patients (11%). The prevalence and severity of CSA were higher in patients with ischemic cardiomyopathy than in patients with nonischemic cardiomyopathy (P<0.05). Exercise tolerance and echocardiographic indices of systolic and diastolic function were similar in patients without CSA, with mild CSA, and with severe CSA. Heart rate variability was markedly depressed in patients with CSA (P<0.05). Patients with severe CSA also had a higher incidence of nonsustained ventricular tachycardia (P=0.05).

Conclusions— CSA is highly prevalent in patients with asymptomatic LV dysfunction. The severity of CSA may not be related to the severity of hemodynamic impairment. Severe CSA is associated with impaired cardiac autonomic control and with increased cardiac arrhythmias.

Key Words: sleep • nervous system, autonomic • tachyarrhythmias • heart failure

	Introduction

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In patients with overt heart failure, there is a high prevalence of nocturnal periodic breathing with central apneas (central sleep apnea: CSA).^1–4 CSA is associated with increased arrhythmic risk³ and may indicate increased mortality in heart failure.⁴ Autonomic responses to CSA may contribute to the adverse prognosis in these patients.^2,5 Patients with left ventricular (LV) dysfunction without heart failure also have neurohumoral activation and are at risk for progression to overt heart failure.⁶ Sleep-disordered breathing has been invoked as a possible mechanism mediating the progression of cardiac disease in these patients.⁷ However, there are no data examining the prevalence and characteristics of sleep-disordered breathing in patients with asymptomatic LV dysfunction.

The goals of the present study were as follows: (1) to evaluate prospectively the prevalence and the nature of sleep-disordered breathing, particularly CSA, in patients with asymptomatic LV dysfunction; and (2) to test the hypothesis that increasing severity of CSA in these patients is associated with greater hemodynamic compromise, impaired cardiac autonomic regulation, and cardiac arrhythmias.

	Methods

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We prospectively studied consecutive patients referred to the Cardiology Department of the Medical Center of Rehabilitation, Veruno, Italy, between January 1999 and December 2000 who were found to have LV systolic dysfunction due to either ischemic or nonischemic cardiomyopathy. Patients were referred for one of the following: (1) functional evaluation of asymptomatic LV dysfunction, (2) evaluation of chest pain, or (3) rehabilitation after myocardial infarction or cardiac surgery. They were eligible if the echocardiographic left ventricular ejection fraction was 40% in the absence of any history or clinical diagnosis of overt heart failure.^8–10 Patients were excluded if they had any of the following: primary valvular heart disease, obstructive lung disease (as demonstrated by a forced expiratory volume per second/forced vital capacity [FEV₁/FVC] <70%), clinical signs of central or peripheral nervous system impairment, a history of stroke, or a history of cocaine or alcohol abuse.

Forty-seven patients (5 women; mean age, 59±12 years; LV ejection fraction, 27±6%) met the entry criteria. Thirty-eight patients (81%) had coronary artery disease (CAD) with a previous myocardial infarction as the presumptive cause of the LV dysfunction. Nine patients (19%) were thought to have idiopathic dilated cardiomyopathy (no CAD). Among patients with CAD, 19 (50%) had a history of a previous coronary revascularization by coronary artery bypass grafting (CABG).

All patients gave written, informed consent agreeing to participate in this prospective study, which had been approved by the Science and Ethics Committee of the Institution.

Study Protocol
Patient evaluation included historic data collection, functional classification, Doppler echocardiography, spiroergometric test, thallium-201 myocardial scintigraphy, 24-hour Holter recording, and a sleep study. Functional status was determined according to the New York Heart Association classification.

Echocardiography
A complete 2D echocardiography and Doppler ultrasound examinations were performed using a Hewlett-Packard ultrasound system (model 77729-A or 77622-A).

Spiroergometry Test
Multistage symptom-limited bicycle exercise testing with spirometry was used to evaluate exercise tolerance and peak oxygen consumption (Ergometrics 800S, Sensormedics).

Myocardial Scintigraphy
Nuclear imaging by thallium-201 at rest and after stress was performed to evaluate myocardial perfusion.

