This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bradley, T. D. Articles by Floras, J. S. Search for Related Content PubMed PubMed Citation Articles by Bradley, T. D. Articles by Floras, J. S. Related Collections Congestive Other Treatment Other diagnostic testing Epidemiology

(Circulation. 2003;107:1822.)
© 2003 American Heart Association, Inc.

Special Review

Sleep Apnea and Heart Failure

Part II: Central Sleep Apnea

T. Douglas Bradley, MD; John S. Floras, MD, DPhil

From the University of Toronto Centre for Sleep Medicine and Circadian Biology (T.D.B., J.S.F.), the Cardiopulmonary Sleep Disorders and Research Centre of the Toronto General Hospital/University Health Network (T.D.B.) and the Toronto Rehabilitation Institute (T.D.B.), and the Departments of Medicine of the University Health Network and Mount Sinai Hospital (T.D.B., J.S.F.), Toronto, Ontario, Canada.

Correspondence to T. Douglas Bradley, MD, Toronto General Hospital/University Health Network, NU 9-112, 200 Elizabeth St, Toronto, ON, M5G 2C4, Canada. E-mail douglas.bradley{at}utoronto.ca

Key Words: heart failure • respiration • morbidity

	Introduction

Top Introduction Pathophysiology Central Sleep Apnea in... Conclusions References

 
In the first part of this 2-part review, we provided a synopsis of the cardiovascular effects of normal sleep and an overview of the diagnostic, pathophysiological, and therapeutic implications of obstructive sleep apnea (OSA) in the setting of heart failure (HF). In this second part, we turn our attention to central sleep apnea (CSA), commonly referred to as Cheyne-Stokes respiration. This breathing disorder has a strikingly higher prevalence in patients with HF as compared with the general population with normal left ventricular function, and when present appears to have adverse prognostic implications. Our objective in Part II of this review is to provide a broad perspective of the pathophysiological and clinical significance of CSA in HF.

	Pathophysiology

Top Introduction Pathophysiology Central Sleep Apnea in... Conclusions References

 
CSA associated with Cheyne-Stokes respiration is a form of periodic breathing in which central apneas and hypopneas alternate with periods of hyperventilation that have a waxing-waning pattern of tidal volume. Figure 1 illustrates the proposed mechanisms that underlie periodic oscillations in ventilation in HF. Unlike OSA, CSA likely arises as a consequence of HF. Thus, the presence of CSA may alert the physician to the necessity of intensifying HF therapy. The current debate is whether CSA is simply a reflection of severely compromised cardiac function with elevated left ventricular filling pressures, or whether, for the same degree of cardiac dysfunction, CSA exerts unique and independent pathological effects on the failing myocardium. Although there are not yet sufficient data to resolve this controversy within the confines of this review, we will discuss evidence on both sides of this issue.

View larger version (47K): [in this window] [in a new window]   Figure 1. Pathophysiology of central sleep apnea in heart failure (HF). HF leads to increased left ventricular (LV) filling pressure. The resulting pulmonary congestion activates lung vagal irritant receptors, which stimulate hyperventilation and hypocapnia. Superimposed arousals cause further abrupt increases in ventilation and drive PaCO2 below the threshold for ventilation, triggering a central apnea. Central sleep apneas are sustained by recurrent arousals resulting from apnea-induced hypoxia and the increased effort to breathe during the ventilatory phase because of pulmonary congestion and reduced lung compliance. Although central apneas have a different pathophysiology than obstructive apneas and are not associated with the generation of exaggerated negative intrathoracic pressure, they both increase sympathetic nervous system activity (SNA). The consequent increases in blood pressure (BP) and heart rate (HR) increase myocardial O2 demand in the face of reduced supply. This chain of events contributes to a pathophysiological vicious cycle.

Most HF patients with CSA hyperventilate chronically because of stimulation of pulmonary vagal irritant receptors by pulmonary congestion^1–3 and enhanced central and peripheral chemosensitivity.^4,5 When patients lie flat, increased venous return from the extremities causes central fluid accumulation and pulmonary congestion that stimulates vagal irritant receptors in the lungs to elicit reflex hyperventilation. Central apnea is usually initiated during sleep by a further acute increase in ventilation and reduction in PaCO₂ that is triggered by a spontaneous arousal.⁶ When PaCO₂ falls below the threshold level required to stimulate breathing, the central drive to respiratory muscles and airflow cease, and central apnea ensues.⁷ Apnea persists until PaCO₂ rises above the threshold required to stimulate ventilation.^6,8

In contrast to OSA, arousals are not required for the initiation of airflow at the termination of central apneas. Indeed, arousals frequently follow the resumption of breathing and thereby facilitate the development of oscillations in ventilation by recurrently stimulating hyperventilation and reducing PaCO₂ below the apneic threshold.⁶ The length of the subsequent ventilatory phase is inversely proportional to cardiac output, reflecting delayed transmission of changes in arterial blood gas tensions from the lungs to the chemoreceptors. Accordingly, compared with subjects with CSA but without HF, those with HF have a longer ventilatory phase during which tidal volume rises and falls more gradually.⁹ Thus, the prolonged circulation time in HF sculpts this Cheyne-Stokes respiratory pattern. However, among HF patients with and without CSA, no significant differences in lung to peripheral chemoreceptor circulation time or cardiac output have been observed.^2,9 Consequently, prolonged circulation time appears not to play a key role in initiating central apneas. Rather, its major influence is on the lengths of the hyperpneic phase and of the total periodic breathing cycle. Once triggered, the pattern of alternating hyperventilation and apnea is sustained by the combination of increased respiratory chemoreceptor drive, pulmonary congestion, arousals, and apnea-induced hypoxia, which cause oscillations in PaCO₂ above and below the apneic threshold.^4–6 Inhalation of a CO₂-enriched gas to raise PaCO₂ abolishes CSA.⁸

CSA elicits chemical, neural, and hemodynamic oscillations similar to those observed in OSA.^10–12 Apnea, hypoxia, CO₂ retention, and arousal provoke periodic elevations in sympathetic activity^13,14 (Figure 2). In patients with pulmonary congestion whose lung compliance is reduced, the increased inspiratory efforts between apneas will also lower intrathoracic pressure and increase left ventricular transmural pressure, and therefore afterload.¹⁵ Potential relationships between CSA and markers of inflammation, oxidative stress, or vascular endothelial dysfunction have yet to be reported.

