Introduction
Obstructive sleep apnea (OSA) is a growing public health problem.1 The prevalence of the disorder has been increasing rapidly over the last 2 decades in line with the obesity epidemic in the developed world.2-4 It is estimated that OSA affects nearly 1 billion people worldwide. However, a significant proportion of patients remain undiagnosed,5 with one estimate suggesting that more than 30 million people are undiagnosed in Europe alone.1 There is a male to female predominance of 2 to 1, and OSA is more common in the middle-aged and elderly population.6
Obstructive sleep apnea is characterized by recurrent partial or complete upper airway collapse during sleep leading to intermittent hypoxia (IH) and recurrent arousals culminating in disrupted sleep quality that typically manifests as nonrestorative sleep and excessive daytime sleepiness (EDS).7,8
In addition to EDS, OSA is associated with reduced quality of life, poor cognitive function, and road traffic accidents, independent of age or sex.9-11 The principal morbidity and mortality of the condition, however, are due to the increased risk of the development and progression of numerous CVDs.4
A large body of evidence has accumulated to date strengthening the association between OSA and CVD, with increased risk persisting after correction for common cardiovascular risk factors.12 Obstructive sleep apnea is associated with increased incidence of systemic arterial hypertension, coronary artery disease, congestive cardiac failure, and stroke,4,13,14 and although the evidence for these associations is not fully conclusive,15 it points towards a significant burden of disease caused by OSA.
The gold standard treatment for OSA is continuous positive airway pressure (CPAP), which acts to splint the upper airway open during sleep and very effectively treats excessive daytime sleepiness16 and improves quality of life.17 However, its effect on long-term cardiovascular outcomes has been called into question by a number of recent studies (Table 1) which we will discuss below. One potential reason for this lack of benefit is poor adherence to CPAP in both research and general populations.18
Trial descriptor | Outcomes | Treatment | Design, number of participants, treatment | Median follow-up, y | Primary outcome and results |
---|---|---|---|---|---|
Sánchez-de-la-Torre et al, 2020 (ISAACCS)46 | Prevalence of composite outcome of cardiovascular events (cardiovascular death or nonfatal events) | CPAP + usual care vs usual care alone | 2834 patients admitted with ACS, evaluated for OSA with polysomnography and randomized if AHI >15 events/h of sleep, control group without OSA included for comparison | 3.35 | No difference between groups in the incidence of the primary outcome of repeat cardiovascular events. OSA was not associated with an increased risk of cardiovascular events during follow-up when compared with controls. OSA was associated with an increased risk of recurrent cardiovascular events in patients with no previous heart disease and admission for a first ACS |
McEvoy et al, 2016 (SAVE)137 | Composite outcome of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack | CPAP + usual care vs usual care alone | 2717 nonsleepy patients with moderate-severe OSA and established cardiovascular disease | 3.7 | No difference in the incidence of the primary composite outcome measure or any secondary outcome measure. Secondary analysis of patients adherent to CPAP for >4 h/night showed a lower risk of death and of stroke. |
Peker et al, 2016 (RICCADSA)136 | First event of repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality | CPAP vs no CPAP | 244 patients with moderate or severe OSA who did not have daytime sleepiness underwent coronary revascularization prior to trial randomization | 4.75 | No difference between groups in the incidence of the composite endpoint. In the intention-to-treat analysis adherence >4 h/night had lower cardiovascular risk than untreated patients or those receiving CPAP <4 h/night |
Barbé et al, 2012129 | Incidence of systemic hypertension or cardiovascular event | CPAP vs no CPAP | 725 nonsleepy patients with AHI, >20 events/h of sleep with no previous cardiovascular disease | 4 | No difference between groups in the incidence of the composite primary outcome. A post hoc analysis suggested a relative risk reduction of 28% in occurrence of primary outcome in patients who were adherent to CPAP therapy (>4 h/night) |
Abbreviations: ACS, acute coronary syndrome; AHI, apnea-hypopnea index; CPAP, continuous positive airway pressure; OSA, obstructive sleep apnea |
This review aims to summarize the epidemiology of CVD in patients with OSA, the current evidence on pathogenic mechanisms linking OSA and cardiovascular disease (CVD), and briefly discusses the clinical implications and effects of CPAP and other treatment modalities, in order to identify priorities for future research and promote a move towards personalized therapies.
Epidemiology of cardiovascular diseases in obstructive sleep apnea
Systemic arterial hypertension
Hypertension is a well-recognized and well-studied complication of OSA19 with epidemiological data suggesting that there is a strong relationship between OSA and systemic arterial hypertension.20 Cross-sectional population-based studies consistently find an increased prevalence of hypertension in patients with OSA compared with controls. This finding persists even after controlling for potential confounders such as age and obesity, with approximately 50% of patients with OSA having coexisting hypertension.21-24 Studies also show increased likelihood of hypertension with increasing severity of OSA. In the Sleep Heart Health Study (n = 6132), the prevalence of hypertension was 59%, 62%, and 67% in mild, moderate, and severe sleep apnea, respectively.22
Conversely, large prospective longitudinal studies, such as the WSCS (Wisconsin Sleep Cohort Study),21 and a later prospective Spanish study, found moderate-to-severe OSA to be an independent risk factor for incident hypertension in patients who were normotensive at baseline.25 In the WSCS, participants with moderate-to-severe OSA had a 3.2-fold increase in the odds of developing hypertension compared with those without OSA21 and similarly, in the Spanish study, there was an increased incidence of hypertension in patients with untreated OSA compared with those not undergoing treatment.25 Even mild OSA has been reported as an independent risk factor for incident hypertension in patients younger than 60 years.26
Notably, hypertension in OSA has several distinctive characteristics, with an increased prevalence of resistant hypertension, masked hypertension, and nondipping nocturnal blood pressure patterns observed in the OSA population.
