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Obstructive Sleep Apnoea, Congestive Heart Failure and Cardiovascular Disease
ORIGINAL ARTICLE
Original Article
Obstructive Sleep Apnoea, Congestive Heart Failure and Cardiovascular Disease Darren Mansfield, MD, PhD a,∗ and Matthew T. Naughton, MD b a
Epworth Sleep Centre, Epworth Hospital, Richmond, Melbourne, Victoria, Australia Departmemt of Respiratory Medicine, Alfred Hospital Melbourne, Vic., Australia
b
Sleep disordered breathing is a common condition within the general community. Mostly this is represented by obstructive sleep apnoea (OSA), a condition characterized by repetitive occlusions of the upper airway due to retropositioning of the tongue and pharyngeal collapse during sleep. This article covers the key evidence relating OSA to both causation and progression of congestive heart failure and cardiovascular disease including hypertension. The results of recent studies are summarized, and the authors conclude that whilst progress has been made, there remain many gaps in our knowledge in relation to the contribution to the burden of cardiac disease produced by associated conditions such as OSA. Larger studies with important primary endpoints will be required to demonstrate the merit of screening and treating this disorder. (Heart Lung and Circulation 2005;14S:S2–S7) © 2005 Published by Elsevier Inc on behalf of Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand.
Introduction
C
ongestive heart failure (CHF) remains a leading cause of morbidity and mortality in western communities. Despite many interventions that have lowered mortality, it remains a substantial cause of premature death and disease. Although the mortality associated with CHF is appearing to fall with the widespread usage of ACE inhibition, beta blockade and aldosterone antagonism, this condition continues to have an unacceptable mortality rate of 50% over 5 years.1 Heart transplantation and more recent innovations, such as biventricular pacing and ventricular assist devices, may be effective strategies for individuals with CHF but not readily available to the widespread heart failure community. In order to make further inroads in the prevention and treatment of this disorder a great deal of attention has been given to the importance of sleep apnoea and its potential role in both causation and progression of CHF and other cardiovascular diseases. Sleep disordered breathing is a common condition within the general community. Mostly this is represented by obstructive sleep apnoea (OSA), a condition characterized by repetitive occlusions of the upper airway due to retro-positioning of the tongue and pharyngeal collapse during sleep. When the condition causes symptoms related to sleep fragmentation, the prevalence is esti∗ Corresponding author. Mailing address: 89 Bridge Road, Richmond, Victoria 3121, Australia. Tel.: +61 3 9427 1849; fax: + 61 3 9427 8522. E-mail address: [email protected] (D. Mansfield).
mated to be around 4% of adult males and 2% of adult females.2 This article covers the key evidence relating OSA to both causation and progression of CHF and cardiovascular disease including hypertension.
Obstructive Sleep Apnoea and Heart Disease Background Sleep is associated with loss of skeletal muscle tone including the upper airway muscles. Upper airway collapse may result in producing a partial (hypopnoea) or complete (apnoea) cessation of airflow. This leads to ineffective ventilation despite vigorous inspiratory efforts producing episodic hypoxemia and hypercapnia and exaggerated negative intrathoracic pressures. An arousal is an important consequence of an apnoea as it leads to return of muscle tone, patency of the airway and resumption of respiration. Arousals are usually brief and unconscious and the return to sleep exposes the individual to the potential for recurrence. There are numerous predispositions to obstructive sleep apnoea. These include anatomical factors such as retrognathia, inferior hyoid bone, high arched palate and increased nasal resistance. Obesity is an acquired anatomical risk by its effect on tongue size and increase in pharyngeal mural pressures predisposing to collapse. Other factors affect upper airway reflexes and arousal thresholds. Of particular importance is alcohol and sedative medication.
© 2005 Published by Elsevier Inc on behalf of Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand.
1443-9506/04/$30.00 doi:10.1016/j.hlc.2005.08.010
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Acute Physiological Effects of Obstructive Sleep Apnoea Autonomic Activity Normal lung inflation is associated with an inhibitory effect on sympathetic outflow.3 Conversely, an episode of breath holding (quiescent respiration) or an obstructive apnoea (sequential inspiratory efforts against closed airway) leads to inhibition of respiration, which escalates rates of sympathetic nerve discharge. The mechanisms behind the escalation of sympathetic discharge during breath holding or and obstructive apnoea are likely to be multifactorial. Sympathetic discharge that develops over the time course of either a breath-holding episode or obstructive apnoea is eliminated by supplemental oxygen administration.4 Hypoxia may be an important component of this. Other studies have also observed the effect of hypoxia acute sympathetic augmentation5,6 mediated through the peripheral chemoreceptor. Hypercapnia is also shown to produce an escalation of sympathetic nerve activity. Surgical denervation of the carotid body in rats has been shown to negate the effect of chronic intermittent hypoxia on the development of hypertension.7 Sympathetic nerve excitation is abruptly terminated at end expiration. The mechanism behind the observation remains a topic of debate. The reduction coincides precisely with resumption of ventilation, yet the nadir of O2 desaturation is yet to arrive at the peripheral chemoreceptor.8 This observation suggests the involvement of reflex mechanisms such as lung inflation or baroreceptor activity in switching off sympathetic activity, even if these factors are shown to be less important in generating the magnitude of the sympathetic response.
