Sleep-disordered breathing in heart failure: characteristics and implications

Respiratory Physiology & Neurobiology 136 (2003) 153
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Sleep-disordered breathing in heart failure: characteristics and implications Paola A. Lanfranchi a,*, Virend K. Somers b a

b

Research Center, Hoˆpital du Sacre´-Cœur. S400, boul. Gouin Ouest, Montre´al QC H4J ICS, Canada Division of Hypertension and Division of Cardiovascular Diseases, Mayo Clinic, 200 Second Street SW, Do-4-348, Rochester, MN 55905, USA Accepted 22 October 2002

Abstract Sleep-disordered breathing, namely obstructive sleep apnea (OSA) and central sleep apnea (CSA), are both often encountered in the setting of heart failure (HF), and have distinct differences in terms of prevalence, pathophysiology and consequences. OSA is independently associated with an increased risk for cardiovascular disease and for congestive HF in the general population. It is conceivable that this breathing disorder may have particularly deleterious effects in patients with coexisting heart disease, especially in those with a failing heart. There are considerable data addressing the interaction between OSA and the cardiovascular system, which underscore the importance of an early detection of this breathing disorder, especially in patients with HF. CSA is generally considered a consequence rather than a cause of HF, and is correlated with the severity of hemodynamic impairment. However, when present, it is associated with increased arrhythmic risk and higher cardiac mortality. Potential mechanisms implicated in the genesis of this breathing pattern and the possible therapeutic options, which have been proven to be effective in the clinical setting, are discussed. # 2003 Elsevier Science B.V. All rights reserved. Keywords: Disease, central and obstructive sleep apnea; Mammals, humans; Sleep, apnea, obstructive, congestive heart failure

1. Introduction The past two decades have witnessed major advances in understanding the pathophysiology of heart failure (HF). It has become evident that complex neuro-endocrine adaptations accompany the structural and functional changes of the left

* Corresponding author. Tel.: /1-514-338 2459/2222 ext. 2418; fax: /1-514-338 2694. E-mail address: [email protected] (P.A. Lanfranchi).

ventricle and may contribute importantly to the disease progression and the appearance of symptoms (Kjær and Birger, 2001). Therapeutic strategies blocking the renin
/angiotensin and sympathetic systems have led to significant improvement in both symptoms and survival in patients with moderate as well as with severe HF (CONSENSUS Trial Study Group, 1987; SOLVD Investigators, 1991; Packer et al., 1996 CIBIS-II Investigators, 1999; MERIT-HF Study Group, 1999). However, HF remains a major health problem in western countries, accounting for

1569-9048/03/$ - see front matter # 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1569-9048(03)00078-8

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thousands of new cases per year, frequent hospitalizations and a high mortality (American College of Cardiology/American Heart Association Task Force, 2001). Several trials have attempted to identify new diagnostic and prognostic markers in order to facilitate early detection of those patients at greatest risk for development and progression of HF. There has been increasing interest in the role of sleep-disordered breathing (SDB) in patients with HF. It is of significance that both HF and SDB constitute multi-system disorders involving respiratory, cardiovascular and neurohumoral axes. In HF there are two major types of SDB, namely obstructive sleep apnea (OSA) and central sleep apnea (CSA). These operate through different pathophysiological mechanisms, although they can coexist and interact (Tkacova et al., 2001). While often neglected in the clinical practice and scarcely considered by the HF literature for many years, they have recently been gaining recognition on the basis of their clinical relevance (American College of Cardiology/American Heart Association Task Force, 2001). OSA, likely a risk factor for cardiovascular disease (Nieto et al., 2000; Peppard et al., 2000), may also contribute to both the development of HF, and the further deterioration of a failing heart. Moreover, as we will discuss later, OSA shares with HF many aspects of deranged neuro-humoral and immunological function. CSA on the other hand, may be a consequence of HF (Dark et al., 1987; Solin et al., 1999), but when present, may increase the arrhythmic risk (Javaheri et al., 1998b) and impair prognosis (Findley et al., 1985; Hanly and ZuberiKhokhar, 1996; Lanfranchi et al., 1999). In this overview we will summarize the evidence for a special link between SDB and HF, and suggest that screening for nocturnal breathing disorders may be important in the risk stratification of HF. Specifically, we will examine the prevalence and clinical impact of OSA and CSA in HF. Then, we will focus primarily on CSA, discussing the potential mechanisms for the genesis of this breathing pattern in HF, its consequences and possible therapeutic interventions.