View larger version (22K): [in this window] [in a new window]   Figure 2. Recording of CSA with Cheyne-Stokes respiration in a patient with advanced heart failure and atrial fibrillation. Note typical waxing-waning pattern of tidal volume (VT) during hyperpnea and dips in oxyhemoglobin saturation (SaO2) associated with apneas. The central nature of apnea is indicated by the absence of rib cage (RC) and abdominal (ABD) motion. Normally, muscle sympathetic nervous activity (MSNA) is quiescent during sleep. However, in this patient, each cardiac cycle is accompanied by a burst of MSNA, indicating marked sympathetic activation. In addition, note the waxing and waning of MSNA burst amplitude in synchrony with the oscillation of VT and blood pressure (BP).

	Central Sleep Apnea in Patients With Heart Failure

Top Introduction Pathophysiology Central Sleep Apnea in... Conclusions References

 
Epidemiology
There are few epidemiological studies in which the prevalence of CSA in patients with HF has been examined. The 2 largest studies involving 450 and 81 patients reported prevalences of 33% and 40%, respectively.^16,17 The principal risk factors for CSA are male sex, hypocapnia, atrial fibrillation, and increasing age, but not obesity (Table). For reasons that remain to be elucidated, CSA is rarely seen in women with HF.¹⁶ This sex difference may be one explanation for the higher mortality rates suffered by men with HF.¹⁸

View this table: [in this window] [in a new window]   Independent Odds Ratios for Central Sleep Apnea in Patients With Heart Failure

Clinical Features
It is unclear whether there are symptoms specific to CSA. Patients who awake during the peak of ventilation after apnea may report paroxysmal nocturnal dyspnea.¹⁹ Although sleep is fragmented by frequent arousals, only a minority of patients report habitual snoring and excessive daytime sleepiness.¹⁷

In some HF patients, OSA and CSA coexist. In such cases, there is a gradual shift from predominantly obstructive apneas at the beginning of the night to predominantly central apneas toward its end.²⁰ This change occurs in association with a prolongation in circulation time and a downward drift in PCO₂ toward the threshold for apnea. These observations suggest that the repetitive surges in afterload induced by OSA, combined with increased venous return in the recumbent position, cause an overnight deterioration in left ventricular systolic function and an increase in left ventricular filling pressure that lead to hyperventilation and hypocapnia.^3,21–23 These unique observations raise the possibility of a spectrum of periodic breathing in patients with systolic HF that can manifest as predominantly OSA at one point in the time course of the disease and predominantly CSA at another, according to the underlying degree of cardiac dysfunction. They also raise the possibility that over months or years, the presence of OSA could predispose HF patients to CSA, which has more ominous implications for prognosis.

Implications for Progression of Heart Failure
The main clinical significance of CSA in HF is its association with increased mortality. Whether this is simply because Cheyne-Stokes respiration with CSA is a reflection of very poor cardiac function or whether its presence constitutes a separate and additive adverse influence on outcomes remains uncertain. However, where multivariate analyses have been performed to control for potentially confounding risk factors, CSA remained an independent risk factor for death or cardiac transplantation.^24,25 This pathological relationship may be attributed to marked neurohumoral activation, surges in blood pressure and heart rate, and a greater propensity to lethal arrhythmia induced by CSA.^{10–12,26,27}

Unlike OSA, no negative intrathoracic pressure is generated during central apneas.^6,28 Therefore, its impact on afterload should be less than in OSA. Consequently, attention has focused primarily on the adrenergic effects of CSA as the mechanism for disease progression. Compared with HF patients matched for ejection fraction and other clinical characteristics but without sleep-related breathing disorders, those with CSA have higher urinary and circulating norepinephrine concentrations during both sleep and wakefulness.²⁶ The magnitude of these increases is proportional to the frequency of arousals from sleep and the degree of apnea-related hypoxia.

Very low-frequency oscillations in ventilation during periodic breathing disorders, such as CSA, cause heart rate to oscillate at the same frequency, such that heart rate falls during apnea and rises during hyperpnea.¹⁰ This entrainment of heart rate by periodic breathing causes a shift in power spectral density of heart rate from predominantly high frequency during regular breathing (ie, respiratory sinus arrhythmia) to predominantly very low frequency (<0.5 Hz).^12,29–31 CSA entrains cyclical oscillations in heart rate and blood pressure through mechanisms similar to those described for OSA: hypoxia, arousals from sleep, and adrenergic activation.¹⁰ Another likely mechanism is direct cyclic activation of cardiovascular sympathetic neurons by respiratory neurons in the brain stem.^12,32 Although such synchronized oscillations of heart rate with ventilation may optimize ventilation/perfusion matching and thereby maintain efficient gas exchange,³³ they are also associated with detrimental effects. The presence of periodic breathing, very low-frequency oscillations in heart rate, and enhanced peripheral chemoreceptor sensitivity in patients with HF are together associated with a higher mortality rate.^31,34

Treatment of Central Sleep Apnea in Heart Failure
The principal reason for treating CSA is the potential to improve cardiovascular function, quality of life, and longevity.^25,35 At present, there is no consensus as to whether CSA should be treated, and if so, what optimum therapy of CSA in HF might be. Because CSA is to some extent a manifestation of advanced HF, the first consideration is to optimize drug therapy. Aggressive diuresis to lower cardiac filling pressure along with angiotensin-converting enzyme inhibitors and ß-blockers may reduce the severity of CSA.² In some cases, however, metabolic alkalosis arising from diuretic use may predispose to CSA by narrowing the difference between ambient PaCO₂ and the PaCO₂ threshold for apnea.^36–38 ß-adrenergic blockade may also reduce the adverse effects of excessive sympathetic activation that is associated with CSA. Should CSA persist despite aggressive medical therapy for HF, other interventions may be considered.