Resistant hypertension is defined as failure to achieve blood pressure (BP) control to levels less than 140/90 mm Hg despite pharmacological treatment with 3 antihypertensive drugs (including a diuretic).27 The association between OSA and hypertension appears to be particularly prominent in this subgroup. In studies, OSA is found in up to 83% of patients with resistant hypertension.28,29 Also, patients with resistant hypertension have a 2.5-fold increased risk of OSA compared with other hypertensive participants.30 Finally, a meta-analysis of randomized controlled trials (RCTs) has shown improved BP, in particular nocturnal BP in patients with OSA and resistant hypertension treated with CPAP.31
Often, OSA and nocturnal hypertension are not recognized or are masked. Distinct from white-coat hypertension, where BP is elevated in clinical environments but normal at other times, people with masked hypertension have normal BP on review, but elevated BP at other times.32 Masked hypertension is a common feature in patients with OSA, with an increased prevalence in that population compared with the general population,33,34 and is associated with dyslipidemia, increases in arterial stiffness, increased risk of diabetes, sustained hypertension, and CVD.32
Studies involving 24-hour ambulatory BP monitoring have shown that a nondipping nocturnal blood pressure, defined as a drop in blood pressure at night of less than 10%, is particularly prevalent in OSA populations.35,36 Furthermore, a nondipping BP pattern is highly suggestive of OSA, regardless of symptom profile, and the presence of a nondipping nocturnal blood pressure profile is associated with an increased incidence of cardiovascular events regardless of the underlying blood pressure value.37 In one normotensive cohort of patients, the adjusted hazard ratio of cardiovascular events in nondippers was 2.44 compared with dippers.38 Moreover, cardiovascular events are more frequent in patients with OSA and a nondipping BP profile even in the absence of diagnosed hypertension.39
Coronary artery disease / ischemic heart disease
The SHHS (Sleep Heart Health Study) and the WSCS have provided much of the data regarding coronary artery disease (CAD) and OSA. The WSCS participants were younger and had a much stronger association between CAD and OSA, whereby an AHI of more than 30 events/h of sleep resulted in a 2-fold risk of incident coronary artery disease.40 On the other hand, the SHHS reported an equivocal relationship between OSA and incident CAD, finding an increased risk in men younger than 70 years with a hazard ratio of 1.68.41 Meta-analyses support the theory that OSA confers an increased risk of CAD in men, while the relationship between OSA and CAD in women is weaker.42
Imaging studies have also suggested a relationship between CAD and OSA, with a number of studies linking OSA and coronary artery calcification (CAC). Coronary artery calcification is of interest as a possible surrogate marker for primary prevention studies of CAD in patients with OSA, although little is known to date about the influence of CPAP therapy on coronary imaging findings. A report from this department found a significant relationship between OSA severity and the presence and volume of subclinical coronary atherosclerosis, with the relationship remaining when controlled for potentially confounding factors.43 Another German community-based observational study found that OSA was independently related to the amount of CAC found on computed tomography in men under 65 years, and a North American community-based study found a high prevalence of OSA in patients with CAC and an AHI of more than 30 events/h of sleep independently predicted the prevalence of CAC.
Congestive cardiac failure
Sleep-disordered breathing accompanies up to 75% of chronic congestive heart failure cases,48 and the hazard ratio for OSA as a risk factor for incident heart failure with both reduced ejection fraction and heart failure with preserved ejection fraction (HFpEF) was 2.4 in one large study.49 The severity of IH has been shown to be a stronger predictor of outcome than the number of apnea episodes per night. In one study of patients with congestive heart failure, those with minimum oxygen saturation levels in the lowest quartile had a 5-year survival of 50%, while those in the highest quartile had a 5-year survival of 80%.50
The pathophysiology of HFpEF is linked to oxidative stress, sympathetic nervous system activation, and systemic inflammation, all of which are also linked to OSA and to other common comorbidities such as diabetes and obesity.51 Similarly, OSA is strongly linked to the development of atrial fibrillation (AF) and hypertension, which may additionally promote the development of the condition. Data are lacking as to whether treatment with CPAP may ameliorate the progression of HFpEF; however, one small observational study of 36 patients with HFpEF and moderate-severe OSA suggested that treatment with CPAP improved symptoms, cardiac diastolic function, and brain natriuretic peptide (BNP).52
Both OSA and central sleep apnea are prevalent among patients with heart failure. Central sleep apnea in patients with heart failure tends to be associated with Cheyne-Stokes breathing, and is characterized by central apneas that occur during the decrescendo portion of the cyclic respiratory pattern.53 Treatment of central sleep apnea in patients with heart failure in general was called into question by the SERVE-HF study,54 which found a higher incidence of all-cause and cardiovascular mortality in patients with central sleep apnea treated with adaptive servo-ventilation (servo-controlled inspiratory pressure support on top of expiratory positive airway pressure). Posited reasons for this negative outcome included a reduction in cardiac output with positive airway pressure in some patients, or a possible beneficial aspect to the Cheyne-Stokes respiration seen in central sleep apnea and eliminated by adaptive servo-ventilation. A more recent meta-analysis incorporating this study concluded that periodic short-term adaptive servo-ventilation may be of benefit as an adjunctive therapy for patients with central sleep apnea and heart failure; however, prolonged treatment may have negative effects, possibly due to the accumulating stress on the heart working harder against long-term positive airway pressure.55
Cardiac rhythm disorders: atrial fibrillation
Obstructive sleep apnea is highly prevalent in patients with newly diagnosed AF. One recent study found that 82.4% of patients had a positive home sleep apnea test result.56 Of those, 31.6% had moderate sleep apnea and 23.3% had severe sleep apnea. Screening for sleep apnea in this study resulted in initiation and long-term adherence to CPAP therapy in 45% of these patients.
Obstructive sleep apnea is established both as an independent predictor of stroke in patients with AF57 and as a significant risk factor for the development and recurrence of AF.58 Several international guidelines for the management of AF recommend diagnostic workup and treatment of obstructive sleep apnea,59,60 as untreated disease has been shown to reduce the efficacy of both pharmacological and catheter-based antiarrhythmic therapy. The presence of OSA increases the risk of developing AF with a relative risk of 1.7, as found by a recent meta-analysis.61 Multiple observational studies have suggested that CPAP treatment may lower the rate of AF recurrence following electrical cardioversion,58 though data from RCTs are lacking.
Interestingly, symptomatology characteristic of OSA is less predictive in this population than in the general OSA population. Neither the STOP-BANG questionnaire nor the Epworth Sleepiness Scale were predictive of OSA in a large cohort of paroxysmal AF patients.62 Another study found no correlation between self-reported daytime sleepiness and AHI in 442 consecutive patients with paroxysmal or persistent AF, and the Epsworth Sleepiness Scale had no correlation with OSA severity in this population.63
Data tend to support the possibility that intervention reduces paroxysmal AF. In a meta-analysis of 7 prospective cohort studies involving 1087 patients, the use of CPAP was associated with a reduction in AF recurrence, irrespective of whether they underwent pulmonary vein isolation.64 This beneficial effect appears to be stronger for younger, male patients and those with obesity.65
Cerebrovascular disease and stroke
Obstructive sleep apnea is an independent risk factor for stroke,14 it often progresses following stroke, and it is associated with poorer functional outcomes,66,67 cognitive impairment, higher mortality,14,68,69 and stroke recurrence, thereby impacting on both primary and secondary prevention. Overall, after adjusting for potential confounders (age, sex, body mass index, smoking, hypertension, and diabetes), untreated OSA conveys a 2-fold increased risk of stroke.70
Several prospective studies have shown an independent association of moderate-severe OSA and stroke. In the WSCS, an AHI of more than 20 events/h of sleep was associated with an increased risk of stroke over the subsequent 4 years.71 A prospective community-based study found men with an AHI of more than 15 events/h of sleep conferred a 3-fold increased risk of stroke,72 while another study showed a 2-fold increased risk, independent of vascular confounders.14 The risk of stroke is higher in men and increases with increasing AHI,72,73 with a meta-analysis confirming that moderate to severe OSA increases the risk of nonfatal or fatal stroke (pooled relative risk [95% CI], 2.02 [1.4–2.9])42 in this population.