2. Prevalence of SDB in congestive heart failure Table 1 shows the largest prospective (Lofaso et al., 1994; Chan et al., 1997; Javaheri et al., 1998b; Lanfranchi et al., 1999; Tremel et al., 1999) and retrospective (Sin et al., 1999) studies addressing SDB in the context of congestive HF due to systolic and diastolic left ventricular dysfunction. In consecutive patients with HF due to left ventricular systolic dysfunction (evaluated while clinically stable on oral therapy), the following characteristics emerge. First, the prevalence of SDB is extremely high, ranging from 45 to 82%, probably reflecting differences in the study populations (ambulatory versus hospitalized, time from the last instabilization and pharmacological regimen, inclusion or exclusion of obese subjects), and the different diagnostic criteria for sleep apnea, such as the AHI cut-off. Second, the prevalence of OSA is not dissimilar to that reported in the normal population (Young et al., 1993), although OSA tends to be more frequent in newly diagnosed patients with a recent episode of acute decompensation (Tremel et al., 1999), in selected patients with suspected sleep apnea (Sin et al., 1999), and in patients with HF secondary to isolated diastolic dysfunction (Chan et al., 1997). Third, the prevalence of CSA, ranging from 40 to 63%, is strikingly high, suggesting a special link between this breathing disorder and HF (Lofaso et al., 1994; Javaheri et al., 1998b; Lanfranchi et al., 1999; Tremel et al., 1999). OSA is the most frequent breathing disorder in patients with diastolic HF (Chan et al., 1997), a condition where systolic function is preserved, and an impaired relaxation is thought be to be the primary mechanism leading to symptoms (Brutsaert et al., 1993). Interestingly, Chang et al. documented that patients with and without SDB, had similar baseline characteristics (blood pressure, body mass index, and PCO2). However, patients with SDB had greater impairment of ventricular relaxation on echocardiogram, suggesting that the nocturnal breathing disorder may likely be one contributor to the development of the diastolic impairment.

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Table 1 Prevalence of SDB in patients with HF Study

Patients (N )

Diagnostic criteria

Patients with SDB

Patients with OSA

Patients with CSA

Lofaso et al., 1994 Chan et al., 1997a Javaheri et al., 1998b Lanfranchi et al., 1999 Tremel et al., 1999 Sin et al., 1999b

29 20 81 66 34 450

AHI /10 AHI /10 AHI /15 AHI /10 AHI /10 AHI /10

9 (45) 11 (55) 41 (51) 50 (76) 28 (82) 316 (70)

1 (5) 7 (35) 9 (11) 4 (6) 7 (20) 168 (37)

8 (40) 4 (20) 32 (40) 46 (70) 21 (62) 148 (33)

Data are presented as number and percent (in parentheses). AHI, apnea
/hypopnea index. a Consecutive patients with diastolic HF. b Retrospective study.

3. OSA in HF During sleep, repetitive episodes of airway occlusion, with consequent dramatic changes in intrathoracic pressure, hypoxemia and hypercapnia, elicit a wide variety of hemodynamic, autonomic, humoral and neuroendocrine responses. These acute responses, coupled with the chronic effects of OSA on cardiovascular structure and function, may be linked to the development of cardiovascular disease in previously healthy subjects. They may also be particularly deleterious in the setting of preexisting disease, such as in the context of the failing heart. Several observational studies provide compelling evidence for an interaction between OSA and the subsequent development of hypertension (Nieto et al., 2000; Peppard et al., 2000), the major risk factor for development of HF (Levy et al., 1996). Also, data from the Sleep Heart Health Study suggest that OSA may be an independent risk factor for the subsequent development of self-reported HF (Shahar et al., 2001). Anecdotal reports have described cases of pulmonary edema in patients with OSA without evidence of cardiac disease (Chaudhary et al., 1982). OSA has been shown to have a negative impact on left ventricular function (Malone et al., 1991; Kaneko et al., 2003) and functional class (Malone et al., 1991) in patients with HF, as demonstrated by an improvement in these parameters after 4 weeks treatment with CPAP (Fig. 1). Even in normal subjects, the hemodynamic effects of the obstructed apnea, independent of hypox-

emia, result in a significant reduction in stroke volume and cardiac output, proportional to the degree of the negative intrathoracic pressure

Fig. 1. Effects of nasal CPAP therapy on left ventricular ejection fraction (LVEF) (top) and cardiac functional class (bottom) in patients with dilated cardiomyopathy and OSA. The reversibility of OSA is accompanied, after 4 weeks treatment, by a significant improvement in LVEF and functional class. (Reproduced with permission from Malone et al., 1991).