Nocturnal supplemental O₂ has been shown to abolish apnea-related hypoxia, alleviate CSA, and decrease nocturnal norepinephrine levels over periods of 1 night to 1 month.^39–41 Its administration has also been associated with improvements in maximum oxygen uptake during a graded exercise test.⁴² The effects of supplemental oxygen on cardiovascular endpoints over more prolonged periods have not been assessed. However, O₂ has been reported not to cause improvements in cardiac function or quality of life over 1 month.⁴¹ In a 5 day trial, theophylline reduced the severity of CSA but did not cause any improvements in right or left ventricular ejection fraction, quality of life, or clinical outcomes.⁴³ The potential adverse consequences of theophylline’s inotropic and arrhythmogenic effects in patients with advanced HF preclude its long-term use at the present time.

Various forms of noninvasive positive airway pressure, including continuous positive airway pressure (CPAP), bi-level and adaptive pressure support servo-ventilation have been shown in randomized trials to alleviate CSA in HF patients over periods of 1 day to 3 months.^35,44 However, thus far, the only intervention whose effects on cardiovascular outcomes have been evaluated is CPAP. In patients with HF and elevated left ventricular end-diastolic pressure who were studied while awake, CPAP decreases left ventricular afterload by increasing intrathoracic pressure,¹⁵ augments stroke volume,⁴⁵ and reduces cardiac sympathetic activity.⁴⁶ It also decreases preload by impeding venous return and reducing right and left ventricular end-diastolic volume.⁴⁷ In patients with CSA, short-term application of CPAP also reduces the frequency of ventricular ectopic beats.⁴⁸ Randomized trials of 3-months’ duration have demonstrated that nightly application of CPAP increases left ventricular ejection fraction, reduces mitral regurgitation and nocturnal and daytime sympathetic nervous system activity, and improves quality of life.^26,35,49 Of 29 patients with HF and CSA who participated in a randomized trial of CPAP, those who complied with this intervention experienced a significant reduction in the combined rate of mortality and cardiac transplantation over a 5-year period.²⁵ A larger, long-term, multicenter trial to test the effects of CPAP on the combined rate of mortality and cardiac transplantation in HF patients with CSA (the CANadian Positive Airway Pressure trial for patients with congestive heart failure and central sleep apnea [CANPAP]) is presently underway.⁵⁰

In a recent randomized trial, the effect of atrial overdrive pacing on sleep apnea was tested.⁵¹ This study involved a group of patients with no history of HF who had cardiac pacemakers implanted because of symptomatic bradyarrhythmias. Sleep studies were performed, and among those found to have sleep apnea, the pacing rate was increased to 15 bpm above the intrinsic heart rate. This overdrive pacing led to a reduction in the frequency of both central and obstructive apneas by approximately 50%. Because these effects were studied only over a single night, clinical outcomes were not assessed and the mechanism responsible for this effect was not determined. One possibility is that some of these patients may have had pulmonary congestion while in the recumbent position owing to their bradyarrhythmias, or possibly diastolic dysfunction. This may have stimulated hyperventilation and predisposed to CSA.^2,3 Overdrive pacing could have augmented cardiac output and relieved pulmonary congestion, thereby dampening respiratory controller gain, reducing ventilation, increasing PaCO₂, and reducing central apneas and hypopneas. This mechanism would explain a reduction in central but not obstructive events. If upper airway edema accumulated while the patient was in the recumbent position,^52,53 augmentation of cardiac output by overdrive pacing could have alleviated this edema and increased pharyngeal lumenal dimensions. Although the observations of Garrigue et al⁵¹ have generated considerable interest, their implications for the treatment of sleep apnea in general and for sleep apnea in patients with HF in particular are not clear. Further studies will be required to determine the mechanism(s) by which pacing achieves those effects, and to determine whether this approach exerts sustained benefits in selected patients with HF and bradyarrhythmias.

Indications for Sleep Studies in Heart Failure
Indications for sleep studies in patients with HF have not been definitively established. Because the pretest probability of sleep apnea in such patients is approximately 50%^16,17 and treatment may provide at least short-term improvements in cardiovascular function and relief of some of the symptoms of HF,^{24,25,35,41,42,54,55} an argument could be made for the liberal application of this test in the HF population. However, until a clearer picture emerges of how treatment of sleep apnea influences cardiovascular outcomes, polysomnography should be reserved for those patients with the highest likelihood of sleep-related breathing disorders. In addition to risk factors listed in Table 2 of Part I and the Table in Part II, other factors that should raise suspicion of sleep apnea and prompt consideration of polysomnography include a history of loud snoring, witnessed apneas during wakefulness or sleep, paroxysmal nocturnal dyspnea, restless sleep, morning headaches, excessive daytime sleepiness, and insomnia. Until other methods, such as home ambulatory monitoring, are validated for this purpose, in-laboratory polysomnography remains the diagnostic tool of choice.