In addition, observational studies suggest that OSA negatively influences stroke outcome by predisposing to stroke recurrence, increasing the risk of mortality post stroke and worse functional recovery with increased disability. There is a high prevalence (50%) of sleep disorders after stroke, although only a small proportion of patients are referred for sleep testing in the 3-month post-stroke period.74 A 10-year study showed that patients with moderate to severe OSA, independent of disability, had a 75% increase in risk of early death compared with those without OSA.69 Obstructive sleep apnea predicts worse functional outcomes in stroke, being independently associated with worse functional impairment,67 worse modified Rankin scale scores at discharge,75 and a longer rehabilitation stay67 as compared with those without OSA. Hypertension, and specifically a nondipping BP pattern, is implicated in these adverse outcomes.67
Currently there is insufficient evidence as to whether CPAP provides benefit to patients post stroke with regards to functional and neurological recovery. Observational studies suggest that CPAP is associated with reduced stroke risk,76 improved cognitive and function outcomes77 and mortality,68 but these trials were limited by poor CPAP tolerance and adherence.78 Furthermore, a meta-analysis of available RCTs failed to demonstrate benefit of CPAP treatment on stroke risk reduction, although patients who are adherent (>4 hours per day) may still benefit and thus, a trial of treatment may still be justified.70 The ongoing Sleep SMART (Sleep for Stroke Management and Recovery Trial) is a multisite prospective RCT whose primary outcome is to determine the effect of CPAP on reducing stroke recurrence, incidence of ACS and all-cause mortality, and impact on stroke outcome at 3 months, which may provide a more conclusive answer on the role of CPAP in stroke.
Mechanisms of cardiovascular disease in obstructive sleep apnea
Intermittent hypoxia
Intermittent hypoxia is the term given to the repetitive fluctuations in oxygen tension.79 Obstructive sleep apnea causes a typical pattern of IH with repetitive short cycles of desaturation followed by rapid full reoxygenation. It has been shown that IH has different pathophysiological sequelae to chronic sustained hypoxia.80 Mild IH seen typically in patients with mild OSA may be cardioprotective via mechanisms similar to ischemic preconditioning.81 However, severe IH as commonly seen in moderate-severe OSA has been shown in animal studies to cause a sustained rise in blood pressure,82,83 to accelerate the course of atherosclerosis,84,85 and to increase susceptibility to myocardial infarction.86 These findings have been corroborated by a human model of IH using healthy volunteers sleeping in hypoxic tents with oscillations in oxygen saturation, which found a sustained rise in BP after 14 nights of exposure.87 In vitro studies have provided further insight into IH-induced cellular responses and signaling mechanisms, such as the state-of-the-art model developed by our laboratory.88 These mechanistic data tie in with findings from clinical studies demonstrating that markers characterizing the degree of IH are better predictors of hypertension and other CVD than the AHI.89-91
Sleep fragmentation / recurrent arousals
Recurrent arousals occur in response to interrupted ventilation with subsequent hypoxia, hypercapnia, and increased respiratory effort in order to restore ventilation and lead to sleep fragmentation and subsequently to EDS, the primary symptom of OSA. Epidemiological data suggest that daytime sleepiness is predictive of elevated cardiovascular risk and sleep fragmentation has been suggested as an underlying mechanism. Ren et al92 reported that EDS objectively demonstrated by multiple sleep latency testing was an independent predictor of prevalent hypertension in patients with OSA. Mechanistic data are inconclusive in this area; one study found that 12 weeks of sleep fragmentation in mice caused development of endothelial dysfunction and early structural vascular changes,93 but a recent shorter study (30 days) in mice found no impact on left ventricular (LV) function in healthy or heart failure mice.94 Thus, the detailed contribution of sleep fragmentation to CVD requires further translational studies.
Intrathoracic pressure swings
Increased left ventricular transmural pressures
Repeated pressure changes during apneic events have an adverse effect on the cardiovascular system. During an obstructive event, forced inspiration against an occluded airway generates a large negative intrathoracic pressure. This generates increased LV transmural pressures and contributes to increased afterload.95 Venous return is also increased which augments right ventricular preload, with consequential right ventricular distension and leftward septal displacement during diastole impairing LV filling. The combined effects of increased LV afterload and reduced preload leads to a reduction in stroke volume and cardiac output.96 This effect is more pronounced in heart failure patients.95
Also, increased LV transmural pressure increased myocardial oxygen demand, while apnea-induced hypoxia leads to coronary vasoconstriction and reduced oxygen delivery. Overall, both in animal and human studies, these changes lead to myocardial ischemia, impaired contractility, and impaired diastolic relaxation, which over time likely contribute to cardiac remodeling and disease.97,98
Proarrhythmogenesis
Increased LV afterload due to intrathoracic pressure swings causes acute distension of thin-walled atria, leading to vagal activation and shortening of the atrial effective refractory period, promoting arrhythmogenesis. Moreover, simulating obstructive apnea using the Mueller maneuver in healthy subjects is proarrhythmogenic99 resulting in generation of atrial premature beats (shown to be a triggering event in paroxysmal atrial fibrillation) and prolongs ventricular repolarization. Furthermore, as previously mentioned, ventricular remodeling over time as a consequence of repetitive effects of negative intrathoracic pressure alterations is associated with an increased risk of arrhythmogenesis.100
In summary, IH, sleep fragmentation and intrathoracic pressure swings are the principal contributors to the pathogenesis of CVD in OSA. As a net consequence, they trigger intermediate pathogenic pathways, as detailed in Figure 1, culminating in adverse cardiovascular outcomes. Briefly, some of these intermediate mechanisms are discussed below, but as these mechanisms are complex, a full discussion is outside the scope of this review and have been comprehensively explored elsewhere.101
Intermediate mechanisms
Sympathetic activation
Sympathetic activation has been shown to be implicated in OSA-associated AF,58 heart failure,51 and hypertension.102 Several studies have provided evidence of sympathetic excitation in patients with OSA. Early clinical studies observed increased urinary catecholamines in patients with OSA when compared with controls, which fell post tracheostomy.103 Later studies have confirmed elevated urinary and circulating (plasma) catecholamines in patients with OSA,104 while CPAP has been shown to lead to a significant fall.105,106
Evidence from animal and experimental studies imply that IH and recurrent arousals are likely the principal initiators. In rats, an increase in catecholamine levels accompanies a rise in BP in response to IH.107,108 Moreover, carotid body denervation, adrenal medulla removal, and administration of adrenergic receptor antagonists have been shown to abolish the rise in BP associated with IH.109 Healthy participants exposed to IH show signs of sympathetic activation characterized by an increase in the activity of the sympathetic peroneal muscle nerve.87
Sleep fragmentation also plays a role. Taylor et al110 found that the arousal index was the strongest index of daytime muscle sympathetic activity in otherwise healthy participants.