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generated (Tolle et al., 1983). The Mueller maneuver may also contribute significantly to the autonomic hemodynamic response to OSA (Somers et al., 1993). Data from animals during induced OSA (and O2 supplementation) (Chen et al., 2000) and in humans during the Mu¨ller maneuver (Bradley et al., 2001a,b), show that the hemodynamic impact may be more marked and prolonged in subjects with HF than in normal subjects. The intermittent hypoxia can further depress myocardial contractility (Kusuoka et al., 1986) and impair myocardial relaxation (Cargill et al., 1995). Hypoxia also activates the chemoreflex, with cardiac inhibition and bradycardia (Somers et al., 1992), and progressive increases in peripheral sympathetic drive during the apnea (Somers et al., 1995). Hypoxemia during apnea, and increased O2 demand, mainly during rebreathing, may conceivably precipitate ischemic events in patients with reduced coronary reserve (Peled et al., 1999), further compromising the ventricular function and increasing the ventricular vulnerability to malignant arrhythmias (Javaheri et al., 1998b). Significant bradyarrhythmias have also been described in OSA (Guilleminault et al., 1983; Grimm et al., 1996). In the absence of electrophysiologic abnormalities, they have been interpreted as secondary either to the activation of cardio-vagal reflexes (Grimm et al., 1996) from the ventricular mechanical distortions during the intrathoracic pressure changes, or as a consequence of chemoreflex activation, with increased vagal cardiac drive (Daly et al., 1979; Somers et al., 1992). Retrospective data show a 10% prevalence of significant bradyarrhythmias with sinus pauses of 2.5
/13 sec and second degree atrio-ventricular block in a large group of patients with OSA (Guilleminault et al., 1983). The incidence and relevance of bradyarrhythmias in patients with HF and OSA are not known. OSA is also associated with autonomic (Narkiewicz et al., 1998a,b) and humoral changes (Carlson et al., 1993; Dimsdale et al., 1995), known to be markers or mediators of the progression of cardiac failure and predictors of mortality (Saul et al., 1988; Thames et al., 1993; Mortara et al., 1994; Kjær and Birger, 2001). Patients with OSA have increased biochemical markers of inflammation

(Liu et al., 2000; Shamsuzzaman et al., 2002; Vgontzas et al., 2000). Specifically, they have increased levels of tumor necrosis factor (TNFalpha) (Liu et al., 2000; Vgontzas et al., 2000), a cytokine which is also found to be high in HF, and known to exert cardiodepressant and cardiotoxic actions (Levine et al., 1990; Franco et al., 1999). Considerable interest has also focused on brain natriuretic peptide (BNP), which correlates with the degree of left ventricular dysfunction (Maisel, 2001), and may predict sudden death in patients with HF (Berger et al., 2002). BNP is a neurohormone secreted mainly in the cardiac ventricles in response to volume expansion and pressure overload (Chen et al., 2000). The hemodynamic changes induced during OSA, could potentially contribute and/or further potentiate these increments of BNP. Indeed, preliminary data suggest that OSA patients without HF have higher nocturnal levels of BNP, which correlate with the elevations in blood pressure and the duration of the apneas (Kita et al., 1998). In patients with OSA there also appears to be a significant alteration in endothelium-dependent vascular control (Hedner, 1996; Kato et al., 2000; Kraiczi et al., 2001; Phillips et al., 1999), involving impaired NO mediated vasodilation (Kato et al., 2000; Kraiczi et al., 2001) and increased production of endothelin-1 (Phillips et al., 1999). In HF, endothelium dependent vasodilation may also be impaired (Ramsey et al., 1995). Endothelin-1 concentrations may be higher in HF and correlate with the severity of pulmonary hypertension (Cody et al., 1992) and a worse prognosis (Pousset et al., 1997). Altered endothelial function may be implicated in the excessive vasoconstriction of small arteries, and has been invoked as factor promoting reduced compliance of the large arteries. The latter, by causing the reflected pressure waves from the periphery to return earlier to the heart before aortic valve closure (Laskey and Kussmaul, 1987), may lead to an increased LV end-systolic stress and dilation. Finally, reduced mechanical distensibility of the large arteries, by reducing the magnitude of the deformation of the baroreceptors and their neural discharge (Kircheeim, 1976), could be an additional factor responsible for baroreceptor dysfunc-