	Conclusions

Top Introduction Pathophysiology Central Sleep Apnea in... Conclusions References

 
Sleep-related breathing disorders are common in HF, and the pathophysiologies of these 2 conditions are intimately linked. Nevertheless, the clinical implications of these breathing disorders are not widely recognized and are seldom taken into account in the evaluation and management of HF. The conventional approach to the evaluation and management of HF may therefore need to be modified in view of the growing body of evidence that the acute and chronic mechanical, hemodynamic, autonomic, and chemical effects of OSA and CSA place patients with HF at increased risk of accelerated disease progression. Indeed, CSA is now known to be an independent risk factor for diminished life expectancy in HF. Standard pharmacological approaches to HF may have little or no impact on these breathing disturbances and their consequences. However, promising results of small scale randomized trials of therapy aimed at relieving these sleep-related breathing disorders suggest that this strategy has the potential to improve cardiovascular outcomes in patients with HF.^{24,25,35,41,42,54,55} More intensive investigation of potential diagnostic algorithms and therapies, including large scale randomized controlled clinical trials, will be required to test these hypotheses and determine the optimal approach to such patients.

	Acknowledgments

 
This work was supported by the Canadian Institutes of Health Research (grants MOP-11607 and UI-14909). Dr Bradley holds a Canadian Institutes of Health Research Senior Scientist Award, and Dr Floras is a Career Investigator of the Heart and Stroke Foundation of Ontario.

	Footnotes

 
This article is Part II of a 2-part article. Part I appeared in the April 1, 2003, issue of Circulation (Circulation. 2003;107:1671–1678).

	References

Top Introduction Pathophysiology Central Sleep Apnea in... Conclusions References

 
1. Yu J, Zhang JF, Fletcher EC. Stimulation of breathing by activation of pulmonary peripheral afferents in rabbits. J Appl Physiol. 1998; 85: 1485–1492.[Abstract/Free Full Text]

2. 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]

3. Lorenzi-Filho G, Azevedo ER, Parker JD, et al. Relationship of PaCO₂ to pulmonary wedge pressure in heart failure. Eur Respir J. 2002; 19: 37–40.[Abstract/Free Full Text]

4. 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]

5. 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.[Abstract/Free Full Text]

6. 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]

7. Bradley TD, Phillipson EA. Central sleep apnea. Clin Chest Med. 1992; 13: 493–505.[Medline] [Order article via Infotrieve]

8. Lorenzi-Filho G, Rankin F, Bies I, et al. Effects of inhaled carbon dioxide and oxygen on Cheyne-Stokes respiration in patients with heart failure. Am J Respir Crit Care Med. 1999; 159: 1490–1498.[Abstract/Free Full Text]

9. Hall MJ, Xie A, Rutherford R, et al. Cycle length of periodic breathing in patients with and without heart failure. Am J Respir Crit Care Med. 1996; 154: 376–381.[Abstract]

10. Trinder J, Merson R, Rosenberg JI, et al. Pathophysiological interactions of ventilation, arousals, and blood pressure oscillations during Cheyne-Stokes respiration in patients with heart failure. Am J Respir Crit Care Med. 2000; 162: 808–813.[Abstract/Free Full Text]

11. Franklin KA, Sandstrom E, Johansson G, et al. Hemodynamics, cerebral circulation, and oxygen saturation in Cheyne-Stokes respiration. J Appl Physiol. 1997; 83: 1184–1191.[Abstract/Free Full Text]

12. Lorenzi-Filho G, Dajani HR, Leung RS, et al. Entrainment of blood pressure and heart rate oscillations by periodic breathing. Am J Respir Crit Care Med. 1999; 159: 1147–1154.[Abstract/Free Full Text]

13. Narkiewicz K, Montano N, Cogliati C, et al. Altered cardiovascular variability in obstructive sleep apnea. Circulation. 1998; 98: 1071–1077.[Abstract/Free Full Text]

14. Phillipson EA, Bowes G. Control of breathing during sleep. In: Cherniack NS, Widdicombe JG, eds. Handbook of Physiology: Control of Breathing. vol. 2. Bethesda, Md: Williams and Wilkins; 1986: 649–689.

15. Naughton MT, Rahman MA, Hara K, et al. Effect of continuous positive airway pressure on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure. Circulation. 1995; 91: 1725–1731.[Abstract/Free Full Text]

16. 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]

17. 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]

18. Ho KK, Pinsky JL, Kannel WB, et al. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol. 1993; 22: 6A–13A.[Medline] [Order article via Infotrieve]

19. Harrison TR, King CE, Calhoun JA, et al. Congestive heart failure: Cheyne-Stokes respiration as the cause of dyspnea at the onset of sleep. Arch Int Med. 1934; 53: 891–910.

20. Tkacova R, Niroumand M, Lorenzi-Filho G, et al. Overnight shift from obstructive to central apneas in patients with heart failure: role of PCO₂ and circulatory delay. Circulation. 2001; 103: 238–243.[Abstract/Free Full Text]

21. Tilkian AG, Guilleminault C, Schroeder JS, et al. Hemodynamics in sleep-induced apnea: studies during wakefulness and sleep. Ann Intern Med. 1976; 85: 714–719.[Abstract/Free Full Text]

22. Tolle FA, Judy WV, Yu PL, et al. Reduced stroke volume related to pleural pressure in obstructive sleep apnea. J Appl Physiol. 1983; 55: 1718–1724.[Abstract/Free Full Text]

23. Gibbs JS, Cunningham D, Shapiro LM, et al. Diurnal variation of pulmonary artery pressure in chronic heart failure. Br Heart J. 1989; 62: 30–35.[Abstract/Free Full Text]

24. 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]

25. Sin DD, Logan AG, Fitzgerald FS, et al. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation. 2000; 102: 61–66.[Abstract/Free Full Text]

26. 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]

27. Javaheri S, Corbett WS. Association of low PaCO₂ with central sleep apnea and ventricular arrhythmias in ambulatory patients with stable heart failure. Ann Intern Med. 1998; 128: 204–207.[Abstract/Free Full Text]

28. Bradley TD, Floras JS. Pathophysiologic interactions between sleep apnea and congestive heart failure. In: Bradley TD, Floras JS, eds. Sleep Apnea: Implications in Cardiovascular and Cerebrovascular Disease. Lung Biology in Health and Disease. vol. 146. New York, NY: Marcel Dekker 2000: 385–414.