Inflammation
Inflammation is involved in the pathogenesis of atherosclerosis and related CVD. Obstructive sleep apnea is associated with low-grade systemic inflammation, characterized by circulating markers of inflammation, that is, C-reactive protein, cytokines (eg, interleukin 6, tumor necrosis factor α), and adhesion molecules (vascular cell adhesion molecule 1).106 Animal and cell culture studies have supported the critical role of IH as a potent inflammatory stimulus which is central to the pathogenies of vascular disease in OSA.73,84,85,111 Murine studies, using apolipoprotein E-knockout mice (ApoE-/- mice) showed that atherosclerotic lesions in response to IH are associated with systemic and vascular inflammation.84 Furthermore, in mice fed a high-cholesterol diet, IH led to atherosclerotic lesions which did not occur in control animals not exposed to IH.112 Also, cardiovascular remodeling has been shown in mice exposed to IH.113 Additionally, several experimental studies have shown that IH activates the transcription factor nuclear factor kappa B (NF-κB), a key mediator of proinflammatory responses.80 A mouse model of IH showed increased activation of NF-κB in cardiovascular tissues, while increased activation of NF-κB was found in cultured monocytes of patients with OSAS.114,115 Furthermore, circulating downstream products of NF-κB activation such as tumor necrosis factor α are increased in OSA patients as compared with controls and fall with CPAP therapy supporting the key role of this transcription factor in OSA-associated inflammation.80,91 Visceral adipose tissue has emerged as a key source organ of proinflammatory mediators in OSA corroborated by several preclinical studies demonstrating that IH induces a proinflammatory phenotype of adipose tissue.88,116 However, while the impact of IH-induced adipose tissue inflammation on metabolic diseases is well-explored, further studies are required to delineate the role of adipose tissue on vascular inflammation and subsequent CVD in OSA.
However, despite numerous studies showing inflammation as an important mediator in IH-induced CVD, the role of anti-inflammatory treatment on the impact of cardiovascular outcomes is poorly investigated.
Oxidative stress
Oxidative stress results from an imbalance between the production of reactive oxygen species (ROS) and antioxidant mechanisms to eliminate them. While ROS play a key role in regulating cell function, at high concentrations, ROS may lead to oxidative stress and subsequent cell damage.117 Oxidative stress is thought to be a central mechanism in CVD with evidence from cell culture and animal studies linking oxidative stress to the pathogenesis of endothelial dysfunction, vascular inflammation, and atherosclerosis.118,119 This process is mostly mediated through disruption of the vasoprotective nitric oxide axis.119
In OSA, repetitive episodes of hypoxia, followed by reoxygenation, likely illicit cell damage through ROS production.120 Several animal studies have demonstrated that IH leads to surges of ROS and lipid peroxidation. In rodent models, IH-induced oxidative stress is characterized by superoxide anion production, increase in lipid peroxidation in vessels, heart, and brain, and an increase in nicotinamide adenine dinucleotide phosphate oxidase expression.121,122 Also, in rodents, the beneficial effects of antioxidant treatment during IH has been shown, with abolishment of endothelial dysfunction, vascular remodeling, and hypertension.121 However, the role of oxidative stress in CVD in humans remains controversial. Studies evaluating oxidative stress (by measuring oxidative stress markers such as F2-isoprostanes, oxidized low-density lipoprotein) in OSA have yielded equivocal results. This may be due in part to differences in the number of participants, selection criteria, and study design.123 Moreover, CPAP has failed to show benefit in several RCTs106 and so far, antioxidant treatment has failed to improve the cardiometabolic consequences of OSA, albeit this subject needs exploration in larger RCTs.124
Further, more detailed accounts of the pathophysiological processes that lead to adverse cardiovascular and metabolic outcomes in OSA are reviewed and detailed elsewhere.13,79,88,125
Effect of continuous positive airway pressure treatment on cardiovascular events
The gold standard treatment for OSA is CPAP, which acts to splint open the upper airways during sleep, as mentioned earlier. It has positive effects on daytime sleepiness and quality of life, but the long-term treatment effect of adequate CPAP therapy on cardiovascular health remains controversial. There is consistent evidence in epidemiological studies that there are higher cardiovascular-related morbidity and mortality rates in patients with severe untreated OSA than in patients on CPAP or patients who do not have severe OSA.126 However, one major limitation of nonrandomized studies of CPAP treatment is that patients who are nonadherent to CPAP therapy may also be noncompliant with other aspects of chronic disease management.127,128 Recent large-scale randomized CPAP studies have attempted to define the benefits of CPAP, but adherence has been a universal stumbling block.
One Spanish study looked at primary prevention of CVD by randomizing patients with moderate or severe OSA without daytime sleepiness to CPAP or conservative treatment.129 Their endpoints included the need for antihypertensive drugs (AHT) or the development of a number of cardiovascular endpoints. No difference was found after 4 years of follow-up between patients randomized to CPAP and those to conservative treatment. However, a post hoc subanalysis suggested that if adherence was more than 4 h/night, the incidence of AHT and cardiac events was reduced.
Studies evaluating the effect of CPAP on hypertension suggest a benefit of OSA treatment. Randomized controlled trials and meta-analyses have found that CPAP significantly reduces systolic and diastolic BP, albeit the effect size is small (mean, 2.6 mm Hg).130 However, this level of reduction is clinically relevant as evidence suggests that a reduction in BP of 1 to 2 mm Hg is associated with a reduction in major cardiovascular events, stroke, and heart failure.131 Moreover, the benefit of CPAP might be more marked in those with resistant hypertension132 and when used in combination with drug therapy.133 However, some studies failed to show a consistent benefit with CPAP on blood pressure.129,134,135 The conflicting results may represent different study populations, CPAP adherence rates, sample size, and duration of follow-up. For example, most studies comprised patient with EDS. In those in which this cohort of patient was excluded, no reduction in BP was shown following CPAP initiation,129 highlighting the importance of personalized treatment approaches.
The role of CPAP therapy on cardiovascular outcomes in general remains a topic of substantial debate. In the RICCADSA trial, 244 patients with moderate or severe OSA who did not have daytime sleepiness underwent coronary revascularization and were randomized to CPAP or conservative treatment for 57 months.136 There was no difference in the composite endpoint of repeat revascularization, myocardial infarction, stroke and cardiovascular mortality in the intention-to-treat analysis, but again, adherence of more than 4 h/night had lower cardiovascular risk than untreated patients or those receiving CPAP less than 4 h/night. In the SAVE (Sleep Apnea Cardiovascular Endpoints) study, patients with established cardiovascular or cerebrovascular disease along with moderate-severe OSA were randomized to CPAP plus usual care or usual care alone.137 The oxygen desaturation index was used to define moderate-severe OSA, and the primary outcome was a composite of death from cardiovascular causes, myocardial infarction, stroke, hospitalization for heart failure, acute coronary symptoms, or TIA. CPAP use did not significantly reduce occurrence of the primary endpoint in the intention-to-treat analysis. However, again propensity score-matched analyses showed that patients with good CPAP adherence had a lower risk of stroke and a lower risk of the composite endpoint of cerebrovascular events.
Thus, it is clear that poor adherence to CPAP affects therapeutic response in patients with OSA, and that improved patient selection and phenotyping is required for optimal treatment benefit. Furthermore, most studies excluded the most-sleepy patients, which represent a specific phenotype that may not be representative of the general OSA population in terms of comorbidity risk.138 The recent report of Mazzotti et al,139 who evaluated the relationship of different symptom subtypes, indicated that the sleepiness subtype is associated with a significantly higher incidence of adverse cardiovascular outcomes compared with other subtypes.
