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Heart failure and obstructive apnoea
SLEEP MEDICINE
Sleep Medicine Reviews, Vol. 2, No. 2, pp 93-103, 1998
)reviewsl
REVIEW ARTICLE
Heart failure Matthew
and obstructive
apnoea
T. Naughton
Alfred Sleep Disorders and Ventilatory Medicine, Alfred Hospital and Monash
Failure Service, Department of Respiratory University, Prahran, Victoria, Australia
Obsfrucfivesleepapnoea (0SA)mayaggravafeheartfailure throughfhemechanismsofsleeprelatedarousals, sysfemichypertension (awakeandasleep)and negativeintrathoracicpressurezuhichincreasecardiacaferload at times of asphyxia and hypoxaemia. Reversal of OSA with nasal continuous positive airway pressure (CPAP), in the setting of heart failure, may return cardiac function to neaynormal values.
Key words: heart failure, sleep apnoea, Cheyne-Stokes respiration, positive airway pressure
Introduction Most patients with heart failure complain of fatigue and dyspnoea related to sleep. Many such patients have either obstructive sleep apnoea (OSA) or Cheyne-Stokes respiration with central sleep apnoea (CSR-CSA). The former patient group have an increased left ventricular transmural pressure, via an elevated systemic blood pressure and exaggerated negative intrathoracic pressure, at a time of hypoxaemia and increased cardiac and respiratory work, which may precipitate heart failure. The later patient group develop a periodic breathing pattern characterized by increased sympathetic activity, hyperventilation, delayed cardiac to chemoreceptor circulation time and reduced blood gas buffering capacity, probably secondary to severe heart failure. This two-part review attempts to provide evidence in support of the above hypotheses, discuss treatment options and hopefully raise questions that will stimulate further research.
Heart
failure
Epidemiology Heart failure is one of the most prevalent, costly and lethal diseases in the Western society. It affects 1% of the general middle-aged population, and doubles in prevalence
Correspondence to be addressed to: Matthew T. Naughton, Alfred Sleep Disorders and Ventilatory Failure Service, Alfred Hospital, Commercial Rd, Prahran, 3181, Victoria, Australia (email: [email protected]) 1087-0792/98/020093 + 11 $12.00/O
0 1998 W.B. Saunders Company Ltd
M. T. Naughton
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for every decade above 50 years of age [l]. In the United States, conservative estimates suggest there are 2 million patients with congestive heart failure (CHF) and 400 000 new cases per annum, resulting in 900 000 hospital admissions and 200 000 deaths per year [l]. Over the past decade, the incidence has doubled, independent of age [l], mainly as a result of improved survival following myocardial infarction [2]. During the 40-year period from 1948 to 1988, no significant improvement in survival in patients suffering from CHF was observed [3]. As approximately 50% of patients with CHF will be dead in 5 years, a prognosis which rivals that of many malignancies [l], the search for new therapeutic strategies must continue.
Pafhogenesis-a
failure
fo confracf
or relax?
Patients with heart failure have signs of pulmonary congestion, elevated jugular venous pressure, pleural effusion, ankle swelling, cardiomegaly (clinically or on radiograph), and a gallop heart rhythm. This clinical syndrome is referred to as congestive heart failure (CHF). Historically, CHF was thought of as an abnormality solely of systolic contraction. However, in 1984, Dougherty et al. reported that a third of patients with severe congestive heart failure had normal left ventricular (LV) systolic function [4]. Detailed studies suggested that those with normal systolic function and clinically defined CHF indeed had abnormally reduced LV compliance, now termed diastolic dysfunction [4]. Objective assessment of diastolic dysfunction required an elevated end-diastolic pressure (at rest or precipitated by exercise) with normal end-diastolic volume and systolic function [stroke volume and left ventricular ejection fraction (LVEF)] or delayed rates of LV filling on echocardiography. Systemic hypertension, hypoxia, obesity, myocardial ischaemia and ventricular interdependence (right ventricular enlargement in the presence of an intact pericardium) are well described causes of diastolic dysfunction [5], which may coexist with underlying obstructive sleep apnoea (OSA). Although diastolic dysfunction does not contribute to the mortality seen with systolic dysfunction, if left untreated, diastolic dysfunction is thought to progress to overt systolic heart failure 151. Systolic heart failure can be defined as a reduction in left ventricular contractile function and is usually a result of extensive myocardial ischaemic damage, long standing and/or poorly treated systemic hypertension, valvular heart disease, alcohol, or of unknown causes (idiopathic). Objective assessment of left ventricular systolic function is recommended in such patients with nuclear cardiac gated blood pool scan (LVEF), echocardiography (reduced fractional shortening) or right heart catheter [impaired cardiac output often associated with an elevated pulmonary capillary wedge pressure (PCWP)]. The LVEF remains the single most important test, based upon both diagnostic and prognostic insights, although it bears little relation to symptoms of heart failure. Compensatory mechanisms augment myocardial contractile function and preserve tissue perfusion in patients with CHF [6,7]. These include activation of the sympathetic and the renin-angiotensin-aldosterone systems (as a result of arterial high pressure baroreceptor perception of hypotension and relative renal hypoperfusion, respectively) plus release of vasopressin, endothelin and atria1 natriuretic peptide (as a result of cardiac chamber dilatation). Thus, in the early stages of CHF, compensatory neurohumoral mechanisms may increase systolic function, thereby rendering the patient asymptomatic, particularly if coupled with medical therapy.
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Later in the disease process, CHF may worsen due to the inability of compensatory mechanisms to maintain adequate systolic function in the face of disease progression. Higher neurohumoral activity corresponds with reduced survival [6,7]. Moreover, high levels of sympathetic activity may cause myocardial cell damage, skeletal muscle wasting, and fatal tachyarrhythmias [7-91.