24-Hour Ambulatory Electrocardiographic Recording
24-hour ECG recordings were performed (Marquette 8500) to evaluate arrhythmias and to assess heart rate variability. The 24-hour heart rate variability was quantified in the time domain: the mean normal-to-normal R-R interval (NN), the standard deviation of mean NN (sdNN), the standard deviation of all 5-minute mean RR intervals (SDANN), the mean of all 5-minute standard deviations of RR intervals (SD), and the percentage of >50 ms differences between adjacent NN (pNN50) were measured.¹¹

Sleep Study
All patients underwent an overnight sleep study by means of an unattended system (Merlin, Healthdyne Inc) that recorded body position, cardiotachography, nasal-oral air flow, chest and abdominal effort, and pulse oximetry. Apnea was defined as cessation of airflow lasting at least 10 s. A central apnea was defined as the absence of flow and thoracoabdominal movements, and an obstructive apnea was defined as the absence of airflow in the presence of thoracoabdominal movements. Hypopnea was defined as 50% decrease in the sum of thoracoabdominal movements lasting 10 s, followed by a reduction in SaO₂ of at least 4%.¹²

We accepted a threshold of apnea-hypopnea index (AHI) 15/h as diagnostic for sleep-disordered breathing³ and an AHI 30/h as severe sleep-disordered breathing.⁴ Therefore, we evaluated patients in 3 groups: (1) those without sleep apnea (AHI<15/h), (2) those with mild sleep apnea (AHI=15 to 29/h), and (3) those with severe sleep apnea (AHI30/h).

The total duration of ventilation-apnea cycle (cycle-length)¹³ was also measured from the first breath following an apnea to the first breath after the following apnea.

Statistical Analysis
All descriptive data are presented as mean±SEM. Differences between groups of patients were compared by one-way ANOVA and, for variables with a non-normal distribution, by Kruskall-Wallis analysis. Frequency of variables was assessed by ² test with a Yates correction. P<0.05 was considered significant.

	Results

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Periodic breathing with CSA occurred in 26 patients (55%). In 17 patients (36%), severe sleep apnea, as defined by an AHI 30/h, was noted. Significant obstructive sleep apnea, as expressed by an AHI 10, was found in 5 patients (11%; range of AHI, 18 to 49/h), who were excluded from further analysis, thus leading to a final population of 42 patients with and without CSA.

History, demographics, physical examination findings, and nocturnal breathing data according to the diagnosis of CSA are presented in Figure 1 and Table 1. The prevalence and severity of CSA was higher in patients with ischemic cardiomyopathy compared with patients with nonischemic cardiomyopathy (P<0.05; Figure 1). Patients with severe CSA were older than patients without CSA (P<0.05; Table 1). A higher resting heart rate was found in patients with mild CSA when compared with those without CSA and severe CSA (P<0.05). No differences were evident between all the groups in terms of body mass index, baseline arterial blood pressure, and medications.

View larger version (22K): [in this window] [in a new window]   Figure 1. Prevalence of CSA according to the cause of cardiac disease. Patients with CAD showed a higher prevalence of CSA than patients without CAD.

View this table: [in this window] [in a new window]   TABLE 1. Clinical Data and Sleep Findings in Patients Without CSA and With Mild and Severe CSA

The cycle-length was similar in the patients without CSA (9 of 16 patients with AHI<15/h had sequences of periodic breathing which made the measurement possible), with mild CSA, and with severe CSA (Table 1). Echocardiographic evaluation showed that the 3 groups of patients had similar indices of LV systolic and diastolic function and similar left atrial sizes (Figure 2).

View larger version (29K): [in this window] [in a new window]   Figure 2. Hemodynamic and functional indices according to the presence and the severity of CSA. The patients without sleep apnea (no CSA) and with mild and severe CSA showed similar values of LV ejection fraction (LVEF), early deceleration (dec) time, left atrial (LA) size, minutes of exercise, and peak O2.

Exercise tolerance and peak oxygen consumption (O₂) evaluations, which were obtained in 27 patients (64%), were also not different between the groups (Figure 2). Myocardial scintigraphy documented the presence of residual ischemia in 8 of the 35 patients with CAD (23%) and in 4 of the 15 patients with CAD and severe CSA (27%). The 24-hour Holter recordings were available in 39 of the 42 patients. Patients with both mild and severe CSA showed a significantly lower pNN50 than patients without CSA (P<0.05; Table 2 and Figure 3).