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tion widely documented in HF (Thames et al., 1993) and also evident in OSA (Narkiewicz et al., 1998b). Thus OSA may be particularly detrimental in patients with HF, by worsening cardiac function, predisposing to arrhythmias, and potentiating neuro-endocrine derangements which contribute to the pathophysiology and progression of HF. This underscores the particular importance of early detection and treatment of OSA in HF.

4. CSA in CHF Almost a century ago it was evident that sleep in patients in end stage HF was often ‘‘broken, restless, and frequently disturbed by frightful dreams’’ (Osler, 1918) and that ‘‘a form of distressed breathing [Cheyne
/Stokes respiration]’’, sometimes was ‘‘so marked that the patient’s rest is disturbed during the period of increased breathing’’ (Mackenzie, 1923). What has become evident in the past decade is that this nocturnal breathing disorder is highly frequent, not only in patients with advanced HF, but also in those with relatively preserved functional class (Table 1). This breathing disorder is characterized by repetitive central apneas interrupted by hyperventilatory phases, where the tidal volume shows a typical waxing
/waning pattern. It occurs predominantly during stage 1
/2 of non-REM sleep, when the ventilation is driven by a chemical mechanism directed at maintaining the homeostasis of carbon dioxide (Kreiger, 2000). The hemodynamics of CSA
/CSR, in the absence of obstruction and respiratory effort during the apnea, differ from the hemodynamic consequences observed in OSA. The available data on the hemodynamic effects of CSA, although limited, seem to exclude a direct effect on after-load and stroke volume. In sedated animals, a reduction of cardiac output has been observed as an effect of the hypoxia-related bradycardia (Tarasiuk and Scharf, 1994). However, the recurrent apneas and the related changes in blood gases can induce an increase in the sympathetic neural drive through chemoreflex activation. The arousals,

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evident during the hyperventilatory phases (Davies et al., 1999), are an additional stimulant for sympathetic activation (van de Borne et al., 1998) and increases in blood pressure and catecholamines. Indeed, overnight urinary and daytime plasma norepinephrine concentrations have been reported to be markedly higher in patients with HF and CSR than in similar HF patients without CSR, and seemed to be directly related to the frequency of arousals from sleep and the degree of hypoxia, but not to the ejection fraction (Naughton et al., 1995a). In contrast, recent data from the same group suggested that the daytime enhanced sympathetic activity in HF patients with CSA (as expressed by body and cardiac norepinephrine spillover) is related to the degree of hemodynamic dysfunction rather than to severity of the breathing disorder. Given this discrepancy, the relative contributions of hemodynamic compromise and sleep apnea on the sympathetic hyperactivity, found in these patients, would require further clarifications. CSA is associated with increased incidence of arousals, which hinder the transition to a deeper sleep. Like OSA, CSA has an impact on the sleep architecture of HF patients (Javaheri et al., 1998b). The sleep efficiency is reduced, and can be associated with daytime sleepiness, fatigue and cognitive impairment (Staniforth et al., 2001), symptoms which may be misinterpreted as signs of low cardiac output, but which are rather the consequence of a restless night of disturbed sleep. Because of differences in the underlying pathophysiology of breathing control, hypoxia could be theoretically less important during CSA than during OSA. However, little (Sin et al., 1999) or no (Javaheri et al., 1998b) differences are reported in the levels of O2 saturation during CSA when compared with OSA in HF. It is notable that even in the structurally normal heart, severe central apnea can be life threatening (Pesek et al., 1999). In HF, in particular, prolonged apneas have been shown to induce profound hypoxemia (Cripps et al., 1992; Davies et al., 1991), eventually resulting, together with the sympathetic activation, in an imbalance between oxygen delivery and consumption and an increased ventricular vulnerability predisposing to malignant ventricular arrhythmias