Effects
of heart failure
on sleep
Although fatigue, insomnia and sleepiness are common symptoms of patients with CHF, very little research has elucidated the pathophysiology responsible for these symptoms. Reduced cardiac output, increased cardiac, respiratory and skeletal muscle work, reduced amounts of total, slow wave and REM sleep in association with marked sleep fragmentation due to arousals and apnoeas from sleep and drug side effects have been proposed [lO,ll]. Periodic leg movements during sleep occur in about 50% of patients with CHF and are associated with shortened sleep latency (6-7 minutes) [12].
Medical
therapies
for CHF
The end point of therapy is to increase quality and quantity of life. Diuretics and digoxin reduce symptoms of CHF and presumably increased quality of life, but neither has been shown to improve survival [13]. Following the observation that stroke volume increases with arterial dilatation (LV afterload reduction) in CHF [14], a study of patients with CHF over a 42-month period, revealed that the afterload reducing agent enalapril (an angiotensin-converting enzyme inhibitor) reduced mortality (39.4% in the placebo group vs 35.2% in the enalapril-treated group) [15]. Yet, the mortality in the enalapril group was still unacceptably high and only 58 lives were saved, a small fraction of the 2569 patients studied [15]. More recently, carvedilol (a beta-adrenergic blocker with alpha-blocking and antioxidant capacities) showed a slight improvement in survival [16,17]. Although cardiac transplantation improves overall survival, it is associated with significant co-morbidity and limited donor organ availability [lS].
Effects
of heart
Lung function
failure
on breathing
(awake)
tests
Heart failure causes increased pulmonary vascular blood volume, followed by interstitial and thereafter alveolar oedema. Several studies have shown that patients with severe CHF have a restrictive ventilatory defect with slightly impaired diffusing capacity [19-211. Diffusing capacity is said to correlate inversely with PCWP [20]. Pulmonary restriction improves with medical therapy directed at the underlying CHF [19] or following heart transplant [21]. Following cardiac transplant, the improvement in functional residual capacity correlates significantly with the reduction in cardiac volume as estimated on chest radiograph [21], suggesting that much of the pulmonary restriction relates to cardiomegaly. As 50% of the body’s oxygen is stored within the lungs, reduced lung volumes due to CHF may contribute to hypoxaemia.
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M. T. Naughton
Pleural pressure
swings
During tidal breathing awake at rest, patients with CHF generate a 2-3-fold increase in the pleural pressures compared with control subjects [22] which diminish with medical therapy [23]. As pleural pressures equate with pericardial pressures, the larger subatmospheric pressures on inspiration in CHF contribute to a greater left ventricular afterload [24]. Reduced lung compliance, increased airway resistance [25] or increased respiratory drive (from vagal afferent stimulation [26] or the effects of sympathetic activity upon chemosensitivity) [27] are thought to be responsible for the larger subatmospheric pressures. As the pressure-respiratory rate product is also greater in CHF patients [22], respiratory effort (and possibly respiratory work) is greater than nonCHF controls. Accordingly the respiratory pump muscles require a greater proportion of cardiac output thereby creating a relative steal phenomenon [28].
Hypocapnia Patients with heart failure, who have central sleep apnoea, also have a tendency to have hypocapnia in the absence of hypoxaemia [lo] while awake. Whether this is due to an increased central CO, chemosensitivity [29] or simply a leftward shift in the CO, ventilatory response curve (due to tonically activated pulmonary vagi [26], peripheral chemoreceptors bathed in blood containing elevated levels of norepinephrine [27], or the effect of arousal state), remains to be determined.
Skeletal
myopathy
Skeletal myopathy may play a role in sleep disordered breathing [30,31], as has been proposed in exercise-induced dyspnoea [32]. The exercise limitation of patients with CHF cannot be explained by reduced cardiac output alone [33] and may in part be due to reduced skeletal and respiratory muscle strength [30,31,34]. Animals withpacinginduced CHF develop decreased diaphragm strength with increased fatiguability [32]. Three factors are thought to contribute to the skeletal myopathy of CHF, namely: (1) muscle hypoperfusion due to an attenuated pressor response to exercise; (2) abnormal vascular function; and (3) reduction in the intrinsic capacity of the muscle [32]. Recently the ventilatory response to exercise was reported to correlate with peripheral chemosensitivity, thereby suggesting a role for the carotid body in determining exercise capacity [33], analogous to the role that chemosensitivity plays in sleep disordered breathing in CHF [29,35].
Heart
failure
and obstructive
sleep apnoea
Introduction Obstructive sleep apnoea (OSA) is a condition in which repetitive upper airway obstructions occur during sleep giving rise to recurrent apnoeas. Three key pathological effects of obstructive apnoeas are: (1) large negative intrathoracic pressure swings; (2) hypoxaemia; and (3) arousals from sleep. Hypoxaemia and arousals lead to bursts of
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systemic hypertension which, like large negative intrathoracic pressure swings, act to increase left ventricular afterload. OSA may lead to heart failure if severe or in patients with co-existent cardiovascular risk factors.