Future directions
A number of important questions remain open regarding the diagnosis, risk stratification, and treatment of OSA. It is increasingly clear that conventional measures of OSA severity such as the AHI, do not correlate well with the severity of clinical symptoms,140-142 nor do they correlate optimally with associated cardiovascular morbidity and mortality.143 Markers such as the hypoxic burden, which characterize the severity of IH as a key pathophysiological trigger of CVD, appear to be better correlated with end-organ consequences of OSA. Data from the ESADA (European Sleep Apnoea Database) cohort study showed that the AHI was not an independent predictor of prevalent hypertension after adjustment for the oxygen desaturation index (ODI), whereas the ODI was a significant independent predictor (OR, 2.01; 95% CI, 1.61–2.51) for the fourth quartile as compared with the first quartile of the 4% ODI.89 Another recent cohort study in 2872 men found that patients with severe nocturnal hypoxemia had a 1.8-fold increased risk of stroke compared with those without nocturnal hypoxia,144 and nocturnal hypoxemia was an independent risk factor for major adverse cardiac events.
Ongoing research into management of CVD in OSA is complicated by the early adoption of CPAP and its confirmed effect on quality of life, sleepiness, and road traffic accidents, leading to difficulty carrying out RCTs especially in patients who report EDS. This has led to the exclusion of very sleepy patients from large randomized trials of CPAP therapy and this may have contributed in part to their equivocal results. Furthermore, most trials of CPAP have been in the context of secondary prevention of CVD. However, CPAP may be most beneficial for early CVD but primary prevention trials are particularly difficult to design in OSA, given the large cohort and prolonged follow-up required, along with the difficulties in withholding CPAP.
Phenotyping of OSA will be crucial for future clinical disease classification and therapeutic modality selection, especially as therapeutic options expand. Cluster analyses have shown promise but need to be validated using prospective studies, and several phenotypic subgroups are now recognized that vary in polysomnography findings, clinical features, and risk of complications.145,146 Traits such as a high burden of periodic leg movements of sleep, frequent arousals and more severe hypoxia despite a low AHI (<15 events/h of sleep) are predictive of adverse CVD outcome,147 and symptom subtypes such as excessive sleepiness139 or comorbid insomnia146 may predict an increased risk of congestive cardiac failure or comorbid CVD.
Efforts have also been made more recently to subclassify patients with OSA by their underlying pathophysiological mechanisms, such as impaired anatomy, a low arousal threshold, ventilatory control instability, and ineffective upper airway muscles during sleep. A number of overlapping phenotypes have been recognized.148 This improved phenotyping reveals potential targets for pharmacologic therapy of OSA, although this area remains in its infancy. Of these, the weight-loss promoting agent, liraglutide, is a promising pharmaceutical compound to establish an indication for OSA149 but requires further evaluation. A number of antidepressant medications have been evaluated for their role in improving upper airway muscle efficacy, while carbonic anhydrase inhibitors such as acetazolamide are of interest as a potential treatment for ventilatory control instability,150 and benzodiazepines have been used to target a low arousal threshold.151 Finally, there are studies ongoing into using transcutaneous electrical stimulation to increase neuromuscular tone of the upper airway dilator muscles of patients with OSA during sleep.152
In summary, a personalized medicine approach that encompasses a range of patient factors has an increasingly important role in this complex and multifactorial disease process. Some OSA phenotypes may drive CVD or metabolic dysfunction to a greater degree than others, and thus accurate phenotyping may be a better approach in the prediction of adverse outcomes or death than the AHI. Appropriate patient selection will allow targeted use of CPAP and other therapeutic options, with the aim of improving long-term cardiovascular health in this patient cohort.
Prof. Walter McNicholas, MD, FERS, Department of Respiratory and Sleep Medicine, St. Vincent’s Hospital Group, Elm Park, Dublin 4, D04 T6F4 Ireland, phone: +35 312214000, email: walter.mcnicholas@ucd.ie
June 11, 2021.
June 14, 2021.
June 29, 2021.
None declared.
O’Donnell C, O’Mahony AM, McNicholas WT, Ryan S. Cardiovascular manifestations in obstructive sleep apnea: current evidence and potential mechanisms. Pol Arch Intern Med. 2021; 131: 550-560. doi:10.20452/pamw.16041
- 1.
- Benjafield AV, Ayas NT, Eastwood PR, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med. 2019; 7: 687-698.Crossref
- 2.
- Peppard PE, Young T, Barnet JH, et al. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013; 177: 1006-1014.Crossref
- 3.
- Franklin KA, Lindberg E. Obstructive sleep apnea is a common disorder in the population-a review on the epidemiology of sleep apnea. J Thorac Dis. 2015; 7: 1311-1322.
- 4.
- Lévy P, Kohler M, McNicholas WT, et al. Obstructive sleep apnoea syndrome. Nat Rev Dis Primers. 2015; 1: 15015.Crossref
- 5.
- Kapur V, Strohl KP, Redline S, et al. Underdiagnosis of sleep apnea syndrome in U.S. communities. Sleep Breath. 2002; 6: 49-54.
- 6.
- Heinzer R, Vat S, Marques-Vidal P, et al. Prevalence of sleep-disordered breathing in the general population: the HypnoLaus study. Lancet Respir Med. 2015; 3: 310-318.Crossref
- 7.
- Malhotra A, White DP. Obstructive sleep apnoea. Lancet. 2002; 360: 237-245.Crossref
- 8.
- Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993; 328: 1230-1235.Crossref
- 9.
- Vinnikov D, Blanc PD, Alilin A, et al. Fatigue and sleepiness determine respiratory quality of life among veterans evaluated for sleep apnea. Health Qual Life Outcomes. 2017; 15: 48.Crossref
- 10.
- Tregear S, Reston J, Schoelles K, Phillips B. Obstructive sleep apnea and risk of motor vehicle crash: systematic review and meta-analysis. J Clin Sleep Med. 2009; 5: 573-581.Crossref
- 11.
- Kerner NA, Roose SP. Obstructive sleep apnea is linked to depression and cognitive impairment: evidence and potential mechanisms. Am J Geriatr Psychiatry. 2016; 24: 496-508.Crossref
- 12.
- Sarkar P, Mukherjee S, Chai-Coetzer CL, McEvoy RD. The epidemiology of obstructive sleep apnoea and cardiovascular disease. J Thorac Dis. 2018; 10: S4189-S4200.Crossref
- 13.
- McNicholas WT, Bonsigore MR. Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J. 2007; 29: 156-178.
- 14.
- Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005; 353: 2034-2041.Crossref
- 15.
- Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation. 2010; 122: 352-360.Crossref
- 16.
- Tomfohr LM, Ancoli-Israel S, Loredo JS, Dimsdale JE. Effects of continuous positive airway pressure on fatigue and sleepiness in patients with obstructive sleep apnea: data from a randomized controlled trial. Sleep. 2011; 34: 121-126.Crossref
- 17.
- Siccoli MM, Pepperell JCT, Kohler M, et al. Effects of continuous positive airway pressure on quality of life in patients with moderate to severe obstructive sleep apnea: data from a randomized controlled trial. Sleep. 2008; 31: 1551-1558.Crossref
- 18.