Haemodynamic Effects Obstructive apnoeas is associated with ventilation against an occluded airway. Attempts at inflating the lung in the absence of airflow are associated with a fall in intrathoracic pressure. The fluctuations in intrathoracic pressure during repetitive ventilatory efforts against a closed airway unfavourably affect cardiac preload and afterload. Cardiac afterload is determined by the left ventricular transmural pressure. This is determined by subtracting the intrathoracic pressure from the left ventricular end systolic pressure9 (Fig. 1). The resultant effect of exaggerated falls in intrathoracic pressure during inspiration increases in left ventricular afterload. Coincidentally, venous return increases due to a fall in central venous pressure. The consequent increase in right ventricular end diastolic volume has a significant effect on left ventricular filling. This observation, termed ventricular interdependence arises through both left and right ventricles sharing a common septum. The positioning of the septum will depend on comparative left or right ventricular end diastolic volumes and will directly affect filling of the corresponding ventricle.10 The effect of increased afterload and reduced preload is a reduction in stroke volume11–13 and cardiac output14
Figure 1. Diagram of intrathoracic pressure changes in: (a) normal ventilation; (b) obstructive sleep apnoea; and (c) CPAP therapy.
which appears to be directly related to magnitude of the intrathoracic pressure drop.13,15
Arousal Responses Arousal from sleep terminates apnoea through resumption of upper airway reflexes and return of muscle tone, which restores airway patience. Arousal responses may play an essential protective role against the consequences of prolonged apnoea. There are three mechanisms by which an arousal may occur to terminate the apnoea. Arousals are triggered by the effects of increases in ventilatory effort16 and hypoxia,17 and to a lesser degree, hypercapnia.18 This leads to apnoea termination and resumption of ventilation. Isolated arousals in the absence of an apnoea are associated with a small and transient increase in blood pressure with a small sympathetic discharge.19 An arousal associated with apnoea termination results is at least twice the haemodynamic response as a
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result of increased sympathetic tone, vasoconstriction and increased cardiac output. Experiments in dogs have shown that arousal appears to have a direct effect on cardiac sympathetic activity independent from effects of arterial blood gases, lung volume or ventilation.20 Despite this, the peak hypertensive response to apnoea coincides with the nadir of desaturation (5–7 s postapnoea), highlighting the importance of hypoxic mediated effects on sympathetic nerve activity and consequent blood pressure responses.
Chronic Physiological Effects Sympathetic Nerve Activity Repetitive hypoxia leads to sustained elevations in sympathetic nerve activity.8 More than hypercapnia, hypoxia appears to underpin these chronic physiological changes in sympathetic tone.21 Other reports demonstrate that persistent elevation of sympathetic nerve activity occurs if the hypoxic stimulus is either sustained5 or intermittent as is observed in OSA.22 Patients with severe obstructive sleep apnoea have been shown to have persistent elevation of sympathetic tone8 which attenuates over time with appropriate CPAP therapy.23,24 This finding may explain the coexistence of chronic hypertension frequently observed in this population.
Peripheral Endothelial Function Endothelial dysfunction has been associated with cardiovascular disease. Much attention has turned to the effects of sleep apnoea and its associated repetitive hypoxic insults on vascular function. Endothelin-1 is an acute vasoconstrictor and an indirect measure of endothelial function. Endothelin levels have been shown to be normal in some studies of OSA patients25,26 but have been shown to rise acutely with the onset of OSA in another27 and chronic elevation been shown in a fourth study.28 Further work in this area is required in order to implicate endothelin-1 in the pathogenesis of vascular dysfunction associated with OSA. Direct measures of vascular function can be performed by measuring vasodilatory responses to hypoxia, flow mediated vasodilation in response to ischaemia or infusion of vasoactive substances. Hedner et al. have shown that patients with severe OSA exposed to isocapnic hypoxia have an abnormal large presser response compared to control subjects. This results from an exaggerated vasocontrictor response to hypoxia.29 Forearm infusion of vasoactive substances such as acetyl-choline were not shown to demonstrate abnormal endothelial function in one study,30 yet others have shown reduced dilator responses to forearm infusions of acetylcholine31,32 and nitroprusside.31 More recently numerous other hormones related to the vascular system have been implicated in OSA. Homocysteine,33 angiotensin II34 brain natiuretic peptide35 and insulin levels36 have been shown to be elevated. The precise significance of these findings remains to be established.