Pathophysiology Negative intrathoracic pressures Negative intrathoracic pressure generated by futile inspiratory efforts against an occluded upper airway during sleep may reach as low as - 100 cmH,O ( - 75 mmHg). Several potentially harmful physiological events may occur such as: (1) an elevated pressure gradient across the LV wall (transmural pressure) [24,36-391; (2) distension of right ventricle and leftward shift of the interventricular septum with impedance to LV filling [36,40]; (3) an increase in LV end-systolic and end-diastolic volumes 136, 411; (4) reduced cardiac fibre shortening [36]; (5) im p airment of LV relaxation and prolongation of relaxation time, which further impede LV filling [36,40,42]. Overall there is an increase in cardiac work and energy expenditure. In subjects with normal cardiac function, the net haemodynamic effect is generally a transient reduction in stroke volume and cardiac output over the course of obstructive apnoeas that is proportional to the negative intrathoracic pressure generated [36,43]. Hypoxaemia Hypoxaemia related to apnoea can also have a number of detrimental cardiovascular effects. First, it causes pulmonary vasoconstriction, increases pulmonary artery pressure [44-46] and right ventricular afterload which can reduce cardiac output directly or indirectly by increasing leftward interventricular septal shift [40,47]. Second, hypoxia can reduce both myocardial contractility and impair myocardial relaxation (diastolic dysfunction), both of which could also decrease cardiac output [36,48]. Third, it increases sympathetic nervous system activity (SNA) [49] via stimulation of carotid body chemoreceptors [50], an effect potentiated when the sympatho-inhibitory effects of lung expansion are removed 1511. Resultant tachycardia reduces absolute diastole time, and thereby time for diastolic filling and coronary perfusion. Increased SNA to the peripheral vasculature will cause vasoconstriction and tend to increase systemic blood pressure [49,50]. Finally, hypoxia is also thought to promote atherogenesis, although mechanisms remain obscure [52,53]. Arousals Arousals usually terminate obstructive apnoeas by restoring upper airway dilator muscle tone and patency. In association with the abrupt increase in ventilation, SNA reaches a peak and then abruptly decreases [49]. The pathophysiology of sympathetic activation at the termination of apnoeas involves the combined effects of hypoxia, increases in Pco~, and the startle response related to arousals from sleep [49,54]. The sympathetic nervous system-mediated vasoconstriction contributes to the acute blood pressure increases at the termination of apnoeas since sympathetic blockade prevents them [55]. Stroke volume may indeed increase during the arousal period thereby contributing to the overall rise in blood pressure shortly after the arousal and helps explain why blood pressure rises to a peak shortly after arousal at a time when SNA is falling abruptly from its peak level 1491. A number of studies have also demonstrated increased SNA to skeletal muscles or plasma norepinephrine concentrations both
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during sleep and wakefulness in patients with OSA compared to control subjects [49,56]. These findings further point to the potential role of the SNA in mediating both acute and chronic elevations in blood pressure in patients with OSA.
Adverse
sequelae
Systemic hypertension Several studies have demonstrated that approximately 50% of patients with OSA have daytime hypertension [57]. In an epidemiological study, Hla et al. [58] showed that OSA was a risk factor for daytime hypertension independent of body weight, age and sex. Further evidence for a causal relationship between OSA and daytime hypertension was provided by Brooks et al. [59] They showed, in a chronic dog model, that OSA caused hypertension that was sustained into wakefulness. Although auditory stimuli caused acute rises in blood pressure during sleep of the same magnitude as those observed in response to intermittent obstructive apnoeas, only the recurrent obstructive apnoeas gave rise to sustained hypertension during wakefulness. Therefore, although arousals can increase blood pressure acutely, additional factors related to obstructive apnoea appear to be necessary for the development of awake hypertension. Increased thrombogenicity Intermittent hypoxia and elevations in SNA may be responsible for the increases in platelet aggregability [60] and fibrinogen levels [61] that have been reported in some patients with OSA. These factors, in combination with hypertension, could play a role in the precipitation of acute cardiac and cerebrovascular ischaemic events, and possibly even in progression of atherogenesis [62,63]. Cardiac failure OSA burdens the heart by increasing LV afterload, either through acute or chronic elevations in systemic blood pressure, or by generation of exaggerated negative intrathoracic pressure or a combination of the two. Obviously, chronic hypertension alone is a risk factor for LV hypertrophy and failure [1,3]. However, Hedner et al. [62] have also shown that normotensive patients with OSA have thicker LV walls than normotensive control subjects without OSA. These findings strongly suggest that even in the absence of daytime hypertension, intermittent sleep-related increases in LV afterload could lead to LV hypertrophy. Patients with OSA may also have mild degrees of LV dysfunction. This was suggested by an uncontrolled study in which long-term application of CPAP to patients with OSA, but with no history of cardiac disease and LV ejection fractions (LVEF) within the normal range, was associated with a small, but significant improvement in LVEF (from 59 to 63%) [64]. The adverse consequences of OSA on the cardiovascular system are liable to be more pronounced in individuals with diseased or failing hearts, which are sensitive to changes in afterload, than in those whose cardiac function is normal and relatively afterload insensitive [14,36,41]. Malone et al. [65] highlighted a very important relationship between CHF due to idiopathic dilated cardiomyopathy and OSA. Tempory reversal of OSA with CPAP treatment was associated with marked improvements in cardiac function and symptoms which returned to baseline once CPAP was withdrawn [65]. Cistulli et al. have reported that patients with Marfans syndrome have a high
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prevalence of OSA, probably related to upper airway skeletal and connective tissue abnormalities and resultant increased resistance [66]. Moreover, they have reported progression of aortic root dilatation in those with untreated OSA, which has major prognostic importance as survival is inversely related to aortic root diameter in such patients [66]. Importantly, progression of aortic root dilatation was arrested by the reversal of OSA with CPAP in two patients with Marfans syndrome [66]. lschaemia and arrhythmias Obstructive apnoeas can precipitate cardiac ischaemia in patients both with [67] and without 1681 a history of ischaemic heart disease. These ischaemic changes presumably arose from the combined effects of increased LV afterload, hypoxia and increased cardiac sympathetic activity and were prevented by CPAI? Patients with recent myocardial infarction or nocturnal angina have been reported to have a high prevalence of OSA [67,69]. Precipitation, or worsening of cardiac ischaemia by OSA could aggravate both systolic and diastolic left ventricular dysfunction, particularly in patients with CHF due to ischaemic cardiomyopathy [43,46]. Finally, since approximately one-third of patients with CHF die suddenly, presumably of cardiac arrhythmias [l/9], nocturnal cardiac arrhythmias triggered by OSA, including sinus bradycardia, second degree heart block, supraventricular and ventricular tachycardia [70,71] could adversely affect outcome in patients with CHF.