View this table: [in this window] [in a new window]   TABLE 2. Twenty-Four-Hour ECG Data in Patients Without CSA and With Mild and Severe CSA

View larger version (22K): [in this window] [in a new window]   Figure 3. Heart rate variability and ventricular arrhythmias according to the presence and the severity of CSA. Patients with CSA had a significantly lower pNN50 than patients without CSA. Patients with severe CSA, when compared with those with absent or mild CSA, showed increased premature ventricular contractions (PVCs) and more frequent runs of nonsustained ventricular tachycardia (NSVT) in the daytime. sdNN indicates the standard deviation of mean NN.

Patients with severe CSA tended to have a significantly higher occurrence of ventricular arrhythmias, as expressed by 24-hour premature ventricular contractions and day and nighttime premature ventricular contractions. Nonsustained ventricular tachycardias occurred almost exclusively in patients with severe CSA (Table 2 and Figure 3). Among severe CSA patients, those with residual ischemia did not show increased arrhythmias compared with those without ischemia: the number of premature ventricular contractions per hour was 21±76 in the ischemic group versus 125±48 in the nonischemic group (P=NS). Notably, only one patient with residual ischemia had ventricular tachycardia.

ANOVA did not show age, diabetes, cause of the disease, or history of CABG to influence the relationship between CSA and either the reduced heart rate variability or the increased ventricular arrhythmias.

	Discussion

Top Abstract Introduction Methods Results Discussion Conclusions References

 
The novel findings in the present study are, first, that there is a very high prevalence of sleep-disordered breathing in patients with severe but asymptomatic LV dysfunction. The nature of the sleep-disordered breathing is primarily CSA, which was present in 55% of patients. Second, in contrast to patients with overt heart failure, there is no evidence of increased hemodynamic and functional compromise in patients with LV dysfunction and CSA. Indices such as LV ejection fraction, early deceleration time, exercise tolerance, and peak oxygen consumption are similar even in patients with the most severe CSA (AHI 30/h) compared with those with mild or absent CSA. Cycle-length, an index that may reflect hemodynamics and circulation time,¹³ was similar in the patients without CSA and with mild and severe CSA. Nevertheless, there is impaired cardiac autonomic control and electrical instability in patients with severe CSA, as evidenced by a dramatic reduction in pNN50 and increased ventricular arrhythmias.

Measurements of heart rate variability in the time domain provide objective assessments of abnormalities in neural circulatory control¹¹ and predict prognosis in post-myocardial infarction and heart failure patients.^14,15 Specifically, a diminished pNN50 is associated with increased runs of nonsustained ventricular tachycardia in patients with hypertrophic obstructive cardiomyopathy.¹⁶ In patients with heart failure, lower pNN50 is an independent predictor of increased cardiac mortality.¹⁷

The pNN50 is a subtle indicator of cardiac autonomic control and is thought to reflect mainly the vagal component of cardiac regulation^11,18; indeed, it is one of the earliest indicators of cardiac autonomic dysfunction. This has been demonstrated in patients with diabetes.^18,19 Also, patients with the earliest phases of Chaga’s disease (when LV function is still normal) manifest abnormalities in pNN50, even though other measures of heart rate control are preserved.²⁰ Our present data show that in patients with asymptomatic LV dysfunction and CSA, pNN50 is reduced even in those with mild CSA.

Direct evidence of cardiac electrical instability in patients with severe CSA is apparent in the increased ventricular arrhythmias. Although CSA is especially prevalent in those patients with ischemic, compared with idiopathic LV dysfunction, the increased cardiac arrhythmias in patients with CSA does not seem to be a function of cardiac ischemia per se.

Javaheri et al³ noted an association between sleep apnea and ventricular arrhythmias in patients with heart failure. Javaheri²¹ subsequently observed that attenuation of sleep-disordered breathing by continuous positive airway pressure was accompanied by a significant reduction in ventricular arrhythmias, indicating a possible cause-effect relationship. We have extended these earlier observations in heart failure by demonstrating that patients with asymptomatic LV dysfunction also have a high prevalence of CSA, and that in these patients, severe CSA is associated with impairment in heart rate variability and increased cardiac arrhythmias.