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Outcomes Systemic Hypertension It is commonly accepted that OSA causally contributes to the development of hypertension and is often regarded as the most common cause of secondary hypertension. However a critical evaluation of the studies in this area leave room for doubt . . .. A causal link between OSA and hypertension has been aggressively explored on the basis of a high biological plausibility. The effects of hypoxia, hypercapnia, baroreceptor desensitization and arousal responses all serve to potentially contribute to acute and chronic augmentation of the sympathetic nervous system. Sympathetic activation remains the most popular and likely explanation for the development of chronic hypertension should a causal relationship be proven. Patients with OSA fail to demonstrate the normal nocturnal dipping of blood pressure during sleep.37 Non-dipping may be a feature more characteristic of underlying OSA as distinct from the hypertensive population without OSA.38 Also the characteristics of ‘‘dippers’’ and ‘‘nondippers’’ may be obscured by nocturnal arousal as a result of automatic cuff inflation in ambulatory blood pressure monitoring. Consequently some studies have questioned the precision of intermittent BP recording.39 Continuous non-invasive blood pressure recordings with photoplethysmography do not interfere with sleep and thus may be better suited for overnight continuous blood pressure monitoring. Epidemiological data have shown a relationship between obstructive sleep apnoea and hypertension in both general40–43 and CHF populations.44 Four large observational studies of unselected patients have shown a relationship between OSA and hypertension independent of known confounding variables. The studies ranged from sample sizes of 1000 in the Wisconsin cohort (Young et al.)40,41 to 6000 patients in the Sleep Heart Health Study.45 The odds ratio for the association of hypertension varied from 4.15 in the Wisconsin cohort to 1.37 in the larger Sleep Heart Health Study. Peppard et al.43 have performed a prospective study to determine if the presence of OSA is a risk factor for the future development of hypertension. They recruited over 700 patients who were observed over a minimum 4-year period. Compared to patients without sleep disordered breathing (AHI = 0), the odds ratio of developing hypertension over a minimum of 4 years with sleep apnoea (AHI > 15/h) when controlled for age, gender, body mass index and alcohol, was highly significant at 2.89. Whilst these epidemiological trials are large, well designed and executed, with concordant findings, a causal link cannot be proven from observational data of this kind. Interventional trials can generally overcome the potential (unknown or uncontrolled for) confounding influences. A number of randomized controlled trials examining the effect of alleviating OSA on blood pressure have produced mixed results due to variations in patient selection and methodology. A curiosity that applies to all of these studies pertains to the fact that hypertension
Mansfield and Naughton Obstructive sleep apnoea, congestive heart failure and cardiovascular disease
was not an inclusion criteria. Lowering blood pressure in normotension is difficult. Two randomized controlled trials have shown no collective effect on daytime blood pressure in patients who underwent treatment with CPAP for OSA.46,47 In a controlled parallel designed trial of 118 patients with OSA (23% with hypertension), mean systemic pressure fell with CPAP by 2.5 mmHg (delta between groups 3.3 mmHg) over 4 weeks. The effect was most pronounced in the severe OSA group and hypertensive patients (6.6 mmHg fall in mean systemic blood pressure).48 In another study of a cross over design of 68 patients (all normotensive), average 24 h diastolic blood pressure was shown to fall by 1.5 mmHg over 4 weeks.49 The majority of this effect was attributed to improvements in nocturnal blood pressure and the greatest effect was seen in patients with more severe OSA (in which systolic blood pressure also fell). This study had no hypertensive patients which may have accounted for the minor effects CPAP achieved on overall blood pressure. One study has shown a large blood pressure fall with CPAP therapy in OSA. This study selected 60 moderate to severe OSA patients and a high percentage of hypertension (66%) over 9-week average period in a randomized parallel design.50 Continuous non-invasive blood pressure measurements demonstrated a very large reduction in mean arterial pressure of 9.9 mmHg in the intervention group. Although this study generated impressive results, it was limited by an unusually large dropout rate of 49% for ‘‘technical issues’’ and inadvertent introduction of new antihypertensives during the trial period. The epidemiological data are consistent yet the interventional trials are suggestive but not conclusive in their findings. There is a general trend observed even among the negative studies toward a more significant response among patients with either more severe hypertension and/or more severe OSA. Clinical questions of the importance of OSA in the development of hypertension and the capacity for alleviation of OSA to mediate blood pressure reductions are best addressed by studying the relevant population of hypertensive subjects. All of the above interventional trials have failed to do this.