Therapy The approach to therapy of OSA in patients with CHF should, in general, be similar to that in patients without CHF. Weight loss in the obese, avoidance of alcohol and sedative medications that could increase the tendency for upper airway collapse, should be routinely recommended. Marked improvements in cardiac function can be noted in obese CHF patients who are able to lose substantial weight [72]. CPAP reliably abolishes obstructive apnoeas and in so doing should consolidate sleep, eliminate apnoea-related hypoxia, improve myocardial oxygen delivery, reduce SNA, and decrease LV afterload by increasing intrathoracic pressure and reducing blood pressure [49,65]. Abolition of OSA in CHF patients by CPAP could also reduce myocardial ischaemia [65,67] and cardiac arrhythmias. There is, however, only one study that has systematically addressed the effects of CPAP in patients with CHF and coexistent OSA [65]. Malone and coworkers [65] studied the effects of nocturnally administered CPAP over a l-month period in eight male patients with “idiopathic” dilated cardiomyopathy and coexistent OSA. In association with complete abolition of OSA by CPAP, there was a significant improvement in LVEF (from 37 to 49%) measured while awake in the daytime. Symptoms of sleep apnoea and CHF were improved. Following a l-week withdrawal of CPAP in a subset of four of these patients, there was a significant reduction in LVEF (from 53 to 45%) and worsening of symptoms. These data indicate that elimination of OSA by CPAP was responsible for the improvement in cardiac function and strongly suggests that OSA was contributing to the development of LV dysfunction. The effects of mandibular advancement devices and upper airway surgery have not been studied in patients with OSA and CHF. However, one should exercise caution
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M. T. Naughton
in their use in this setting. Because these treatments seldom provide ination of OSA 1731, they may prove not to be effective in improving The risks of general anaesthesia for elective upper airway surgery CHF must also be taken into consideration. Where general measures alleviating OSA and CPAP is poorly tolerated, tracheostomy may be alternative therapy because it should abolish OSA [74].
complete elimcardiac function. in patients with are ineffective in considered as an
Conclusion Obstructive sleep apnoea creates a unique set of physiological events which are likely to aggravate CHF. Acutely during sleep, there are elevations in systemic blood pressure combined with reductions in intrathoracic pressures associated with fragmentation and loss of sleep and asphyxia-related derangements in blood gas tensions. Over months to years there may be resetting of chemoreceptors and baroreceptors that allow the night-time physiological derangement to spill over to the day-time and thereby allow systemic and pulmonary pressures to rise and hypoxaemia-hypercapnia to occur. Practice Points In patients with heart f&me: 1, Approximately 30% of such patients Will have diastolic rather than systolic heart
‘,I; failure. ‘2. ‘Obstructive sleep ajmoea should be considered as a contributing factor to the ‘..,: development of both forms of heart failure. 3.’ Treatment of obstructive sleep apnoea with mandibular advancement splints or upper aitiay surgery should only be used with great caution until further “’ ”‘evidence regarding their efficacy becomes available. Research Agenda
Future directions for research should include: 1.. Examining the importance of obstructive sleep ,Iheart failure relative to other more “established” 2, Determination of the night-to-night variability of with medical therapy for heart failure. 3:, Larger and longer term studies of the effect of , dysfunction.
apnoea in the pathogenesis of risk factors. obstructive and central apnoea apnoea reversal upon cardiac
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by an asterisk.
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57 Carlson JT, Hedner JA. Ejnell H et al. High prevalence of hypertension in sleep apnea patients independent of obesity. Am J Respiv Crit Care Med 1994; 150: 72-77. 58 Hla KM, Young TB, Bidwell T et al. Sleep apnea and hypertension. A population-based study. Ann Intern Med 1994; 120: 382-388. $59 Brooks D, Horner RL, Kozar LF et al. Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. I Clin Invest 1997; 99: 106-109. 60 Bokinsky G, Miller M, Ault K et al. Spontaneous platelet activation and aggregation during obstructive sleep apnea and its response to therapy with nasal continuous positive airway pressure. A preliminary investigation. Chest 1995; 108: 625-630. 61 Chin K, Ohi M, Kita H et al. Effects of NCPAP therapy on fibrinogen levels in obstructive sleep apnea syndrome. Am J Respir Crit Cave Med 1996; 153: 1972-1976. 62 Hedner J, Ejnell H, Caidahl K. Left ventricular hypertrophy independent of hypertension in patients with obstructive sleep apnea. J Hypertens 1990; 8: 941-946. 63 Hedner J. Vascular function in OSA. Sleep 1996; 19: S213-S217. 64 Krieger J, Grucker D, Sforza E et al. Left ventricular ejection fraction in obstructive sleep apnea. Effect of long term treatment with nasal continuous positive airway pressure. Chest 1991; 100: 917-921. “65 Malone S, Liu PI’, Holloway R et al. Obstructive sleep apnoea in patients with idiopathic dilated cardiomyopathy: effects of continuous positive airway pressure. Lancet 1991; 338: 1480-1484. 66 Cistulli PA, Wilcox I, Jeremy R et al. Aortic root dilatation in Marfan’s syndrome. A contribution from obstructive sleep apnea? Chest 1997; 111: 1763-1766. “67 Franklin KA, Nilsson JB, Sahlin C et al. Sleep apnoea and nocturnal angina. Lancet 1995; 345: 1085-1087. 68 Hanly PJ, Sasson Z, Zuberi N et al. ST-segment depression during sleep in obstructive sleep apnea. Am J Cavdiol 1993; 71: 1341-1345. *69 Hung J, Whitford EG, Parsons RW et al. Association of sleep apnoea with myocardial infarction in men. Lancet 1990; 336: 261-264. 70 Cripps T, Rocker G, Stradling J. Nocturnal hypoxemia and arrhythmias in patients with impaired left ventricular function. Br Heavt ] 1992; 68: 382-386. 71 Zwillich C, Devlin T, White D, Douglas NJ, Weil J, Martin R. Bradycardia during sleep apnoea; characteristics and mechanisms. J Clin Invest 1982; 69: 1286-1292. 72 Alpert MA, Terry BE, Mulekar M et al. Cardiac morphology and left ventricular function in normotensive morbidly obese patients with and without congestive heart failure, and effect of weight loss. Am J Cavdiol 1997; 80: 736-740. 73 Ferguson KA, Ono T, Lowe AA et al. A randomized cross over study of an oral appliance vs nasal continuous positive airway pressure in the treatment of mild to moderate obstructive sleep apnea. Chest 1996; 109: 1269-1275. 74 Fletcher EC, Miller J, Scaaf JW et al. Urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension. Sleep 1987; 10: 3544.