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(Javaheri et al., 1998b). As a confirmation of the contribution of CSA
/CSR in increasing the arrhythmic distress in patients with HF, a reduction of ventricular arrhythmias has been show to parallel the reduction in respiratory events induced by CPAP (Javaheri, 2000). CSA
/CSR may also affect outcome in HF patients (Findley et al., 1985; Hanly and ZuberiKhokhar, 1996; Lanfranchi et al., 1999). Among clinically stable patients with moderate-to severe HF the presence of an AHI ]/30 may identify patients at high risk for cardiac mortality (Fig. 2), independent of other known risk factors, including ejection fraction, peak V˙ O2 and non invasive indices of elevated filling pressure (Lanfranchi et al., 1999). Marked abnormalities in autonomic cardiovascular control (circadian and nocturnal RR variability and cardiac baroreflex responses) parallel the severity of CSA
/CSR, suggesting that autonomic dysfunction might play a role in worsening the outcome in these patients.

5. Pathophysiology of periodic breathing The pathophysiological mechanisms responsible for periodic breathing are still unclear. Among the theories proposed, the ‘‘instability’’ hypothesis has received the most attention (Khoo et al., 1982;

Fig. 2. Cumulative survival without cardiac mortality according to apnea
/hypopnea index (AHI). The cumulative 1 and 2 year cardiac mortality was, respectively, 21.4 and 50% in patients with AHI ]/30/h vs. 5.4 and 26.2% in those with AHI B/30/h (P B/0.01). (Modified from Lanfranchi et al., 1999).

Khoo, 2000; Pinna et al., 2000; Francis et al., 2000). This theory explains periodic breathing as a self-sustaining oscillation due to the loss of stability in the closed-loop chemical control of ventilation, due, in HF, to an enhanced loop gain (hyperventilation), a slow circulation time between lungs and chemoreceptors, and inability to adjust to perturbations in the blood gases. During non-REM sleep, when the regulatory mechanism of ventilation is driven by chemical stimuli, hyperventilation, triggered by any perturbation, lowers PCO2 below the apnea threshold, thus initiating the apnea. The consequent hypoxia and hypercapnia elicits chemoreflex activation and subsequent hyperventilation. This is a mechanism frequently active in healthy controls, in whom there may be isolated central apneas. However, in the presence of ‘‘instability’’ in the control loop, this event can initiate the periodic breathing, with oscillations of PCO2 below and above the apnea threshold. Hyperventilation and hypocapnia have been thought to play a central role in promoting instability and CSA
/CSR in HF (Hanly et al., 1993; Naughton et al., 1993; Javaheri and Corbett, 1998a). This tendency to hyperventilate has been attributed to the mechanical stimulation of pulmonary vagal afferents by pulmonary congestion. As confirmation, clinical studies showed that the severity of AHI correlates with invasive (Solin et al., 1999) and non-invasive (Giannuzzi et al., 1994; Lanfranchi et al., 1999) indices of elevated pulmonary capillary pressure and high filling pressure. Also, in patients having both OSA and CSA during the same night, OSA events were reported to predominate at the beginning of the night and CSA events to predominate at the end of the night (Tkacova et al., 2001). This overnight shift from OSA to CSA was associated with a lowering of PCO2 and a progressive lengthening of the circulatory delay. The investigators concluded that hemodynamic deterioration could have occurred, with OSA eventually leading to impairment of cardiac output, increased pulmonary congestion and eventually providing the stimulus for the increased ventilatory responsiveness typical of CSA.