In patients with overt heart failure, CSA correlated with pulmonary capillary wedge pressure, as measured by invasive²² and noninvasive^23,24 approaches. In our present study of patients with LV dysfunction without overt heart failure, the presence and severity of CSA was not associated with increased ventricular impairment or hemodynamic indices of increased filling pressure (Figure 2). The presence and severity of sleep apnea also did not correlate with the ventilation-apnea length in our patients (Table 1). The cycle-length in our patients with severe CSA (48 s), although higher than the cycle-length reported in patients with idiopathic CSA and normal ventricular function (35 s),¹³ is significantly lower than the cycle-length reported in patients with CSA and heart failure (69 s).^13,24 In our present study, the cycle-length was similar for all patients, thus confirming that the degree of hemodynamic dysfunction reflected by this index is equally present in these 3 groups and, therefore, is not the primary factor inducing CSA in our patients.

What would be the potential mechanisms for CSA in asymptomatic LV dysfunction? CSA is known to be strongly associated with heart failure or neurological lesions. Nevertheless, nocturnal periodic breathing with central apneas has also been recognized in healthy subjects,²⁵ indicating that it cannot be completely accounted for by either "cardiogenic" or "neurogenic" origins. It is currently believed that instability of respiration control may account for most of the observations of periodic breathing in disease, as well as in health.²⁶ Periodic breathing has been explained as a self-sustaining oscillation due to the loss of stability in the closed-loop chemical control of ventilation²⁶ due, in heart failure, to an enhanced loop gain (hyperventilation), a slow circulation time between lungs and chemoreceptors, and inability to adjust to perturbations in the blood gases.²⁴

Heart failure patients with CSA–Cheyne-Stokes respiration (CSR) tend to hyperventilate.²⁷ This tendency to hyperventilate has been attributed in part to the afferent stimulation from pulmonary venous congestion.²² However, CSA-CSR does not always occur in patients with severely compromised hemodynamic and pulmonary congestion.²⁸ Indeed, an enhanced ventilatory chemoreflex response to CO₂ may play a crucial role in the development of CSA-CSR in heart failure.²⁹ Although the chemoreflex was not evaluated in our study, our CSA patients showed a tendency to lower values of daytime PCO₂.

Small lung volumes may contribute to ventilatory instability by impairing the capacity to buffer changes in blood gases during transient changes in ventilation. Total lung capacity was not measured in our study. However, in our patients with an AHI 15/h, FVC was 92% of predicted versus 82% to 86% reported in previous series of patients with CSA in the setting of heart failure.^13,27

A delayed feedback control by a prolonged circulation time due to a reduced cardiac output is, in heart failure, a further factor promoting instability. The estimated circulation time (which is about one-third of the cycle-length)¹³ in our subjects was slightly increased but significantly lower than the values shown in the literature for heart failure.^13,18 The small increments in circulation time we estimated would be unlikely to promote periodic breathing, unless concomitant with an increased chemosensitivity.²⁴

Finally, impaired baroreflex control may also induce an instability in the control of ventilation. Baroreflex deactivation augments the ventilatory response to stimulation of the peripheral chemoreceptors.³⁰ Baroreflex control is disturbed in patients with even mild impairment of ventricular function,³¹ possibly resulting in enhanced chemoreflex gain. Augmented peripheral chemosensitivity may contribute to periodic breathing in awake heart failure patients, as well as to CSA and to autonomic dysfunction.³² Therefore, it is conceivable that chemoreflex-baroreflex interactions may be implicated in the genesis of abnormalities in breathing control leading to CSA in patients with LV dysfunction.

Limitations of the study include, first, that sleep monitoring was conducted using an unattended system. Nevertheless, this is a valid approach to monitoring cardiorespiratory function during sleep.³³ Second, patients were on drug therapy during these studies. In mitigation, an important objective of this study was to avoid interruption of the normal therapy. Furthermore, there was no difference in distribution of drug therapy in the different populations of apnea severity. A third limitation is that the CSA tended to be greater in older patients, which is consistent with findings in other studies.³⁴ However, analysis with age as a covariate did not indicate any interaction between age and apnea index in measurements of autonomic dysfunction or arrhythmias.

	Conclusions

Top Abstract Introduction Methods Results Discussion Conclusions References

 
Patients with severe but asymptomatic LV dysfunction have a high prevalence of CSA. Severe CSA is associated with impaired cardiac autonomic control and increased cardiac arrhythmias but not with greater hemodynamic impairment. Patients with asymptomatic LV dysfunction are at risk for progression to overt heart failure and for sudden death, particularly in the setting of ischemic LV dysfunction. The high prevalence of severe CSA in patients with ischemic LV dysfunction and the association between severe CSA and both cardiac autonomic dysfunction and cardiac arrhythmias suggest that sleep-disordered breathing may be implicated in increased cardiovascular risk in patients with impaired LV function, even in the absence of overt heart failure.