Sleep Medicine Reviews, Vol. 2, No. 2, pp 93-103, 1998
)reviewsl
REVIEW ARTICLE
Heart failure Matthew
and obstructive
apnoea
T. Naughton
Alfred Sleep Disorders and Ventilatory Medicine, Alfred Hospital and Monash
Failure Service, Department of Respiratory University, Prahran, Victoria, Australia
Obsfrucfivesleepapnoea (0SA)mayaggravafeheartfailure throughfhemechanismsofsleeprelatedarousals, sysfemichypertension (awakeandasleep)and negativeintrathoracicpressurezuhichincreasecardiacaferload at times of asphyxia and hypoxaemia. Reversal of OSA with nasal continuous positive airway pressure (CPAP), in the setting of heart failure, may return cardiac function to neaynormal values.
Key words: heart failure, sleep apnoea, Cheyne-Stokes respiration, positive airway pressure
Introduction Most patients with heart failure complain of fatigue and dyspnoea related to sleep. Many such patients have either obstructive sleep apnoea (OSA) or Cheyne-Stokes respiration with central sleep apnoea (CSR-CSA). The former patient group have an increased left ventricular transmural pressure, via an elevated systemic blood pressure and exaggerated negative intrathoracic pressure, at a time of hypoxaemia and increased cardiac and respiratory work, which may precipitate heart failure. The later patient group develop a periodic breathing pattern characterized by increased sympathetic activity, hyperventilation, delayed cardiac to chemoreceptor circulation time and reduced blood gas buffering capacity, probably secondary to severe heart failure. This two-part review attempts to provide evidence in support of the above hypotheses, discuss treatment options and hopefully raise questions that will stimulate further research.
Heart
failure
Epidemiology Heart failure is one of the most prevalent, costly and lethal diseases in the Western society. It affects 1% of the general middle-aged population, and doubles in prevalence
Correspondence to be addressed to: Matthew T. Naughton, Alfred Sleep Disorders and Ventilatory Failure Service, Alfred Hospital, Commercial Rd, Prahran, 3181, Victoria, Australia (email: [email protected]) 1087-0792/98/020093 + 11 $12.00/O
0 1998 W.B. Saunders Company Ltd
M. T. Naughton
94
for every decade above 50 years of age [l]. In the United States, conservative estimates suggest there are 2 million patients with congestive heart failure (CHF) and 400 000 new cases per annum, resulting in 900 000 hospital admissions and 200 000 deaths per year [l]. Over the past decade, the incidence has doubled, independent of age [l], mainly as a result of improved survival following myocardial infarction [2]. During the 40-year period from 1948 to 1988, no significant improvement in survival in patients suffering from CHF was observed [3]. As approximately 50% of patients with CHF will be dead in 5 years, a prognosis which rivals that of many malignancies [l], the search for new therapeutic strategies must continue.
Pafhogenesis-a
failure
fo confracf
or relax?
Patients with heart failure have signs of pulmonary congestion, elevated jugular venous pressure, pleural effusion, ankle swelling, cardiomegaly (clinically or on radiograph), and a gallop heart rhythm. This clinical syndrome is referred to as congestive heart failure (CHF). Historically, CHF was thought of as an abnormality solely of systolic contraction. However, in 1984, Dougherty et al. reported that a third of patients with severe congestive heart failure had normal left ventricular (LV) systolic function [4]. Detailed studies suggested that those with normal systolic function and clinically defined CHF indeed had abnormally reduced LV compliance, now termed diastolic dysfunction [4]. Objective assessment of diastolic dysfunction required an elevated end-diastolic pressure (at rest or precipitated by exercise) with normal end-diastolic volume and systolic function [stroke volume and left ventricular ejection fraction (LVEF)] or delayed rates of LV filling on echocardiography. Systemic hypertension, hypoxia, obesity, myocardial ischaemia and ventricular interdependence (right ventricular enlargement in the presence of an intact pericardium) are well described causes of diastolic dysfunction [5], which may coexist with underlying obstructive sleep apnoea (OSA). Although diastolic dysfunction does not contribute to the mortality seen with systolic dysfunction, if left untreated, diastolic dysfunction is thought to progress to overt systolic heart failure 151. Systolic heart failure can be defined as a reduction in left ventricular contractile function and is usually a result of extensive myocardial ischaemic damage, long standing and/or poorly treated systemic hypertension, valvular heart disease, alcohol, or of unknown causes (idiopathic). Objective assessment of left ventricular systolic function is recommended in such patients with nuclear cardiac gated blood pool scan (LVEF), echocardiography (reduced fractional shortening) or right heart catheter [impaired cardiac output often associated with an elevated pulmonary capillary wedge pressure (PCWP)]. The LVEF remains the single most important test, based upon both diagnostic and prognostic insights, although it bears little relation to symptoms of heart failure. Compensatory mechanisms augment myocardial contractile function and preserve tissue perfusion in patients with CHF [6,7]. These include activation of the sympathetic and the renin-angiotensin-aldosterone systems (as a result of arterial high pressure baroreceptor perception of hypotension and relative renal hypoperfusion, respectively) plus release of vasopressin, endothelin and atria1 natriuretic peptide (as a result of cardiac chamber dilatation). Thus, in the early stages of CHF, compensatory neurohumoral mechanisms may increase systolic function, thereby rendering the patient asymptomatic, particularly if coupled with medical therapy.