Congestive Heart Failure The relationship between hypertension and OSA remains unclear in its magnitude; however, the association between OSA and cardiovascular diseases remains to be more extensively studied. Intervention trials in this context are difficult to conduct when leaving control groups of OSA untreated for extended timeframes, and to date have not been performed. A number of cross sectional studies have linked a relationship of OSA to coronary artery disease.42,51,52 The Sleep Heart Health Study is the largest currently available database examining relationships between sleep apnoea and cardiovascular endpoints.42 In this study 6424 patients underwent unattended polysomnography of which 16% reported data of cardiovascular disease (myocardial infarction, angina, coronary revascularization
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procedure, heart failure, or stroke). The relative odds of OSA being associated with cardiovascular disease were 1.42 when controlled for known confounders. The odds of OSA being associated with CHF were greater at 2.38. Conversely OSA is also shown to be prevalent among patients with CHF estimated between 11 and 37%.53–55 The pathophysiological consequences of OSA could plausibly lead to the progression of underlying CHF including escalated sympathetic nerve activity and ventricular ectopy.56 A number of case reports and uncontrolled trials have suggested that heart function improves if co-existent OSA is identified and treated. Malone et al. evaluated 8 patients with idiopathic dilated cardiomyopathy and severe OSA.57 Their uncontrolled report found a 12% improvement in left ventricular ejection fraction (LVEF) after 4 weeks of nasal CPAP. Furthermore, in all four patients in whom CPAP was withdrawn, LVEF fell by 8% after one week. Given such a large improvement in LVEF, putting many of the eight patients into the normal range, some have speculated that OSA may be a cause rather than just a contributor to idiopathic dilated cardiomyopathy. Other small uncontrolled studied have shown improvements in ejection fraction if OSA is alleviated in absence58,59 and presence of systolic dysfunction.60 Small patient numbers and uncontrolled study design have limited all these trials. Recently two trials have shown improvement in heart function with CPAP in randomized controlled study design.61,62 In the trial by Kaneko et al., 24 patients with coexistent CHF and OSA were randomized to one month of CPAP or no treatment. An improvement of 8.8% in left ventricular ejection fraction (LVEF) was observed in the CPAP group after 1 month of treatment. A fall in mean systemic blood pressure by 10 mmHg was also demonstrated. In a larger patient series over three months, our group showed a 5% improvement in 55 patients with less severe CHF and mild to moderate OSA. We also showed that this improvement was associated with a one third fall in overnight urinary catecholamine excretion and improved quality of life scores. These studies were small yet promising in their results. Larger randomized controlled trials are required before firm conclusions as to the magnitude of the burden of disease that OSA contributes in the heart failure population. MORTALITY. Several mortality studies have been recently published which further supports the relationship between obstructive sleep apnoea and cardiovascular disease.63–65 Doherty et al.64 compared survival between 168 OSA patients who were compliant with (107 patients) or intolerant of CPAP (61 patients) over an average 7.5year period. Despite the untreated group having less severe sleep apnoea they incurred a mortality rate of 14.8% compared to the CPAP tolerant group of 1.9%. CamposRodriguez et al. analyzed 871 patients over a 5-year period with OSA who had been recommended CPAP treatment. Survival among the CPAP non-compliant group was significantly lower than the fully compliant group (85.5% versus 96.4%, p = 0.01). Marin et al.63 demonstrated that the mortality impact of OSA is dose dependant. Two hun-
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dred and sixty-four healthy males, 377 simple snorers, 403 patients with untreated mild/moderate sleep apnoea, 372 patients with severe OSA compliant on CPAP and 235 patients with severe OSA unable to comply with CPAP were studied over average 10.1-year period. This study demonstrated a risk of fatal (odds ratio 2.87) and non-fatal (odds ratio 3.17) cardiovascular events compared to the healthy population. Simple snorers did not appear to have excess mortality. Although controlled for confounding variables, these studies support but do not prove a relationship between OSA and excess mortality. The comparator of untreated OSA because of compliance problems introduces an unmeasurable study bias that undoubtedly exaggerates the findings. The ideal study that randomizes patients with OSA to treatment or no treatment poses an ethical challenge.
Conclusion Despite the results of recent trials, there remain many gaps in our knowledge in relation to the contribution to the burden of cardiac disease produced by associated conditions such as OSA. In order to engage a greater level of interest from cardiologists and general physicians alike, larger studies with important primary endpoints will be required. Such trials are achievable and will be ultimately necessary in order to convince all health care providers of the merit of screening and treating this disorder.