	Acknowledgments

 
This study was supported by grant Ricerca corrente anno 1999–2000 from the Salvatore Maugeri Foundation, Pavia, Italy, and by grants NIH-HL65176, HL61560, HL40602, and RR00585 from the National Institutes of Health. Dr Somers is an Established Investigator of the American Heart Association.

Received September 18, 2002; revision received October 28, 2002;

	References

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1. Findley LJ, Zwillich CW, Ancoli-Israel S, et al. Cheyne-Stokes breathing during sleep in patients with left ventricular heart failure. South Med J. 1985; 78: 11–15.[Medline] [Order article via Infotrieve]

2. Naughton MT, Benard DC, Liu PP, et al. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med. 1995; 152: 473–479.[Abstract]

3. Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure: types and their prevalences, consequences, and presentations. Circulation. 1998; 97: 2154–2159.[Abstract/Free Full Text]

4. Lanfranchi PA, Braghiroli A, Bosimini E, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation. 1999; 99: 1435–1440.[Abstract/Free Full Text]

5. van de Borne P, Oren R, Abouassaly C, et al. Effect of Cheyne-Stokes respiration on muscle sympathetic nerve activity in severe congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1998; 81: 432–436.[CrossRef][Medline] [Order article via Infotrieve]

6. Benedict CR, Shelton B, Johnstone DE, et al. Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction: SOLVD Investigators. Circulation. 1996; 94: 690–697.[Abstract/Free Full Text]

7. Floras JS. Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J Am Coll Cardiol. 1993; 22: 72A–84A.[Medline] [Order article via Infotrieve]

8. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial: the SAVE Investigators. N Engl J Med. 1992; 327: 669–677.[Abstract]

9. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions: the SOLVD Investigators. N Engl J Med. 1992; 327: 685–691.[Abstract]

10. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary: A report of the American College of Cardiology/American Heart Association Task force on practice guidelines (Committee to revise the 1995 guidelines for the evaluation and management of heart failure). Circulation. 2001; 104: 2996–3007.[Free Full Text]

11. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation. 1996; 93: 1043–1065.[Free Full Text]

12. Meoli AL, Clark RW, Coleman JA, et al, for the Clinical Practice Review Committee. Hypopnea in sleep-disordered breathing in adults. Sleep. 2001; 24: 469–470.[Medline] [Order article via Infotrieve]

13. Solin P, Roebuck T, Swieca J, et al. Effects of cardiac dysfunction on non-hypercapnic central sleep apnea. Chest. 1998; 113: 104–110.[Abstract/Free Full Text]

14. Kleiger RE, Miller JP, Bigger JT Jr, et al. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987; 59: 256–262.[CrossRef][Medline] [Order article via Infotrieve]

15. Ponikowski P, Anker SD, Chua TP, et al. Depressed heart rate variability as an independent predictor of death in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1997; 79: 1645–1650.[CrossRef][Medline] [Order article via Infotrieve]

16. Uemura S, Tomoda Y, Fujimoto S, et al. Heart rate variability and ventricular arrhythmia in clinically stable patients with hypertrophic cardiomyopathy. Jpn Circ J. 1997; 61: 819–826.[CrossRef][Medline] [Order article via Infotrieve]

17. Szabo BM, van Veldhuisen DJ, van der Veer N, et al. Prognostic value of heart rate variability in chronic congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol. 1997; 79: 978–980.[CrossRef][Medline] [Order article via Infotrieve]

18. Ewing DJ, Neilson JM, Shapiro CM, et al. Twenty four hour heart rate variability: effects of posture, sleep, and time of healthy controls and comparison with bedside tests of autonomic function in diabetic patients. Br Heart J. 1991; 65: 239–244.[Abstract/Free Full Text]

19. Osterhues HH, Grossmann G, Kochs M, et al. Heart rate variability for discrimination of different types of neuropathy in patients with insulin-dependent diabetes mellitus. J Endocrinol Invest. 1998; 21: 24–30.[Medline] [Order article via Infotrieve]