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and obstructive
apnoea
95
Later in the disease process, CHF may worsen due to the inability of compensatory mechanisms to maintain adequate systolic function in the face of disease progression. Higher neurohumoral activity corresponds with reduced survival [6,7]. Moreover, high levels of sympathetic activity may cause myocardial cell damage, skeletal muscle wasting, and fatal tachyarrhythmias [7-91.
Effects
of heart failure
on sleep
Although fatigue, insomnia and sleepiness are common symptoms of patients with CHF, very little research has elucidated the pathophysiology responsible for these symptoms. Reduced cardiac output, increased cardiac, respiratory and skeletal muscle work, reduced amounts of total, slow wave and REM sleep in association with marked sleep fragmentation due to arousals and apnoeas from sleep and drug side effects have been proposed [lO,ll]. Periodic leg movements during sleep occur in about 50% of patients with CHF and are associated with shortened sleep latency (6-7 minutes) [12].
Medical
therapies
for CHF
The end point of therapy is to increase quality and quantity of life. Diuretics and digoxin reduce symptoms of CHF and presumably increased quality of life, but neither has been shown to improve survival [13]. Following the observation that stroke volume increases with arterial dilatation (LV afterload reduction) in CHF [14], a study of patients with CHF over a 42-month period, revealed that the afterload reducing agent enalapril (an angiotensin-converting enzyme inhibitor) reduced mortality (39.4% in the placebo group vs 35.2% in the enalapril-treated group) [15]. Yet, the mortality in the enalapril group was still unacceptably high and only 58 lives were saved, a small fraction of the 2569 patients studied [15]. More recently, carvedilol (a beta-adrenergic blocker with alpha-blocking and antioxidant capacities) showed a slight improvement in survival [16,17]. Although cardiac transplantation improves overall survival, it is associated with significant co-morbidity and limited donor organ availability [lS].
Effects
of heart
Lung function
failure
on breathing
(awake)
tests
Heart failure causes increased pulmonary vascular blood volume, followed by interstitial and thereafter alveolar oedema. Several studies have shown that patients with severe CHF have a restrictive ventilatory defect with slightly impaired diffusing capacity [19-211. Diffusing capacity is said to correlate inversely with PCWP [20]. Pulmonary restriction improves with medical therapy directed at the underlying CHF [19] or following heart transplant [21]. Following cardiac transplant, the improvement in functional residual capacity correlates significantly with the reduction in cardiac volume as estimated on chest radiograph [21], suggesting that much of the pulmonary restriction relates to cardiomegaly. As 50% of the body’s oxygen is stored within the lungs, reduced lung volumes due to CHF may contribute to hypoxaemia.
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M. T. Naughton
Pleural pressure
swings
During tidal breathing awake at rest, patients with CHF generate a 2-3-fold increase in the pleural pressures compared with control subjects [22] which diminish with medical therapy [23]. As pleural pressures equate with pericardial pressures, the larger subatmospheric pressures on inspiration in CHF contribute to a greater left ventricular afterload [24]. Reduced lung compliance, increased airway resistance [25] or increased respiratory drive (from vagal afferent stimulation [26] or the effects of sympathetic activity upon chemosensitivity) [27] are thought to be responsible for the larger subatmospheric pressures. As the pressure-respiratory rate product is also greater in CHF patients [22], respiratory effort (and possibly respiratory work) is greater than nonCHF controls. Accordingly the respiratory pump muscles require a greater proportion of cardiac output thereby creating a relative steal phenomenon [28].
Hypocapnia Patients with heart failure, who have central sleep apnoea, also have a tendency to have hypocapnia in the absence of hypoxaemia [lo] while awake. Whether this is due to an increased central CO, chemosensitivity [29] or simply a leftward shift in the CO, ventilatory response curve (due to tonically activated pulmonary vagi [26], peripheral chemoreceptors bathed in blood containing elevated levels of norepinephrine [27], or the effect of arousal state), remains to be determined.
Skeletal
myopathy
Skeletal myopathy may play a role in sleep disordered breathing [30,31], as has been proposed in exercise-induced dyspnoea [32]. The exercise limitation of patients with CHF cannot be explained by reduced cardiac output alone [33] and may in part be due to reduced skeletal and respiratory muscle strength [30,31,34]. Animals withpacinginduced CHF develop decreased diaphragm strength with increased fatiguability [32]. Three factors are thought to contribute to the skeletal myopathy of CHF, namely: (1) muscle hypoperfusion due to an attenuated pressor response to exercise; (2) abnormal vascular function; and (3) reduction in the intrinsic capacity of the muscle [32]. Recently the ventilatory response to exercise was reported to correlate with peripheral chemosensitivity, thereby suggesting a role for the carotid body in determining exercise capacity [33], analogous to the role that chemosensitivity plays in sleep disordered breathing in CHF [29,35].