- Bakker JP, Weaver TE, Parthasarathy S, Aloia MS. Adherence to CPAP: what should we be aiming for, and how can we get there? Chest. 2019; 155: 1272-1287.Crossref
- 19.
- Torres G, Sánchez-de-la-Torre M, Barbé F. Relationship between OSA and hypertension. Chest. 2015; 148: 824-832.Crossref
- 20.
- Hou H, Zhao Y, Yu W, et al. Association of obstructive sleep apnea with hypertension: a systematic review and meta-analysis. J Glob Health. 2018; 8: 010405.Crossref
- 21.
- Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000; 342: 1378-1384.Crossref
- 22.
- Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA. 2000; 283: 1829-1836.Crossref
- 23.
- Silverberg DS, Oksenberg A. Are sleep-related breathing disorders important contributing factors to the production of essential hypertension? Curr Hypertens Rep. 2001; 3: 209-215.Crossref
- 24.
- Young T, Peppard P, Palta M, et al. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med. 1997; 157: 1746-1752.Crossref
- 25.
- Marin JM, Agusti A, Villar I, et al. Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA. 2012; 307: 2169-2176.Crossref
- 26.
- Vgontzas AN, Li Y, He F, et al. Mild-to-moderate sleep apnea is associated with incident hypertension: age effect. Sleep. 2019; 42: zsy265.Crossref
- 27.
- Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013; 34: 2159-2219.Crossref
- 28.
- Logan AG, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens. 2001; 19: 2271-2277.Crossref
- 29.
- Gonçalves SC, Martinez D, Gus M, et al. Obstructive sleep apnea and resistant hypertension: a case-control study. Chest. 2007; 132: 1858-1862.Crossref
- 30.
- Demede M, Pandey A, Zizi F, et al. Resistant hypertension and obstructive sleep apnea in the primary-care setting. Int J Hypertens. 2011; 2011: 340929.Crossref
- 31.
- Labarca G, Schmidt A, Dreyse J, et al. Efficacy of continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA) and resistant hypertension (RH): systematic review and meta-analysis. Sleep Med Rev. 2021; 58: 101446.Crossref
- 32.
- Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018; 39: 3021-3104.Crossref
- 33.
- Baguet JP, Lévy P, Barone-Rochette G, et al. Masked hypertension in obstructive sleep apnea syndrome. J Hypertens. 2008; 26: 885-892.Crossref
- 34.
- Drager LF, Pedrosa RP, Diniz PM, et al. The effects of continuous positive airway pressure on prehypertension and masked hypertension in men with severe obstructive sleep apnea. Hypertension. 2011; 57: 549-555.Crossref
- 35.
- Ancoli-Israel S, Stepnowsky C, Dimsdale J, et al. The effect of race and sleep-disordered breathing on nocturnal BP “dipping”: analysis in an older population. Chest. 2002; 122: 1148-1155.Crossref
- 36.
- Loredo JS, Ancoli-Israel S, Dimsdale JE. Sleep quality and blood pressure dipping in obstructive sleep apnea. Am J Hypertens. 2001; 14: 887-892.Crossref
- 37.
- Crinion SJ, Ryan S, Kleinerova J, et al. Nondipping nocturnal blood pressure predicts sleep apnea in patients with hypertension. J Clin Sleep Med. 2019; 15: 957-963.Crossref
- 38.
- Hermida RC, Ayala DE, Mojón A, Fernández JR. Blunted sleep-time relative blood pressure decline increases cardiovascular risk independent of blood pressure level - the “normotensive non-dipper” paradox. Chronobiol Int. 2013; 30: 87-98.Crossref
- 39.
- Sasaki N, Ozono R, Edahiro Y, et al. Impact of non-dipping on cardiovascular outcomes in patients with obstructive sleep apnea syndrome. Clin Exp Hypertens. 2015; 37: 449-453.Crossref
- 40.
- Hla KM, Young T, Hagen EW, et al. Coronary heart disease incidence in sleep disordered breathing: the Wisconsin Sleep Cohort Study. Sleep. 2015; 38: 677-684.Crossref
- 41.
- Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure. Circulation. 2010; 122: 352-360.Crossref
- 42.
- Dong JY, Zhang YH, Qin LQ. Obstructive sleep apnea and cardiovascular risk: meta-analysis of prospective cohort studies. Atherosclerosis. 2013; 229: 489-495.Crossref
- 43.
- Kent BD, Garvey JF, Ryan S, et al. Severity of obstructive sleep apnoea predicts coronary artery plaque burden: a coronary computed tomographic angiography study. Eur Respir J. 2013; 42: 1263-1270.Crossref
- 44.
- Lee C-H, Sethi R, Li R, et al. Obstructive sleep apnea and cardiovascular events after percutaneous coronary intervention. Circulation. 2016; 133: 2008-2017.
- 45.
- Qu H, Guo M, Zhang Y, Shi D-Z. Obstructive sleep apnea increases the risk of cardiac events after percutaneous coronary intervention: a meta-analysis of prospective cohort studies. Sleep Breath. 2018; 22: 33-40.Crossref
- 46.
- Sánchez-de-la-Torre M, Sánchez-de-la-Torre A, Bertran S, et al. Effect of obstructive sleep apnoea and its treatment with continuous positive airway pressure on the prevalence of cardiovascular events in patients with acute coronary syndrome (ISAACC study): a randomised controlled trial. Lancet Respir Med. 2020; 8: 359-367.
- 47.
- Zapater A, Sánchez-de-la-Torre M, Benítez ID, et al. The effect of sleep apnea on cardiovascular events in different acute coronary syndrome phenotypes. Am J Respir Crit Care Med. 2020; 202: 1698-1706.
- 48.
- Oldenburg O, Lamp B, Faber L, et al. Sleep-disordered breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients. Eur J Heart Fail. 2007; 9: 251-257.Crossref
- 49.
- Gong FF, Jelinek MV, Castro JM, et al. Risk factors for incident heart failure with preserved or reduced ejection fraction, and valvular heart failure, in a community-based cohort. Open Heart. 2018; 5: e000782.Crossref
- 50.
- Watanabe E, Kiyono K, Matsui S, et al. Prognostic importance of novel oxygen desaturation metrics in patients with heart failure and central sleep apnea. J Card Fail. 2017; 23: 131-137.Crossref
- 51.
- Sanderson JE, Fang F, Lu M, et al. Obstructive sleep apnoea, intermittent hypoxia and heart failure with a preserved ejection fraction. Heart. 2021; 107: 190-194.Crossref
- 52.
- Yoshihisa A, Suzuki S, Yamaki T, et al. Impact of adaptive servo‐ventilation on cardiovascular function and prognosis in heart failure patients with preserved left ventricular ejection fraction and sleep‐disordered breathing. Eur J Heart Fail. 2013; 15: 543-550.Crossref
- 53.
- Naughton M, Benard D, Tam A, et al. Role of hyperventilation in the pathogenesis of central sleep apneas in patients with congestive heart failure. Am Rev Respir Dis. 1993; 148: 330-338.Crossref
- 54.
- Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive servo-ventilation for central sleep apnea in systolic heart failure. N Engl J Med. 2015; 373: 1095-1105.Crossref
- 55.
- Han Y-C, Shen Z-J, Zhang S-Y, et al. Efficacy of adaptive servo-ventilation and continuous positive airway pressure treatment in chronic heart failure with sleep-disordered breathing: a systematic review and meta-analysis. Heart Fail Rev. 2021; 26: 521-529.Crossref
- 56.
- Shapira-Daniels A, Mohanty S, Contreras-Valdes FM, et al. Prevalence of undiagnosed sleep apnea in patients with atrial fibrillation and its impact on therapy. JACC Clin Electrophysiol. 2020; 6: 1499-1506.Crossref
- 57.
- Yaranov DM, Smyrlis A, Usatii N, et al. Effect of obstructive sleep apnea on frequency of stroke in patients with atrial fibrillation. Am J Cardiol. 2015; 115: 461-465.Crossref
- 58.
- Linz D, McEvoy RD, Cowie MR, et al. Associations of obstructive sleep apnea with atrial fibrillation and continuous positive airway pressure treatment: a review. JAMA Cardiol. 2018; 3: 532-540.Crossref
- 59.
- Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016; 37: 2893-2962.
- 60.
- Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. EP Europace. 2018; 20: e1-e160.
- 61.
- Zhao E, Chen S, Du Y, Zhang Y. Association between sleep apnea hypopnea syndrome and the risk of atrial fibrillation: a meta-analysis of cohort study. Biomed Res Int. 2018; 2018: 5215868.Crossref
- 62.
- Traaen GM, Øverland B, Aakerøy L, et al. Prevalence, risk factors, and type of sleep apnea in patients with paroxysmal atrial fibrillation. IJC Heart & Vasculature. 2020; 26: 100447.
- 63.
- Kadhim K, Middeldorp ME, Elliott AD, et al. Self-reported daytime sleepiness and sleep-disordered breathing in patients with atrial fibrillation: SNOozE-AF. Can J Cardiol. 2019; 35: 1457-1464.Crossref
- 64.
- Shukla A, Aizer A, Holmes D, et al. Effect of obstructive sleep apnea treatment on atrial fibrillation recurrence: a meta-analysis. JACC Clin Electrophysiol. 2015; 1: 41-51.Crossref
- 65.
- Qureshi WT, Nasir UB, Alqalyoobi S, et al. Meta-analysis of continuous positive airway pressure as a therapy of atrial fibrillation in obstructive sleep apnea. Am J Cardiol. 2015; 116: 1767-1773.Crossref
- 66.
- Aaronson JA, van Bennekom CAM, Hofman WF, et al. Obstructive sleep apnea is related to impaired cognitive and functional status after stroke. Sleep. 2015; 38: 1431-1437.Crossref
- 67.
- Kaneko Y, Hajek VE, Zivanovic V, et al. Relationship of sleep apnea to functional capacity and length of hospitalization following stroke. Sleep. 2003; 26: 293-297.Crossref
- 68.
- Martínez-García MA, Soler-Cataluña JJ, Ejarque-Martínez L, et al. Continuous positive airway pressure treatment reduces mortality in patients with ischemic stroke and obstructive sleep apnea: a 5-year follow-up study. Am J Respir Crit Care Med. 2009; 180: 36-41.Crossref
- 69.
- Sahlin C, Sandberg O, Gustafson Y, et al. Obstructive sleep apnea is a risk factor for death in patients with stroke: a 10-year follow-up. Arch Intern Med. 2008; 168: 297-301.Crossref
- 70.
- Bassetti CLA, Randerath W, Vignatelli L, et al. EAN/ERS/ESO/ESRS statement on the impact of sleep disorders on risk and outcome of stroke. Eur Respir J. 2020; 55:1901104.Crossref
- 71.
- Arzt M, Young T, Finn L, et al. Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med. 2005; 172: 1447-1451.Crossref
- 72.
- Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med. 2010; 182: 269-277.Crossref
- 73.
- Azarbarzin A, Sands SA, Stone KL, et al. The hypoxic burden of sleep apnoea predicts cardiovascular disease-related mortality: the Osteoporotic Fractures in Men Study and the Sleep Heart Health Study. Eur Heart J. 2019; 40: 1149-1157.Crossref
- 74.
- Brown DL, Jiang X, Li C, et al. Sleep apnea screening is uncommon after stroke. Sleep Med. 2019; 59: 90-93.Crossref
- 75.
- Selic C, Siccoli MM, Hermann DM, Bassetti CL. Blood pressure evolution after acute ischemic stroke in patients with and without sleep apnea. Stroke. 2005; 36: 2614-2618.Crossref
- 76.
- Martínez-García MA, Galiano-Blancart R, Román-Sánchez P, et al. Continuous positive airway pressure treatment in sleep apnea prevents new vascular events after ischemic stroke. Chest. 2005; 128: 2123-2129.Crossref
- 77.
- Aaronson JA, Hofman WF, van Bennekom CA, et al. Effects of continuous positive airway pressure on cognitive and functional outcome of stroke patients with obstructive sleep apnea: a randomized controlled trial. J Clin Sleep Med. 2016; 12: 533-541.Crossref
- 78.
- Khot SP, Morgenstern LB. Sleep and stroke. Stroke. 2019; 50: 1612-1617.Crossref
- 79.
- Ryan S. Mechanisms of cardiovascular disease in obstructive sleep apnoea. J Thorac Dis. 2018; 10: S4201-S4211.Crossref
- 80.
- Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation. 2005; 112: 2660-2667.Crossref
- 81.
- Almendros I, Wang Y, Gozal D. The polymorphic and contradictory aspects of intermittent hypoxia. Am J Physiol Lung Cell Mol Physiol. 2014; 307: L129-L140.Crossref
- 82.
- Fletcher EC, Lesske J, Qian W, et al. Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats. Hypertension. 1992; 19: 555-561.Crossref
- 83.
- Brooks D, Horner RL, Kozar LF, et al. Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. J Clin Invest. 1997; 99: 106-109.Crossref
- 84.
- Arnaud C, Poulain L, Lévy P, Dematteis M. Inflammation contributes to the atherogenic role of intermittent hypoxia in apolipoprotein-E knock out mice. Atherosclerosis. 2011; 219: 425-431.Crossref
- 85.
- Arnaud C, Beguin PC, Lantuejoul S, et al. The inflammatory preatherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5 inhibition. Am J Respir Crit Care Med. 2011; 184: 724-731.Crossref
- 86.
- Belaidi E, Joyeux-Faure M, Ribuot C, et al. Major role for hypoxia inducible factor-1 and the endothelin system in promoting myocardial infarction and hypertension in an animal model of obstructive sleep apnea. J Am Coll Cardiol. 2009; 53: 1309-1317.Crossref
- 87.
- Tamisier R, Pépin JL, Remy J, et al. 14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans. Eur Respir J. 2011; 37: 119-128.Crossref
- 88.