20. Ribeiro AL, Moraes RS, Ribeiro JP, et al. Parasympathetic dysautonomia precedes left ventricular systolic dysfunction in Chaga’s disease. Am Heart J. 2001; 141: 260–265.[Medline] [Order article via Infotrieve]

21. Javaheri S. Effects of continuous positive airway pressure on sleep apnea and ventricular irritability in patients with heart failure. Circulation. 2000; 101: 392–397.[Abstract/Free Full Text]

22. Solin P, Bergin P, Richardson M, et al. Influence of pulmonary capillary wedge pressure on central apnea in heart failure. Circulation. 1999; 99: 1574–1579.[Abstract/Free Full Text]

23. Giannuzzi P, Imparato A, Temporelli PL, et al. Doppler-derived mitral deceleration time of early filling as a strong predictor of pulmonary capillary wedge pressure in postinfarction patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 1994; 23: 1630–1637.[Abstract]

24. Francis DP, Willson K, Davies CL, et al. Quantitative general theory for periodic breathing in chronic heart failure and its clinical implications. Circulation. 2000; 102: 2214–2221.[Abstract/Free Full Text]

25. Cherniack NS. Respiratory dysrhythmias in sleep. N Engl J Med. 1981; 305: 325–330.[Medline] [Order article via Infotrieve]

26. Khoo MCK, Kronauer RE, Strohl KH, et al. Factors inducing periodic breathing in humans: a general model. J Appl Physiol. 1982; 53: 644–659.[Abstract/Free Full Text]

27. Naughton M, Benard D, Tam A, et al. Role of hyperventilation in the pathogenesis of central sleep apneas in patients with congestive heart failure. Am Rev Respir Dis. 1993; 148: 330–338.[Medline] [Order article via Infotrieve]

28. Krachman SL, D’Alonzo GE, Berger TJ, et al. Comparison of oxygen therapy with nasal continuous positive airway pressure on Cheyne-Stokes respiration during sleep in congestive heart failure. Chest. 1999; 116: 1550–1557.[Abstract/Free Full Text]

29. Javaheri S. A mechanism of central sleep apnea in patients with heart failure. N Engl J Med. 1999; 341: 949–954.[Abstract/Free Full Text]

30. Somers VK, Mark AL, Abboud FM. Interactions of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans. J Clin Invest. 1991; 86: 1953–1957.

31. Grassi G, Seravalle G, Cattaneo BM, et al. Sympathetic activation and loss of reflex sympathetic control in mild congestive heart failure. Circulation. 1995; 92: 3206–3211.[Abstract/Free Full Text]

32. Ponikowski P, Anker SD, Chua TP, et al. Oscillatory breathing patterns during wakefulness in patients with chronic heart failure: clinical implications and role of augmented peripheral chemosensitivity. Circulation. 1999; 100: 2418–2424.[Abstract/Free Full Text]

33. Ferber R, Millman R, Coppola M, et al. Portable recording in the assessment of obstructive sleep apnea: ASDA standard of practice. Sleep. 1994; 17: 378–392.[Medline] [Order article via Infotrieve]

34. 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. Am J Respir Crit Care Med. 1999; 160: 1101–1106.[Abstract/Free Full Text]

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				D. Yumino and T. D. Bradley Central Sleep Apnea and Cheyne-Stokes Respiration Proceedings of the ATS, February 15, 2008; 5(2): 226 - 236. [Abstract] [Full Text] [PDF]

				T. Brack, I. Thuer, C. F. Clarenbach, O. Senn, G. Noll, E. W. Russi, and K. E. Bloch Daytime Cheyne-Stokes Respiration in Ambulatory Patients With Severe Congestive Heart Failure Is Associated With Increased Mortality Chest, November 1, 2007; 132(5): 1463 - 1471. [Abstract] [Full Text] [PDF]

				O. Oldenburg, L. Faber, J. Vogt, A. Dorszewski, F. Szabados, D. Horstkotte, and B. Lamp Influence of cardiac resynchronisation therapy on different types of sleep disordered breathing Eur J Heart Fail, August 1, 2007; 9(8): 820 - 826. [Abstract] [Full Text] [PDF]

				S. Javaheri, R. Shukla, H. Zeigler, and L. Wexler Central Sleep Apnea, Right Ventricular Dysfunction, and Low Diastolic Blood Pressure Are Predictors of Mortality in Systolic Heart Failure J. Am. Coll. Cardiol., May 22, 2007; 49(20): 2028 - 2034. [Abstract] [Full Text] [PDF]