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Heart Lung and Circulation 2005;14S:S2–S7
Original Article
Obstructive Sleep Apnoea, Congestive Heart Failure and Cardiovascular Disease Darren Mansfield, MD, PhD a,∗ and Matthew T. Naughton, MD b a
Epworth Sleep Centre, Epworth Hospital, Richmond, Melbourne, Victoria, Australia Departmemt of Respiratory Medicine, Alfred Hospital Melbourne, Vic., Australia
b
Sleep disordered breathing is a common condition within the general community. Mostly this is represented by obstructive sleep apnoea (OSA), a condition characterized by repetitive occlusions of the upper airway due to retropositioning of the tongue and pharyngeal collapse during sleep. This article covers the key evidence relating OSA to both causation and progression of congestive heart failure and cardiovascular disease including hypertension. The results of recent studies are summarized, and the authors conclude that whilst progress has been made, there remain many gaps in our knowledge in relation to the contribution to the burden of cardiac disease produced by associated conditions such as OSA. Larger studies with important primary endpoints will be required to demonstrate the merit of screening and treating this disorder. (Heart Lung and Circulation 2005;14S:S2–S7) © 2005 Published by Elsevier Inc on behalf of Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand.
Introduction
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ongestive heart failure (CHF) remains a leading cause of morbidity and mortality in western communities. Despite many interventions that have lowered mortality, it remains a substantial cause of premature death and disease. Although the mortality associated with CHF is appearing to fall with the widespread usage of ACE inhibition, beta blockade and aldosterone antagonism, this condition continues to have an unacceptable mortality rate of 50% over 5 years.1 Heart transplantation and more recent innovations, such as biventricular pacing and ventricular assist devices, may be effective strategies for individuals with CHF but not readily available to the widespread heart failure community. In order to make further inroads in the prevention and treatment of this disorder a great deal of attention has been given to the importance of sleep apnoea and its potential role in both causation and progression of CHF and other cardiovascular diseases. Sleep disordered breathing is a common condition within the general community. Mostly this is represented by obstructive sleep apnoea (OSA), a condition characterized by repetitive occlusions of the upper airway due to retro-positioning of the tongue and pharyngeal collapse during sleep. When the condition causes symptoms related to sleep fragmentation, the prevalence is esti∗ Corresponding author. Mailing address: 89 Bridge Road, Richmond, Victoria 3121, Australia. Tel.: +61 3 9427 1849; fax: + 61 3 9427 8522. E-mail address: [email protected] (D. Mansfield).
mated to be around 4% of adult males and 2% of adult females.2 This article covers the key evidence relating OSA to both causation and progression of CHF and cardiovascular disease including hypertension.
Obstructive Sleep Apnoea and Heart Disease Background Sleep is associated with loss of skeletal muscle tone including the upper airway muscles. Upper airway collapse may result in producing a partial (hypopnoea) or complete (apnoea) cessation of airflow. This leads to ineffective ventilation despite vigorous inspiratory efforts producing episodic hypoxemia and hypercapnia and exaggerated negative intrathoracic pressures. An arousal is an important consequence of an apnoea as it leads to return of muscle tone, patency of the airway and resumption of respiration. Arousals are usually brief and unconscious and the return to sleep exposes the individual to the potential for recurrence. There are numerous predispositions to obstructive sleep apnoea. These include anatomical factors such as retrognathia, inferior hyoid bone, high arched palate and increased nasal resistance. Obesity is an acquired anatomical risk by its effect on tongue size and increase in pharyngeal mural pressures predisposing to collapse. Other factors affect upper airway reflexes and arousal thresholds. Of particular importance is alcohol and sedative medication.
© 2005 Published by Elsevier Inc on behalf of Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand.
1443-9506/04/$30.00 doi:10.1016/j.hlc.2005.08.010
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Acute Physiological Effects of Obstructive Sleep Apnoea Autonomic Activity Normal lung inflation is associated with an inhibitory effect on sympathetic outflow.3 Conversely, an episode of breath holding (quiescent respiration) or an obstructive apnoea (sequential inspiratory efforts against closed airway) leads to inhibition of respiration, which escalates rates of sympathetic nerve discharge. The mechanisms behind the escalation of sympathetic discharge during breath holding or and obstructive apnoea are likely to be multifactorial. Sympathetic discharge that develops over the time course of either a breath-holding episode or obstructive apnoea is eliminated by supplemental oxygen administration.4 Hypoxia may be an important component of this. Other studies have also observed the effect of hypoxia acute sympathetic augmentation5,6 mediated through the peripheral chemoreceptor. Hypercapnia is also shown to produce an escalation of sympathetic nerve activity. Surgical denervation of the carotid body in rats has been shown to negate the effect of chronic intermittent hypoxia on the development of hypertension.7 Sympathetic nerve excitation is abruptly terminated at end expiration. The mechanism behind the observation remains a topic of debate. The reduction coincides precisely with resumption of ventilation, yet the nadir of O2 desaturation is yet to arrive at the peripheral chemoreceptor.8 This observation suggests the involvement of reflex mechanisms such as lung inflation or baroreceptor activity in switching off sympathetic activity, even if these factors are shown to be less important in generating the magnitude of the sympathetic response.