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However, CSA
/CSR does not always occur in patients with severely compromised hemodynamic and pulmonary congestion (Krachman et al., 1999) and is highly prevalent in patients with asymptomatic left ventricular dysfunction without overt heart failure (Lanfranchi et al., 2003), suggesting that some additional factors may be implicated in inducing, in certain patients, this breathing pattern. A prolonged circulation time, due to a low cardiac output, may conceivably be responsible for a delay in the sensing of blood gas changes, and therefore, possibly promote a selfsustaining oscillatory behavior (by inducing chemoreflex activation during hyperventilation and chemoreflex inhibition during apnea). However, it has been shown that a pure prolongation of circulatory time in and of itself is unlikely to produce periodic breathing (Guyton et al., 1956). However, in the presence of an increased chemosensitivity, even small increments of circulatory delay can lead to instability of the system and produce periodic breathing (Francis et al., 2000). Indeed, a higher hypercapnic ventilatory response initially documented in patients with CSA when compared with OSA (Wilcox et al., 1998), has been confirmed by several reports in controlled studies (Javaheri et al., 1999; Francis et al., 2000; Topor et al., 2001), clearly indicating that an enhanced chemoreflex sensitivity to carbon dioxide may play a crucial role in the development of CSA
/ CSR in HF. Francis et al. (2000) provided recently a unifying theory which reconciles the clinical controversies regarding the pathogenesis of CSA
/CSR in HF. Using their model, they confirmed that several factors may be implicated in facilitating ventilatory instability in HF patients, including low cardiac output, low ventilation, small lung volumes, high alveolar
/atmospheric CO2 difference, and a long lag to chemoreflex response. Among these, however, an enhanced hypercapnic chemoreflex gain and a prolonged lag to ventilatory response seemed to provide the major contribution to promoting the periodic pattern of ventilation in HF. A recent report (Garrigue et al., 2002), showing a significant reduction of central as well as obstructive respiratory events during overdrive pacing in selected patients with sinus node dys-

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function, may provide new insights into the pathophysiology of SDB. First, the similar efficacy in reducing both OSA and CSA speaks to the possibility of common aspects in the pathogenetic mechanisms of these two disorders, possibly at the level of control of ventilation (Issa and Sullivan, 1986; Orem and Kubin, 2000). OSA and CSA would, therefore, constitute part of a spectrum of periodic breathing which, under certain circumstances (such as visceral obesity and anatomical alterations) may present mainly as OSA, and, in the setting of other circumstances (such as HF), may present mainly as CSA. Second, while the mechanism of benefit of the overdrive pacing is unclear, it suggests the fascinating speculation that cardiac afferents modified by the atrial pacing, might play a role in modulating the central control of respiration (Gottlieb, 2002). Finally, animal studies suggest that ventilation is affected by the water
/salt balance and the hormones involved in the regulation of body fluids such as ANG II and arginine
/vasopressin (Anderson and Jennings, 1988; Jennings and Lockett, 2000; Ohtake and Jennings, 1993; Potter and McCloskey, 1979). In dogs, a high salt intake is associated with a decrease in the PCO2 threshold of the ventilatory response to CO2, with an increased alveolar ventilation and hypocapnia (Anderson and Jennings, 1988). Also, intravenous (Potter and McCloskey, 1979; Ohtake and Jennings, 1993) and brain ANG II (Jennings and Lockett, 2000) appear to stimulate ventilation, possibly via a central mechanism (Potter and McCloskey, 1979). By contrast, arginine
/vasopressin seems to affect ventilation by modulating the brain renin
/angiotensin system (Walker and Jennings, 1994). How these responses are integrated in the respiratory control is unclear. Moreover, data in humans are not available. However, these findings raise the question of whether the water and salt retention as well as the systemic increase in ANG II and arginine
/vasopressin, which are part of the adaptive response to a failing heart, could be additional factors somehow involved in the alteration of control of ventilation in HF which lead to CSA.

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6. Treatment of CSA /CSR 6.1. Treatment of heart failure Hemodynamic improvement following medical treatment is often associated with a significant improvement in the nocturnal breathing pattern (Dark et al., 1987; Walsh et al., 1995). In patients with persistent SDB, especially when CSA
/CSR is associated with marked desaturations and refractory HF, a specific treatment of the breathing disorder should be considered. The evidence of prolonged benefit of early treatment of CSA
/CSR by CPAP, persisting even after withdrawal of therapy, raises the question of whether to start treatment in all patients at the time of initial diagnosis of CSA
/CSR. Several therapeutic approaches have been shown to be potentially effective in reducing CSA
/CSR in HF. Fig. 2 illustrates some of the mechanisms that may be implicated. 6.2. NCPAP Nocturnal nasal CPAP may result in a 50% reduction in central respiratory events, and attenuation of the associated arousals and O2 desaturations (Issa and Sullivan, 1986; Naughton et al., 1995a,b). Hemodynamic improvement, increased lung volumes and slight increases in CO2 above the apnea threshold are some of the possible mechanisms invoked to explain the effectiveness of CPAP in reducing CSA
/CSR in HF. Clinical studies document that prolonged treatment of patients with CSA
/CSR is associated with an improvement in ventricular function and in the plasma and urinary levels of norepinephrine (Naughton et al., 1995a). These effects, in particular those on ventricular function, persist after the treatment has been withdrawn (Naughton et al., 1995b), suggesting that either remodeling of the left ventricle, or a resetting of neural circulatory control mechanisms has occurred. The benefits seem to translate into an improved prognosis. Encouraging, although preliminary, data indicate that NCPAP may improve transplant-free survival in patients with CSA
/CSR. Sin et al. (2000) reported that the mortality rates in treated patients