				S. Garrigue, J.-L. Pepin, P. Defaye, F. Murgatroyd, Y. Poezevara, J. Clementy, and P. Levy High Prevalence of Sleep Apnea Syndrome in Patients With Long-Term Pacing: The European Multicenter Polysomnographic Study Circulation, April 3, 2007; 115(13): 1703 - 1709. [Abstract] [Full Text] [PDF]

				A. Vazir, P.C. Hastings, M. Dayer, H.F. McIntyre, M.Y. Henein, P.A. Poole-Wilson, M.R. Cowie, M.J. Morrell, and A.K. Simonds A high prevalence of sleep disordered breathing in men with mild symptomatic chronic heart failure due to left ventricular systolic dysfunction Eur J Heart Fail, March 1, 2007; 9(3): 243 - 250. [Abstract] [Full Text] [PDF]

				O. Oldenburg, B. Lamp, L. Faber, H. Teschler, D. Horstkotte, and V. Topfer Sleep-disordered breathing in patients with symptomatic heart failure A contemporary study of prevalence in and characteristics of 700 patients Eur J Heart Fail, March 1, 2007; 9(3): 251 - 257. [Abstract] [Full Text] [PDF]

				S. Ferreira, J. Winck, P. Bettencourt, and F. Rocha-Goncalves Heart failure and sleep apnoea: To sleep perchance to dream Eur J Heart Fail, May 1, 2006; 8(3): 227 - 236. [Abstract] [Full Text] [PDF]

				S. M. Caples, R. Wolk, and V. K. Somers Influence of cardiac function and failure on sleep-disordered breathing: evidence for a causative role J Appl Physiol, December 1, 2005; 99(6): 2433 - 2439. [Abstract] [Full Text] [PDF]

				A D Staniforth, S C Sporton, M J Early, J A Wedzicha, A W Nathan, and R J Schilling Ventricular arrhythmia, Cheyne-Stokes respiration, and death: observations from patients with defibrillators Heart, November 1, 2005; 91(11): 1418 - 1422. [Abstract] [Full Text] [PDF]

				L J Cormican and A Williams Sleep disordered breathing and its treatment in congestive heart failure Heart, October 1, 2005; 91(10): 1265 - 1270. [Abstract] [Full Text] [PDF]

				E. Skobel, C. Norra, A. Sinha, C. Breuer, P. Hanrath, and C. Stellbrink Impact of sleep-related breathing disorders on health-related quality of life in patients with chronic heart failure Eur J Heart Fail, June 1, 2005; 7(4): 505 - 511. [Abstract] [Full Text] [PDF]

				F. Series, R. J. Kimoff, D. Morrison, M. H. Leblanc, M. Smilovitch, J. Howlett, A. G. Logan, J. S. Floras, and T. D. Bradley Prospective Evaluation of Nocturnal Oximetry for Detection of Sleep-Related Breathing Disturbances in Patients With Chronic Heart Failure Chest, May 1, 2005; 127(5): 1507 - 1514. [Abstract] [Full Text] [PDF]

				C. Nopmaneejumruslers, Y. Kaneko, V. Hajek, V. Zivanovic, and T. D. Bradley Cheyne-Stokes Respiration in Stroke: Relationship to Hypocapnia and Occult Cardiac Dysfunction Am. J. Respir. Crit. Care Med., May 1, 2005; 171(9): 1048 - 1052. [Abstract] [Full Text] [PDF]

				A. Chen and F. M. Kusumoto QT Dispersion: Much Ado About Something? Chest, June 1, 2004; 125(6): 1974 - 1977. [Full Text] [PDF]

				S. F. Quan and B. J. Gersh Cardiovascular Consequences of Sleep-Disordered Breathing: Past, Present and Future: Report of a Workshop From the National Center on Sleep Disorders Research and the National Heart, Lung, and Blood Institute Circulation, March 2, 2004; 109(8): 951 - 957. [Full Text] [PDF]

				A. S. M. Shamsuzzaman, B. J. Gersh, and V. K. Somers Obstructive Sleep Apnea: Implications for Cardiac and Vascular Disease JAMA, October 8, 2003; 290(14): 1906 - 1914. [Abstract] [Full Text] [PDF]

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