Heart
failure
and obstructive
sleep apnoea
Introduction Obstructive sleep apnoea (OSA) is a condition in which repetitive upper airway obstructions occur during sleep giving rise to recurrent apnoeas. Three key pathological effects of obstructive apnoeas are: (1) large negative intrathoracic pressure swings; (2) hypoxaemia; and (3) arousals from sleep. Hypoxaemia and arousals lead to bursts of
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failure
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apnoea
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systemic hypertension which, like large negative intrathoracic pressure swings, act to increase left ventricular afterload. OSA may lead to heart failure if severe or in patients with co-existent cardiovascular risk factors.
Pathophysiology Negative intrathoracic pressures Negative intrathoracic pressure generated by futile inspiratory efforts against an occluded upper airway during sleep may reach as low as - 100 cmH,O ( - 75 mmHg). Several potentially harmful physiological events may occur such as: (1) an elevated pressure gradient across the LV wall (transmural pressure) [24,36-391; (2) distension of right ventricle and leftward shift of the interventricular septum with impedance to LV filling [36,40]; (3) an increase in LV end-systolic and end-diastolic volumes 136, 411; (4) reduced cardiac fibre shortening [36]; (5) im p airment of LV relaxation and prolongation of relaxation time, which further impede LV filling [36,40,42]. Overall there is an increase in cardiac work and energy expenditure. In subjects with normal cardiac function, the net haemodynamic effect is generally a transient reduction in stroke volume and cardiac output over the course of obstructive apnoeas that is proportional to the negative intrathoracic pressure generated [36,43]. Hypoxaemia Hypoxaemia related to apnoea can also have a number of detrimental cardiovascular effects. First, it causes pulmonary vasoconstriction, increases pulmonary artery pressure [44-46] and right ventricular afterload which can reduce cardiac output directly or indirectly by increasing leftward interventricular septal shift [40,47]. Second, hypoxia can reduce both myocardial contractility and impair myocardial relaxation (diastolic dysfunction), both of which could also decrease cardiac output [36,48]. Third, it increases sympathetic nervous system activity (SNA) [49] via stimulation of carotid body chemoreceptors [50], an effect potentiated when the sympatho-inhibitory effects of lung expansion are removed 1511. Resultant tachycardia reduces absolute diastole time, and thereby time for diastolic filling and coronary perfusion. Increased SNA to the peripheral vasculature will cause vasoconstriction and tend to increase systemic blood pressure [49,50]. Finally, hypoxia is also thought to promote atherogenesis, although mechanisms remain obscure [52,53]. Arousals Arousals usually terminate obstructive apnoeas by restoring upper airway dilator muscle tone and patency. In association with the abrupt increase in ventilation, SNA reaches a peak and then abruptly decreases [49]. The pathophysiology of sympathetic activation at the termination of apnoeas involves the combined effects of hypoxia, increases in Pco~, and the startle response related to arousals from sleep [49,54]. The sympathetic nervous system-mediated vasoconstriction contributes to the acute blood pressure increases at the termination of apnoeas since sympathetic blockade prevents them [55]. Stroke volume may indeed increase during the arousal period thereby contributing to the overall rise in blood pressure shortly after the arousal and helps explain why blood pressure rises to a peak shortly after arousal at a time when SNA is falling abruptly from its peak level 1491. A number of studies have also demonstrated increased SNA to skeletal muscles or plasma norepinephrine concentrations both
M. T. Naughton
98
during sleep and wakefulness in patients with OSA compared to control subjects [49,56]. These findings further point to the potential role of the SNA in mediating both acute and chronic elevations in blood pressure in patients with OSA.
Adverse
sequelae
Systemic hypertension Several studies have demonstrated that approximately 50% of patients with OSA have daytime hypertension [57]. In an epidemiological study, Hla et al. [58] showed that OSA was a risk factor for daytime hypertension independent of body weight, age and sex. Further evidence for a causal relationship between OSA and daytime hypertension was provided by Brooks et al. [59] They showed, in a chronic dog model, that OSA caused hypertension that was sustained into wakefulness. Although auditory stimuli caused acute rises in blood pressure during sleep of the same magnitude as those observed in response to intermittent obstructive apnoeas, only the recurrent obstructive apnoeas gave rise to sustained hypertension during wakefulness. Therefore, although arousals can increase blood pressure acutely, additional factors related to obstructive apnoea appear to be necessary for the development of awake hypertension. Increased thrombogenicity Intermittent hypoxia and elevations in SNA may be responsible for the increases in platelet aggregability [60] and fibrinogen levels [61] that have been reported in some patients with OSA. These factors, in combination with hypertension, could play a role in the precipitation of acute cardiac and cerebrovascular ischaemic events, and possibly even in progression of atherogenesis [62,63]. Cardiac failure OSA burdens the heart by increasing LV afterload, either through acute or chronic elevations in systemic blood pressure, or by generation of exaggerated negative intrathoracic pressure or a combination of the two. Obviously, chronic hypertension alone is a risk factor for LV hypertrophy and failure [1,3]. However, Hedner et al. [62] have also shown that normotensive patients with OSA have thicker LV walls than normotensive control subjects without OSA. These findings strongly suggest that even in the absence of daytime hypertension, intermittent sleep-related increases in LV afterload could lead to LV hypertrophy. Patients with OSA may also have mild degrees of LV dysfunction. This was suggested by an uncontrolled study in which long-term application of CPAP to patients with OSA, but with no history of cardiac disease and LV ejection fractions (LVEF) within the normal range, was associated with a small, but significant improvement in LVEF (from 59 to 63%) [64]. The adverse consequences of OSA on the cardiovascular system are liable to be more pronounced in individuals with diseased or failing hearts, which are sensitive to changes in afterload, than in those whose cardiac function is normal and relatively afterload insensitive [14,36,41]. Malone et al. [65] highlighted a very important relationship between CHF due to idiopathic dilated cardiomyopathy and OSA. Tempory reversal of OSA with CPAP treatment was associated with marked improvements in cardiac function and symptoms which returned to baseline once CPAP was withdrawn [65]. Cistulli et al. have reported that patients with Marfans syndrome have a high