29. Ponikowski P, Chua TP, Amadi AA, et al. Detection and significance of a discrete very low frequency rhythm in RR interval variability in chronic heart failure. Am J Cardiol. 1996; 77: 1320–1326.[CrossRef][Medline] [Order article via Infotrieve]

30. Montara A, Sleight P, Pinna G, et al. Abnormal awake respiratory patterns are common in chronic heart failure and may prevent evaluation of autonomic tone by measures of heart rate variability. Circulation. 1997; 96: 246–252.[Abstract/Free Full Text]

31. 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]

32. Guyenet PG, Koshiya N, Huangfu D, et al. Central respiratory control of A5 and A6 pontine noradrenergic neurons. Am J Physiol. 1993; 264: R1035–R1044.[Medline] [Order article via Infotrieve]

33. Leung RST, Bradley TD. Sleep apnea and cardiovascular disease. Am J Respir Crit Care Med. 2001; 164: 2147–2165.[Free Full Text]

34. Ponikowski P, Chua TP, Piepoli M, et al. Chemoreceptor dependence of rhythms in advanced heart failure. Am J Physiol. 1997; 272: H438–H447.[Medline] [Order article via Infotrieve]

35. Naughton MT, Liu PP, Bernard DC, et al. Treatment of congestive heart failure and Cheyne-Stokes respiration during sleep by continuous positive airway pressure. Am J Respir Crit Care Med. 1995; 151: 92–97.[Abstract]

36. Xie A, Skatrud JB, Puleo DS, et al. Apnea-hypopnea threshold for CO₂ in patients with congestive heart failure. Am J Respir Crit Care Med. 2002; 165: 1245–1250.[Abstract/Free Full Text]

37. Nakayama H, Smith CA, Rodman JR, et al. Effect of ventilatory drive on carbon dioxide sensitivity below eupnea during sleep. Am J Respir Crit Care Med. 2002; 165: 1251–1259.[Abstract/Free Full Text]

38. Bradley TD. Crossing the threshold: implications for central sleep apnea. Am J Respir Crit Care Med. 2002; 165: 1203–1204.[Free Full Text]

39. Hanly PJ, Millar TW, Steljes DG, et al. The effect of oxygen on respiration and sleep in patients with congestive heart failure. Ann Intern Med. 1989; 111: 777–782.[Abstract/Free Full Text]

40. Franklin KA, Eriksson P, Sahlin C, et al. Reversal of central sleep apnea with oxygen. Chest. 1997; 111: 163–169.[Abstract/Free Full Text]

41. Staniforth AD, Kinnear WJ, Starling R, et al. Effect of oxygen on sleep quality, cognitive function and sympathetic activity in patients with chronic heart failure and Cheyne-Stokes respiration. Eur Heart J. 1998; 19: 922–928.[Abstract/Free Full Text]

42. Andreas S, Clemens C, Sandholzer H, et al. Improvement of exercise capacity with treatment of Cheyne-Stokes respiration in patients with congestive heart failure. J Am Coll Cardiol. 1996; 27: 1486–1490.[Abstract]

43. Javaheri S, Parker TJ, Wexler L, et al. Effect of theophylline on sleep-disordered breathing in heart failure. N Engl J Med. 1996; 335: 562–567.[Abstract/Free Full Text]

44. Teschler H, Dohring J, Wang YM, et al. Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med. 2001; 164: 614–619.[Abstract/Free Full Text]

45. Bradley TD, Holloway RM, McLaughlin PR, et al. Cardiac output response to continuous positive airway pressure in congestive heart failure. Am Rev Respir Dis. 1992; 145: 377–382.[Medline] [Order article via Infotrieve]

46. Kaye DM, Mansfield D, Aggarwal A, et al. Acute effects of continuous positive airway pressure on cardiac sympathetic tone in congestive heart failure. Circulation. 2001; 103: 2336–2338.[Abstract/Free Full Text]

47. Mehta S, Liu PP, Fitzgerald FS, et al. Effects of continuous positive airway pressure on cardiac volumes in patients with ischemic and dilated cardiomyopathy. Am J Respir Crit Care Med. 2000; 161: 128–134.[Abstract/Free Full Text]

48. 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]

49. Tkacova R, Liu PP, Naughton MT, et al. Effect of continuous positive airway pressure on mitral regurgitant fraction and atrial natriuretic peptide in patients with heart failure. J Am Coll Cardiol. 1997; 30: 739–745.[Abstract]

50. Bradley TD, Logan AG, Floras JS. Rationale and design of the Canadian Positive Airway Pressure Trial for patients with congestive heart failure and central sleep apnea: The CANPAP Trial. Can J Cardiol. 2001; 17: 677–684.[Medline] [Order article via Infotrieve]

51. Garrigue S, Bordier P, Jais P, et al. Benefit of atrial pacing in sleep apnea syndrome. N Engl J Med. 2002; 346: 4404–412.