Haemodynamic Effects Obstructive apnoeas is associated with ventilation against an occluded airway. Attempts at inflating the lung in the absence of airflow are associated with a fall in intrathoracic pressure. The fluctuations in intrathoracic pressure during repetitive ventilatory efforts against a closed airway unfavourably affect cardiac preload and afterload. Cardiac afterload is determined by the left ventricular transmural pressure. This is determined by subtracting the intrathoracic pressure from the left ventricular end systolic pressure9 (Fig. 1). The resultant effect of exaggerated falls in intrathoracic pressure during inspiration increases in left ventricular afterload. Coincidentally, venous return increases due to a fall in central venous pressure. The consequent increase in right ventricular end diastolic volume has a significant effect on left ventricular filling. This observation, termed ventricular interdependence arises through both left and right ventricles sharing a common septum. The positioning of the septum will depend on comparative left or right ventricular end diastolic volumes and will directly affect filling of the corresponding ventricle.10 The effect of increased afterload and reduced preload is a reduction in stroke volume11–13 and cardiac output14
Figure 1. Diagram of intrathoracic pressure changes in: (a) normal ventilation; (b) obstructive sleep apnoea; and (c) CPAP therapy.
which appears to be directly related to magnitude of the intrathoracic pressure drop.13,15
Arousal Responses Arousal from sleep terminates apnoea through resumption of upper airway reflexes and return of muscle tone, which restores airway patience. Arousal responses may play an essential protective role against the consequences of prolonged apnoea. There are three mechanisms by which an arousal may occur to terminate the apnoea. Arousals are triggered by the effects of increases in ventilatory effort16 and hypoxia,17 and to a lesser degree, hypercapnia.18 This leads to apnoea termination and resumption of ventilation. Isolated arousals in the absence of an apnoea are associated with a small and transient increase in blood pressure with a small sympathetic discharge.19 An arousal associated with apnoea termination results is at least twice the haemodynamic response as a
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result of increased sympathetic tone, vasoconstriction and increased cardiac output. Experiments in dogs have shown that arousal appears to have a direct effect on cardiac sympathetic activity independent from effects of arterial blood gases, lung volume or ventilation.20 Despite this, the peak hypertensive response to apnoea coincides with the nadir of desaturation (5–7 s postapnoea), highlighting the importance of hypoxic mediated effects on sympathetic nerve activity and consequent blood pressure responses.
Chronic Physiological Effects Sympathetic Nerve Activity Repetitive hypoxia leads to sustained elevations in sympathetic nerve activity.8 More than hypercapnia, hypoxia appears to underpin these chronic physiological changes in sympathetic tone.21 Other reports demonstrate that persistent elevation of sympathetic nerve activity occurs if the hypoxic stimulus is either sustained5 or intermittent as is observed in OSA.22 Patients with severe obstructive sleep apnoea have been shown to have persistent elevation of sympathetic tone8 which attenuates over time with appropriate CPAP therapy.23,24 This finding may explain the coexistence of chronic hypertension frequently observed in this population.
Peripheral Endothelial Function Endothelial dysfunction has been associated with cardiovascular disease. Much attention has turned to the effects of sleep apnoea and its associated repetitive hypoxic insults on vascular function. Endothelin-1 is an acute vasoconstrictor and an indirect measure of endothelial function. Endothelin levels have been shown to be normal in some studies of OSA patients25,26 but have been shown to rise acutely with the onset of OSA in another27 and chronic elevation been shown in a fourth study.28 Further work in this area is required in order to implicate endothelin-1 in the pathogenesis of vascular dysfunction associated with OSA. Direct measures of vascular function can be performed by measuring vasodilatory responses to hypoxia, flow mediated vasodilation in response to ischaemia or infusion of vasoactive substances. Hedner et al. have shown that patients with severe OSA exposed to isocapnic hypoxia have an abnormal large presser response compared to control subjects. This results from an exaggerated vasocontrictor response to hypoxia.29 Forearm infusion of vasoactive substances such as acetyl-choline were not shown to demonstrate abnormal endothelial function in one study,30 yet others have shown reduced dilator responses to forearm infusions of acetylcholine31,32 and nitroprusside.31 More recently numerous other hormones related to the vascular system have been implicated in OSA. Homocysteine,33 angiotensin II34 brain natiuretic peptide35 and insulin levels36 have been shown to be elevated. The precise significance of these findings remains to be established.