(n /12) was 25 versus 56% in untreated patients (n /15) (P /0.017). Unfortunately, however, only a fraction of patients with CSA seem to respond to the treatment with CPAP (43%) (Javaheri, 2000). The ongoing Canadian multicenter randomized controlled trial (Bradley et al., 2001a,b) is directed at helping clarify the efficacy and safety of this intervention and should provide knowledge on who will most benefit from this intervention. 6.3. Adaptive servo-ventilator A novel and promising approach, designed for the treatment of CSA in HF, is the adaptive servoventilator which provides a baseline degree of ventilatory support, where the subject’s ventilation is servo-controlled to maintain the ventilation at 90% of the long term average (Teschler et al., 2001). In a cross-over trial conducted in 14 patients in NYHA II
/III, this approach provided an additional 83% reduction in central apneas when compared with nasal CPAP, and was also more easily tolerated. 6.4. Nocturnal O2 supplements Although the rationale for using O2 supplements in CSA is not clear, it has been hypothesized that O2 may stabilize the breathing by removing any enhancement of the hypercapnic chemoreflex and attenuating any independent influence of hypoxic chemoreflex activation on the hyperventilatory response (Francis et al., 2000). O2 has been shown by several groups to be effective in reducing the number of central respiratory events and improving oxygen saturation (Hanly et al., 1989; Franklin et al., 1997; Javaheri et al., 1999), and, in the long term, reducing the overnight urinary excretion of norepinephrine (Staniforth et al., 1998). O2 may variably influence the sleep characteristics (Hanly et al., 1989; Franklin et al., 1997; Staniforth et al., 1998). However, in a series of stable patients in NYHA II
/III classes it appeared that O2 improved sleep quality (increased sleep efficiency and decreased arousals) significantly only in those patients (40%) who were ‘‘fully responsive’’ to O2 (i.e. AHI B/15 during treatment) (Javaheri et al., 1999). In cross-over studies con-

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ducted in HF patients in NYHA functional class III (Teschler et al., 2001) and IV (Krachman et al., 1999), single-night treatments with O2 supplements and nasal CPAP were equally effective in decreasing the AHI, arousal index and degree of desaturation. While a clear advantage of O2 is the greater acceptability by the patients, data on the effect of nocturnal O2 treatment on medium-term clinical and functional end-points are not currently available. Interesting results have been shown with oral theophylline, which, in the short term, resulted in a 50% reduction in AHI and related arousals (Javaheri et al., 1996). Among the potential mechanisms, an increased inotropic effect and a direct stimulation (and stabilization) of the central ventilatory drive have been invoked as playing a role in reducing the respiratory events. Data on long term efficacy and safety are not available at present. Finally, as noted above, overdrive pacing has been shown to elicit a 60% reduction of both central and obstructive apneas in a small group of highly selected patients with symptomatic sinus bradyarrhythmias and coexisting sleep apnea (Garrigue et al., 2002). While interesting, these results should be considered preliminary. A generalization of the results to other categories of patients with sleep apnea is uncertain and has to be proven.

7. Conclusion HF and SDB constitute multi-system disorders involving respiratory, cardiovascular and neuroendocrine axes. OSA, likely a risk factor for cardiovascular disease and ultimately for HF, may be particularly detrimental in patients with HF, by worsening cardiac function, predisposing to arrhythmias, and potentiating neuro-endocrine derangements which contribute to the pathophysiology and progression of HF. CSA seems to derive from the condition of HF. However, when present, CSA may further affect the progression of the disease, promote arrhythmias and impair prognosis. While the hemodynamic impairment with increased pulmonary congestion is considered

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the primary mechanism responsible for the development of CSA, other factors may be implicated in the ventilatory instability, which elicits this pattern of nocturnal breathing.

Acknowledgements We thank Dr Anil Nigam for the help in preparing the manuscript.

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