52. Shepard JW Jr, Pevernagie DA, Stanson AW, et al. Effects of changes in central venous pressure on upper airway size in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 1996; 153: 250–254.[Abstract]

53. Bradley TD, Floras JS. Sleep apnea and heart failure: part I: obstructive sleep apnea. Circulation. 2003; 107: 1671–1678.[Free Full Text]

54. Malone S, Liu PP, Holloway R, et al. Obstructive sleep apnoea in patients with dilated cardiomyopathy: effects of continuous positive airway pressure. Lancet. 1991; 338: 1480–1484.[CrossRef][Medline] [Order article via Infotrieve]

55. Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med. In press.

This article has been cited by other articles:

				G. Fleischmann, G. Fillafer, H. Matterer, F. Skrabal, and P. Kotanko Prevalence of chronic kidney disease in patients with suspected sleep apnoea Nephrol. Dial. Transplant., January 1, 2010; 25(1): 181 - 186. [Abstract] [Full Text] [PDF]

				T. A. Martino and M. J. Sole Molecular Time: An Often Overlooked Dimension to Cardiovascular Disease Circ. Res., November 20, 2009; 105(11): 1047 - 1061. [Abstract] [Full Text] [PDF]

				F. Triposkiadis, G. Karayannis, G. Giamouzis, J. Skoularigis, G. Louridas, and J. Butler The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J. Am. Coll. Cardiol., November 3, 2009; 54(19): 1747 - 1762. [Abstract] [Full Text] [PDF]

				L. R. Goldberg Stressful sleeping. J. Am. Coll. Cardiol., October 27, 2009; 54(18): 1713 - 1714. [Full Text] [PDF]

				Y. Mebrate, K. Willson, C. H. Manisty, R. Baruah, J. Mayet, A. D. Hughes, K. H. Parker, and D. P. Francis Dynamic CO2 therapy in periodic breathing: a modeling study to determine optimal timing and dosage regimes J Appl Physiol, September 1, 2009; 107(3): 696 - 706. [Abstract] [Full Text] [PDF]

				R. L. Verrier and M. E. Josephson Impact of Sleep on Arrhythmogenesis Circ Arrhythm Electrophysiol, August 1, 2009; 2(4): 450 - 459. [Full Text] [PDF]

				J S Floras Should sleep apnoea be a specific target of therapy in chronic heart failure? Heart, July 1, 2009; 95(13): 1041 - 1046. [Abstract] [Full Text] [PDF]

				D Yumino, H Wang, J S Floras, G E Newton, S Mak, P Ruttanaumpawan, J D Parker, and T D Bradley Relationship between sleep apnoea and mortality in patients with ischaemic heart failure Heart, May 1, 2009; 95(10): 819 - 824. [Abstract] [Full Text] [PDF]

				L. Luthje, B. Renner, R. Kessels, D. Vollmann, T. Raupach, B. Gerritse, S. Tasci, J. O. Schwab, M. Zabel, D. Zenker, et al. Cardiac resynchronization therapy and atrial overdrive pacing for the treatment of central sleep apnoea Eur J Heart Fail, March 1, 2009; 11(3): 273 - 280. [Abstract] [Full Text] [PDF]

				G. D. Pinna, R. Maestri, A. Mortara, P. Johnson, D. Andrews, P. Ponikowski, T. Witkowski, E. Robbi, M. T. La Rovere, and P. Sleight Pathophysiological and clinical relevance of simplified monitoring of nocturnal breathing disorders in heart failure patients Eur J Heart Fail, March 1, 2009; 11(3): 264 - 272. [Abstract] [Full Text] [PDF]

				A. Szyszko, C. Franceschini, and J. Gonzalez-Zuelgaray Reliability of a Holter-based methodology for evaluation of sleep apnoea syndrome Europace, January 1, 2009; 11(1): 94 - 99. [Abstract] [Full Text] [PDF]

				B. Sredniawa, R. Lenarczyk, O. Kowalski, P. Pruszkowska-Skrzep, J. Kowalczyk, A. Musialik-Lydka, S. Cebula, and Z. Kalarus Sleep apnoea as a predictor of mid- and long-term outcome in patients undergoing cardiac resynchronization therapy Europace, January 1, 2009; 11(1): 106 - 114. [Abstract] [Full Text] [PDF]

				G. Jayaraman, H. Sharafkhaneh, M. Hirshkowitz, and A. Sharafkhaneh Review: Pharmacotherapy of obstructive sleep apnea Therapeutic Advances in Respiratory Disease, December 1, 2008; 2(6): 375 - 386. [Abstract] [PDF]

				V. K. Somers, D. P. White, R. Amin, W. T. Abraham, F. Costa, A. Culebras, S. Daniels, J. S. Floras, C. E. Hunt, L. J. Olson, et al. Sleep Apnea and Cardiovascular Disease: An American Heart Association/American College of Cardiology Foundation Scientific Statement From the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing In Collaboration With the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health) Circulation, September 2, 2008; 118(10): 1080 - 1111. [Full Text] [PDF]

				E. Ritz Nephrology Potpourri Clin. J. Am. Soc. Nephrol., September 1, 2008; 3(5): 1253 - 1259. [Full Text] [PDF]

				E. N. Simantirakis, S. E. Schiza, N. S. Siafakas, and P. E. Vardas Sleep-disordered breathing in heart failure and the effect of cardiac resynchronization therapy Europace, September 1, 2008; 10(9): 1029 - 1033. [Abstract] [Full Text] [PDF]

				V. K. Somers, D. P. White, R. Amin, W. T. Abraham, F. Costa, A. Culebras, S. Daniels, J. S. Floras, C. E. Hunt, L. J. Olson, et al. Sleep Apnea and Cardiovascular Disease: An American Heart Association/American College of Cardiology Foundation Scientific Statement From the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing In Collaboration With the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health) J. Am. Coll. Cardiol., August 19, 2008; 52(8): 686 - 717. [Full Text] [PDF]