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Outcomes Systemic Hypertension It is commonly accepted that OSA causally contributes to the development of hypertension and is often regarded as the most common cause of secondary hypertension. However a critical evaluation of the studies in this area leave room for doubt . . .. A causal link between OSA and hypertension has been aggressively explored on the basis of a high biological plausibility. The effects of hypoxia, hypercapnia, baroreceptor desensitization and arousal responses all serve to potentially contribute to acute and chronic augmentation of the sympathetic nervous system. Sympathetic activation remains the most popular and likely explanation for the development of chronic hypertension should a causal relationship be proven. Patients with OSA fail to demonstrate the normal nocturnal dipping of blood pressure during sleep.37 Non-dipping may be a feature more characteristic of underlying OSA as distinct from the hypertensive population without OSA.38 Also the characteristics of ‘‘dippers’’ and ‘‘nondippers’’ may be obscured by nocturnal arousal as a result of automatic cuff inflation in ambulatory blood pressure monitoring. Consequently some studies have questioned the precision of intermittent BP recording.39 Continuous non-invasive blood pressure recordings with photoplethysmography do not interfere with sleep and thus may be better suited for overnight continuous blood pressure monitoring. Epidemiological data have shown a relationship between obstructive sleep apnoea and hypertension in both general40–43 and CHF populations.44 Four large observational studies of unselected patients have shown a relationship between OSA and hypertension independent of known confounding variables. The studies ranged from sample sizes of 1000 in the Wisconsin cohort (Young et al.)40,41 to 6000 patients in the Sleep Heart Health Study.45 The odds ratio for the association of hypertension varied from 4.15 in the Wisconsin cohort to 1.37 in the larger Sleep Heart Health Study. Peppard et al.43 have performed a prospective study to determine if the presence of OSA is a risk factor for the future development of hypertension. They recruited over 700 patients who were observed over a minimum 4-year period. Compared to patients without sleep disordered breathing (AHI = 0), the odds ratio of developing hypertension over a minimum of 4 years with sleep apnoea (AHI > 15/h) when controlled for age, gender, body mass index and alcohol, was highly significant at 2.89. Whilst these epidemiological trials are large, well designed and executed, with concordant findings, a causal link cannot be proven from observational data of this kind. Interventional trials can generally overcome the potential (unknown or uncontrolled for) confounding influences. A number of randomized controlled trials examining the effect of alleviating OSA on blood pressure have produced mixed results due to variations in patient selection and methodology. A curiosity that applies to all of these studies pertains to the fact that hypertension
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was not an inclusion criteria. Lowering blood pressure in normotension is difficult. Two randomized controlled trials have shown no collective effect on daytime blood pressure in patients who underwent treatment with CPAP for OSA.46,47 In a controlled parallel designed trial of 118 patients with OSA (23% with hypertension), mean systemic pressure fell with CPAP by 2.5 mmHg (delta between groups 3.3 mmHg) over 4 weeks. The effect was most pronounced in the severe OSA group and hypertensive patients (6.6 mmHg fall in mean systemic blood pressure).48 In another study of a cross over design of 68 patients (all normotensive), average 24 h diastolic blood pressure was shown to fall by 1.5 mmHg over 4 weeks.49 The majority of this effect was attributed to improvements in nocturnal blood pressure and the greatest effect was seen in patients with more severe OSA (in which systolic blood pressure also fell). This study had no hypertensive patients which may have accounted for the minor effects CPAP achieved on overall blood pressure. One study has shown a large blood pressure fall with CPAP therapy in OSA. This study selected 60 moderate to severe OSA patients and a high percentage of hypertension (66%) over 9-week average period in a randomized parallel design.50 Continuous non-invasive blood pressure measurements demonstrated a very large reduction in mean arterial pressure of 9.9 mmHg in the intervention group. Although this study generated impressive results, it was limited by an unusually large dropout rate of 49% for ‘‘technical issues’’ and inadvertent introduction of new antihypertensives during the trial period. The epidemiological data are consistent yet the interventional trials are suggestive but not conclusive in their findings. There is a general trend observed even among the negative studies toward a more significant response among patients with either more severe hypertension and/or more severe OSA. Clinical questions of the importance of OSA in the development of hypertension and the capacity for alleviation of OSA to mediate blood pressure reductions are best addressed by studying the relevant population of hypertensive subjects. All of the above interventional trials have failed to do this.