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prevalence of OSA, probably related to upper airway skeletal and connective tissue abnormalities and resultant increased resistance [66]. Moreover, they have reported progression of aortic root dilatation in those with untreated OSA, which has major prognostic importance as survival is inversely related to aortic root diameter in such patients [66]. Importantly, progression of aortic root dilatation was arrested by the reversal of OSA with CPAP in two patients with Marfans syndrome [66]. lschaemia and arrhythmias Obstructive apnoeas can precipitate cardiac ischaemia in patients both with [67] and without 1681 a history of ischaemic heart disease. These ischaemic changes presumably arose from the combined effects of increased LV afterload, hypoxia and increased cardiac sympathetic activity and were prevented by CPAI? Patients with recent myocardial infarction or nocturnal angina have been reported to have a high prevalence of OSA [67,69]. Precipitation, or worsening of cardiac ischaemia by OSA could aggravate both systolic and diastolic left ventricular dysfunction, particularly in patients with CHF due to ischaemic cardiomyopathy [43,46]. Finally, since approximately one-third of patients with CHF die suddenly, presumably of cardiac arrhythmias [l/9], nocturnal cardiac arrhythmias triggered by OSA, including sinus bradycardia, second degree heart block, supraventricular and ventricular tachycardia [70,71] could adversely affect outcome in patients with CHF.
Therapy The approach to therapy of OSA in patients with CHF should, in general, be similar to that in patients without CHF. Weight loss in the obese, avoidance of alcohol and sedative medications that could increase the tendency for upper airway collapse, should be routinely recommended. Marked improvements in cardiac function can be noted in obese CHF patients who are able to lose substantial weight [72]. CPAP reliably abolishes obstructive apnoeas and in so doing should consolidate sleep, eliminate apnoea-related hypoxia, improve myocardial oxygen delivery, reduce SNA, and decrease LV afterload by increasing intrathoracic pressure and reducing blood pressure [49,65]. Abolition of OSA in CHF patients by CPAP could also reduce myocardial ischaemia [65,67] and cardiac arrhythmias. There is, however, only one study that has systematically addressed the effects of CPAP in patients with CHF and coexistent OSA [65]. Malone and coworkers [65] studied the effects of nocturnally administered CPAP over a l-month period in eight male patients with “idiopathic” dilated cardiomyopathy and coexistent OSA. In association with complete abolition of OSA by CPAP, there was a significant improvement in LVEF (from 37 to 49%) measured while awake in the daytime. Symptoms of sleep apnoea and CHF were improved. Following a l-week withdrawal of CPAP in a subset of four of these patients, there was a significant reduction in LVEF (from 53 to 45%) and worsening of symptoms. These data indicate that elimination of OSA by CPAP was responsible for the improvement in cardiac function and strongly suggests that OSA was contributing to the development of LV dysfunction. The effects of mandibular advancement devices and upper airway surgery have not been studied in patients with OSA and CHF. However, one should exercise caution
100
M. T. Naughton
in their use in this setting. Because these treatments seldom provide ination of OSA 1731, they may prove not to be effective in improving The risks of general anaesthesia for elective upper airway surgery CHF must also be taken into consideration. Where general measures alleviating OSA and CPAP is poorly tolerated, tracheostomy may be alternative therapy because it should abolish OSA [74].
complete elimcardiac function. in patients with are ineffective in considered as an
Conclusion Obstructive sleep apnoea creates a unique set of physiological events which are likely to aggravate CHF. Acutely during sleep, there are elevations in systemic blood pressure combined with reductions in intrathoracic pressures associated with fragmentation and loss of sleep and asphyxia-related derangements in blood gas tensions. Over months to years there may be resetting of chemoreceptors and baroreceptors that allow the night-time physiological derangement to spill over to the day-time and thereby allow systemic and pulmonary pressures to rise and hypoxaemia-hypercapnia to occur. Practice Points In patients with heart f&me: 1, Approximately 30% of such patients Will have diastolic rather than systolic heart
‘,I; failure. ‘2. ‘Obstructive sleep ajmoea should be considered as a contributing factor to the ‘..,: development of both forms of heart failure. 3.’ Treatment of obstructive sleep apnoea with mandibular advancement splints or upper aitiay surgery should only be used with great caution until further “’ ”‘evidence regarding their efficacy becomes available. Research Agenda
Future directions for research should include: 1.. Examining the importance of obstructive sleep ,Iheart failure relative to other more “established” 2, Determination of the night-to-night variability of with medical therapy for heart failure. 3:, Larger and longer term studies of the effect of , dysfunction.
apnoea in the pathogenesis of risk factors. obstructive and central apnoea apnoea reversal upon cardiac
References *l Garg R, Packer M, Pitt B et al. Heart failure in the 1990s: evolution of a major problem in cardiovascular medicine. J Am Co11 Cardiol 1993; 22: 3A-5A.
* The most important
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by an asterisk.
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health
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and obstructive
apnoea
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