				L. C. McKay and J. L. Feldman Unilateral Ablation of Pre-Botzinger Complex Disrupts Breathing during Sleep but Not Wakefulness Am. J. Respir. Crit. Care Med., July 1, 2008; 178(1): 89 - 95. [Abstract] [Full Text] [PDF]

				T. A. Martino, G. Y. Oudit, A. M. Herzenberg, N. Tata, M. M. Koletar, G. M. Kabir, D. D. Belsham, P. H. Backx, M. R. Ralph, and M. J. Sole Circadian rhythm disorganization produces profound cardiovascular and renal disease in hamsters Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2008; 294(5): R1675 - R1683. [Abstract] [Full Text] [PDF]

				C. M. Ryan, S. Juvet, R. Leung, and T. D. Bradley Timing of Nocturnal Ventricular Ectopy in Heart Failure Patients With Sleep Apnea Chest, April 1, 2008; 133(4): 934 - 940. [Abstract] [Full Text] [PDF]

				L. J. Olson, A. M. Arruda-Olson, V. K. Somers, C. G. Scott, and B. D. Johnson Exercise Oscillatory Ventilation*: Instability of Breathing Control Associated With Advanced Heart Failure Chest, February 1, 2008; 133(2): 474 - 481. [Abstract] [Full Text] [PDF]

				J Amit Benjamin and K E Lewis Sleep-disordered breathing and cardiovascular disease Postgrad. Med. J., January 1, 2008; 84(987): 15 - 22. [Abstract] [Full Text] [PDF]

				M. T. La Rovere, G. D. Pinna, R. Maestri, E. Robbi, A. Mortara, F. Fanfulla, O. Febo, and P. Sleight Clinical relevance of short-term day-time breathing disorders in chronic heart failure patients Eur J Heart Fail, September 1, 2007; 9(9): 949 - 954. [Abstract] [Full Text] [PDF]

				T. A. Martino, N. Tata, G. A. Bjarnason, M. Straume, and M. J. Sole Diurnal protein expression in blood revealed by high throughput mass spectrometry proteomics and implications for translational medicine and body time of day Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1430 - R1437. [Abstract] [Full Text] [PDF]

				L. J. Olson and V. K. Somers Treating Central Sleep Apnea in Heart Failure: Outcomes Revisited Circulation, June 26, 2007; 115(25): 3140 - 3142. [Full Text] [PDF]

				A. Noda, H. Izawa, H. Asano, S. Nakata, A. Hirashiki, Y. Murase, S. Iino, K. Nagata, T. Murohara, Y. Koike, et al. Beneficial Effect of Bilevel Positive Airway Pressure on Left Ventricular Function in Ambulatory Patients With Idiopathic Dilated Cardiomyopathy and Central Sleep Apnea-Hypopnea: A Preliminary Study Chest, June 1, 2007; 131(6): 1694 - 1701. [Abstract] [Full Text] [PDF]

				T. A. Martino, N. Tata, D. D. Belsham, J. Chalmers, M. Straume, P. Lee, H. Pribiag, N. Khaper, P. P. Liu, F. Dawood, et al. Disturbed Diurnal Rhythm Alters Gene Expression and Exacerbates Cardiovascular Disease With Rescue by Resynchronization Hypertension, May 1, 2007; 49(5): 1104 - 1113. [Abstract] [Full Text] [PDF]

				H. Wang, J. D. Parker, G. E. Newton, J. S. Floras, S. Mak, K.-L. Chiu, P. Ruttanaumpawan, G. Tomlinson, and T. D. Bradley Influence of Obstructive Sleep Apnea on Mortality in Patients With Heart Failure J. Am. Coll. Cardiol., April 17, 2007; 49(15): 1625 - 1631. [Abstract] [Full Text] [PDF]

				A. M. Luks and E. R. Swenson Travel to high altitude with pre-existing lung disease Eur. Respir. J., April 1, 2007; 29(4): 770 - 792. [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]

				C. H. Manisty, K. Willson, R. Wensel, Z. I. Whinnett, J. E. Davies, W. L. G. Oldfield, J. Mayet, and D. P. Francis Development of respiratory control instability in heart failure: a novel approach to dissect the pathophysiological mechanisms J. Physiol., November 15, 2006; 577(1): 387 - 401. [Abstract] [Full Text] [PDF]

				R. Torchio, C. Gulotta, P. Greco-Lucchina, A. Perboni, L. Avonto, H. Ghezzo, and J. Milic-Emili Orthopnea and tidal expiratory flow limitation in chronic heart failure. Chest, August 1, 2006; 130(2): 472 - 479. [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]

				C Philippe, M Stoica-Herman, X Drouot, B Raffestin, P Escourrou, L Hittinger, P-L Michel, S Rouault, and M-P d'Ortho Compliance with and effectiveness of adaptive servoventilation versus continuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a six month period Heart, March 1, 2006; 92(3): 337 - 342. [Abstract] [Full Text] [PDF]

				J. P. Ribeiro Periodic Breathing in Heart Failure: Bridging the Gap Between the Sleep Laboratory and the Exercise Laboratory Circulation, January 3, 2006; 113(1): 9 - 10. [Full Text] [PDF]

				U. Corra, M. Pistono, A. Mezzani, A. Braghiroli, A. Giordano, P. Lanfranchi, E. Bosimini, M. Gnemmi, and P. Giannuzzi Sleep and Exertional Periodic Breathing in Chronic Heart Failure: Prognostic Importance and Interdependence Circulation, January 3, 2006; 113(1): 44 - 50. [Abstract] [Full Text] [PDF]

				M. E. Young The circadian clock within the heart: potential influence on myocardial gene expression, metabolism, and function Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H1 - H16. [Abstract] [Full Text] [PDF]