Congestive Heart Failure The relationship between hypertension and OSA remains unclear in its magnitude; however, the association between OSA and cardiovascular diseases remains to be more extensively studied. Intervention trials in this context are difficult to conduct when leaving control groups of OSA untreated for extended timeframes, and to date have not been performed. A number of cross sectional studies have linked a relationship of OSA to coronary artery disease.42,51,52 The Sleep Heart Health Study is the largest currently available database examining relationships between sleep apnoea and cardiovascular endpoints.42 In this study 6424 patients underwent unattended polysomnography of which 16% reported data of cardiovascular disease (myocardial infarction, angina, coronary revascularization
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procedure, heart failure, or stroke). The relative odds of OSA being associated with cardiovascular disease were 1.42 when controlled for known confounders. The odds of OSA being associated with CHF were greater at 2.38. Conversely OSA is also shown to be prevalent among patients with CHF estimated between 11 and 37%.53–55 The pathophysiological consequences of OSA could plausibly lead to the progression of underlying CHF including escalated sympathetic nerve activity and ventricular ectopy.56 A number of case reports and uncontrolled trials have suggested that heart function improves if co-existent OSA is identified and treated. Malone et al. evaluated 8 patients with idiopathic dilated cardiomyopathy and severe OSA.57 Their uncontrolled report found a 12% improvement in left ventricular ejection fraction (LVEF) after 4 weeks of nasal CPAP. Furthermore, in all four patients in whom CPAP was withdrawn, LVEF fell by 8% after one week. Given such a large improvement in LVEF, putting many of the eight patients into the normal range, some have speculated that OSA may be a cause rather than just a contributor to idiopathic dilated cardiomyopathy. Other small uncontrolled studied have shown improvements in ejection fraction if OSA is alleviated in absence58,59 and presence of systolic dysfunction.60 Small patient numbers and uncontrolled study design have limited all these trials. Recently two trials have shown improvement in heart function with CPAP in randomized controlled study design.61,62 In the trial by Kaneko et al., 24 patients with coexistent CHF and OSA were randomized to one month of CPAP or no treatment. An improvement of 8.8% in left ventricular ejection fraction (LVEF) was observed in the CPAP group after 1 month of treatment. A fall in mean systemic blood pressure by 10 mmHg was also demonstrated. In a larger patient series over three months, our group showed a 5% improvement in 55 patients with less severe CHF and mild to moderate OSA. We also showed that this improvement was associated with a one third fall in overnight urinary catecholamine excretion and improved quality of life scores. These studies were small yet promising in their results. Larger randomized controlled trials are required before firm conclusions as to the magnitude of the burden of disease that OSA contributes in the heart failure population. MORTALITY. Several mortality studies have been recently published which further supports the relationship between obstructive sleep apnoea and cardiovascular disease.63–65 Doherty et al.64 compared survival between 168 OSA patients who were compliant with (107 patients) or intolerant of CPAP (61 patients) over an average 7.5year period. Despite the untreated group having less severe sleep apnoea they incurred a mortality rate of 14.8% compared to the CPAP tolerant group of 1.9%. CamposRodriguez et al. analyzed 871 patients over a 5-year period with OSA who had been recommended CPAP treatment. Survival among the CPAP non-compliant group was significantly lower than the fully compliant group (85.5% versus 96.4%, p = 0.01). Marin et al.63 demonstrated that the mortality impact of OSA is dose dependant. Two hun-
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dred and sixty-four healthy males, 377 simple snorers, 403 patients with untreated mild/moderate sleep apnoea, 372 patients with severe OSA compliant on CPAP and 235 patients with severe OSA unable to comply with CPAP were studied over average 10.1-year period. This study demonstrated a risk of fatal (odds ratio 2.87) and non-fatal (odds ratio 3.17) cardiovascular events compared to the healthy population. Simple snorers did not appear to have excess mortality. Although controlled for confounding variables, these studies support but do not prove a relationship between OSA and excess mortality. The comparator of untreated OSA because of compliance problems introduces an unmeasurable study bias that undoubtedly exaggerates the findings. The ideal study that randomizes patients with OSA to treatment or no treatment poses an ethical challenge.
Conclusion Despite the results of recent trials, there remain many gaps in our knowledge in relation to the contribution to the burden of cardiac disease produced by associated conditions such as OSA. In order to engage a greater level of interest from cardiologists and general physicians alike, larger studies with important primary endpoints will be required. Such trials are achievable and will be ultimately necessary in order to convince all health care providers of the merit of screening and treating this disorder.
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