				A. I. Pack Advances in Sleep-disordered Breathing Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 7 - 15. [Abstract] [Full Text] [PDF]

				C. Unterberg, L. Luthje, J. Szych, D. Vollmann, G. Hasenfuss, and S. Andreas Atrial overdrive pacing compared to CPAP in patients with obstructive sleep apnoea syndrome Eur. Heart J., December 1, 2005; 26(23): 2568 - 2575. [Abstract] [Full Text] [PDF]

				J. Spaak, Z. J. Egri, T. Kubo, E. Yu, S.-I. Ando, Y. Kaneko, K. Usui, T. D. Bradley, and J. S. Floras Muscle Sympathetic Nerve Activity During Wakefulness in Heart Failure Patients With and Without Sleep Apnea Hypertension, December 1, 2005; 46(6): 1327 - 1332. [Abstract] [Full Text] [PDF]

				T. D. Bradley, A. G. Logan, R. J. Kimoff, F. Series, D. Morrison, K. Ferguson, I. Belenkie, M. Pfeifer, J. Fleetham, P. Hanly, et al. Continuous Positive Airway Pressure for Central Sleep Apnea and Heart Failure. N. Engl. J. Med., November 10, 2005; 353(19): 2025 - 2033. [Abstract] [Full Text] [PDF]

				R. S. T. Leung, M. E. Bowman, T. M. Diep, G. Lorenzi-Filho, J. S. Floras, and T. D. Bradley Influence of Cheyne-Stokes respiration on ventricular response to atrial fibrillation in heart failure J Appl Physiol, November 1, 2005; 99(5): 1689 - 1696. [Abstract] [Full Text] [PDF]

				J. Y. A. Foo, S. J. Wilson, A. P. Bradley, G. R. Williams, M.-A. Harris, and D. M. Cooper Use of Pulse Transit Time To Distinguish Respiratory Events From Tidal Breathing in Sleeping Children Chest, October 1, 2005; 128(4): 3013 - 3019. [Abstract] [Full Text] [PDF]

				L. Luthje, C. Unterberg-Buchwald, D. Dajani, D. Vollmann, G. Hasenfuss, and S. Andreas Atrial Overdrive Pacing in Patients with Sleep Apnea with Implanted Pacemaker Am. J. Respir. Crit. Care Med., July 1, 2005; 172(1): 118 - 122. [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]

				D. Kaye and M. Esler Sympathetic neuronal regulation of the heart in aging and heart failure Cardiovasc Res, May 1, 2005; 66(2): 256 - 264. [Abstract] [Full Text] [PDF]

				J-L. Pepin, P. Defaye, S. Garrigue, Y. Poezevara, and P. Levy Overdrive atrial pacing does not improve obstructive sleep apnoea syndrome Eur. Respir. J., February 1, 2005; 25(2): 343 - 347. [Abstract] [Full Text] [PDF]

				C. M. Ryan and T. D. Bradley Periodicity of Obstructive Sleep Apnea in Patients With and Without Heart Failure Chest, February 1, 2005; 127(2): 536 - 542. [Abstract] [Full Text] [PDF]

				P. Bordier, S. Garrigue, S. Reuter, P. Bordachar, and J. Clementy Death During Polysomnography of a Patient With Cheyne-Stokes Respiration, Respiratory Acidosis, and Chronic Heart Failure Chest, November 1, 2004; 126(5): 1698 - 1700. [Abstract] [Full Text] [PDF]

				A. Mortara, G. D. Pinna, P. Johnson, H. Dargie, M. T. La Rovere, P. Ponikowski, L. Tavazzi, P. Sleight, and on behalf of HHH Investigators A multi-country randomised trial of the role of a new telemonitoring system in CHF: the HHH study (Home or Hospital in Heart Failure). Rational, study design and protocol Eur. Heart J. Suppl., November 1, 2004; 6(suppl_F): F99 - F102. [Abstract] [Full Text] [PDF]

				S. Andreas, H. Reiter, L. Luthje, A. Delekat, R. W. Grunewald, G. Hasenfuss, and V. K. Somers Differential Effects of Theophylline on Sympathetic Excitation, Hemodynamics, and Breathing in Congestive Heart Failure Circulation, October 12, 2004; 110(15): 2157 - 2162. [Abstract] [Full Text] [PDF]

				E. Quintana-Gallego, M. Villa-Gil, C. Carmona-Bernal, G. Botebol-Benhamou, A. Martinez-Martinez, A. Sanchez-Armengol, J. Polo-Padillo, and F. Capote Home respiratory polygraphy for diagnosis of sleep-disordered breathing in heart failure Eur. Respir. J., September 1, 2004; 24(3): 443 - 448. [Abstract] [Full Text] [PDF]

				A.-M. Sinha, E. C. Skobel, O.-A. Breithardt, C. Norra, K. U. Markus, C. Breuer, P. Hanrath, and C. Stellbrink Cardiac resynchronization therapy improves central sleep apnea and Cheyne-Stokes respiration in patients with chronic heart failure J. Am. Coll. Cardiol., July 7, 2004; 44(1): 68 - 71. [Abstract] [Full Text] [PDF]

				A. Tulaimat, B. Mokhlesi, D. Stevens, M. D. Weinstein, T. D. Bradley, J. S. Floras, and K. Usui Continuous Positive Airway Pressure in Patients with Heart Failure N. Engl. J. Med., July 3, 2003; 349(1): 93 - 95. [Full Text] [PDF]

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bradley, T. D. Articles by Floras, J. S. Search for Related Content PubMed PubMed Citation Articles by Bradley, T. D. Articles by Floras, J. S. Related Collections Congestive Other Treatment Other diagnostic testing Epidemiology