- Murphy AM, Thomas A, Crinion SJ, et al. Intermittent hypoxia in obstructive sleep apnoea mediates insulin resistance through adipose tissue inflammation. Eur Respir J. 2017; 49: 1601731.Crossref
- 89.
- Tkacova R, McNicholas WT, Javorsky M, et al. Nocturnal intermittent hypoxia predicts prevalent hypertension in the European Sleep Apnoea Database cohort study. Eur Respir J. 2014; 44: 931-941.Crossref
- 90.
- Azarbarzin A, Sands SA, Stone KL, et al. The hypoxic burden of sleep apnoea predicts cardiovascular disease-related mortality: the Osteoporotic Fractures in Men Study and the Sleep Heart Health Study. Eur Heart J. 2019; 40: 1149-1157.Crossref
- 91.
- Ryan S, Taylor CT, McNicholas WT. Predictors of elevated nuclear factor-kappaB-dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2006; 174: 824-830.Crossref
- 92.
- Ren R, Li Y, Zhang J, et al. Obstructive sleep apnea with objective daytime sleepiness is associated with hypertension. Hypertension. 2016; 68: 1264-1270.Crossref
- 93.
- Carreras A, Zhang SX, Peris E, et al. Chronic sleep fragmentation induces endothelial dysfunction and structural vascular changes in mice. Sleep. 2014; 37: 1817-1824.Crossref
- 94.
- Cabrera-Aguilera I, Benito B, Tajes M, et al. Chronic sleep fragmentation mimicking sleep apnea does not worsen left-ventricular function in healthy and heart failure mice. Front Neurol. 2019; 10: 1364.Crossref
- 95.
- Bradley TD, Hall MJ, Ando S, Floras JS. Hemodynamic effects of simulated obstructive apneas in humans with and without heart failure. Chest. 2001; 119: 1827-1835.Crossref
- 96.
- Parker JD, Brooks D, Kozar LF, et al. Acute and chronic effects of airway obstruction on canine left ventricular performance. Am J Respir Crit Care Med. 1999; 160: 1888-1896.Crossref
- 97.
- Kusuoka H, Weisfeldt ML, Zweier JL, et al. Mechanism of early contractile failure during hypoxia in intact ferret heart: evidence for modulation of maximal Ca2+-activated force by inorganic phosphate. Circ Res. 1986; 59: 270-282.Crossref
- 98.
- Cargill RI, Kiely DG, Lipworth BJ. Adverse effects of hypoxaemia on diastolic filling in humans. Clin Sci (Lond). 1995; 89: 165-169.Crossref
- 99.
- Schlatzer C, Schwarz EI, Sievi NA, et al. Intrathoracic pressure swings induced by simulated obstructive sleep apnoea promote arrhythmias in paroxysmal atrial fibrillation. Europace. 2016; 18: 64-70.Crossref
- 100.
- Drager LF, Bortolotto LA, Figueiredo AC, et al. Obstructive sleep apnea, hypertension, and their interaction on arterial stiffness and heart remodeling. Chest. 2007; 131: 1379-1386.Crossref
- 101.
- Ryan S, Cummins EP, Farre R, et al. Understanding the pathophysiological mechanisms of cardiometabolic complications in obstructive sleep apnoea: towards personalised treatment approaches. Eur Respir J. 2020; 56: 1902295.Crossref
- 102.
- Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet. 2009; 373: 82-93.Crossref
- 103.
- Fletcher EC, Miller J, Schaaf JW, Fletcher JG. Urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension. Sleep. 1987; 10: 35-44.Crossref
- 104.
- Dimsdale JE, Coy T, Ziegler MG, et al. The effect of sleep apnea on plasma and urinary catecholamines. Sleep. 1995; 18: 377-381.
- 105.
- Ziegler MG, Mills PJ, Loredo JS, et al. Effect of continuous positive airway pressure and placebo treatment on sympathetic nervous activity in patients with obstructive sleep apnea. Chest. 2001; 120: 887-893.Crossref
- 106.
- Jullian-Desayes I, Joyeux-Faure M, Tamisier R, et al. Impact of obstructive sleep apnea treatment by continuous positive airway pressure on cardiometabolic biomarkers: a systematic review from sham CPAP randomized controlled trials. Sleep Med Rev. 2015; 21: 23-38.Crossref
- 107.
- Dick TE, Hsieh YH, Wang N, Prabhakar N. Acute intermittent hypoxia increases both phrenic and sympathetic nerve activities in the rat. Exp Physiol. 2007; 92: 87-97.Crossref
- 108.
- Lesske J, Fletcher EC, Bao G, Unger T. Hypertension caused by chronic intermittent hypoxia - influence of chemoreceptors and sympathetic nervous system. J Hypertens. 1997; 15: 1593-1603.Crossref
- 109.
- Drager LF, Polotsky VY, O’Donnell CP, et al. Translational approaches to understanding metabolic dysfunction and cardiovascular consequences of obstructive sleep apnea. Am J Physiol Heart Circ Physiol. 2015; 309: H1101-H1111.Crossref
- 110.
- Taylor KS, Murai H, Millar PJ, et al. Arousal from sleep and sympathetic excitation during wakefulness. Hypertension. 2016; 68: 1467-1474.Crossref
- 111.
- Ryan S, Taylor CT, McNicholas WT. Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome? Thorax. 2009; 64: 631-636.
- 112.
- Savransky V, Nanayakkara A, Li J, et al. Chronic intermittent hypoxia induces atherosclerosis. Am J Respir Crit Care Med. 2007; 175: 1290-1297.Crossref
- 113.
- Dematteis M, Julien C, Guillermet C, et al. Intermittent hypoxia induces early functional cardiovascular remodeling in mice. Am J Respir Crit Care Med. 2008; 177: 227-235.Crossref
- 114.
- Greenberg H, Ye X, Wilson D, et al. Chronic intermittent hypoxia activates nuclear factor-kappaB in cardiovascular tissues in vivo. Biochem Biophys Res Commun. 2006; 343: 591-596.Crossref
- 115.
- Yamauchi M, Tamaki S, Tomoda K, et al. Evidence for activation of nuclear factor kappaB in obstructive sleep apnea. Sleep Breath. 2006; 10: 189-193.Crossref
- 116.
- Ryan S. Adipose tissue inflammation by intermittent hypoxia: mechanistic link between obstructive sleep apnoea and metabolic dysfunction. J Physiol. 2017; 595: 2423-2430.Crossref
- 117.
- Hensley K, Robinson KA, Gabbita SP, et al. Reactive oxygen species, cell signaling, and cell injury. Free Radic Biol Med. 2000; 28: 1456-1462.Crossref
- 118.
- Münzel T, Camici GG, Maack C, et al. Impact of oxidative stress on the heart and vasculature: part 2 of a 3-part series. J Am Coll Cardiol. 2017; 70: 212-229.Crossref
- 119.
- Li H, Horke S, Förstermann U. Vascular oxidative stress, nitric oxide and atherosclerosis. Atherosclerosis. 2014; 237: 208-219.Crossref
- 120.
- Eltzschig HK, Eckle T. Ischemia and reperfusion - from mechanism to translation. Nat Med. 2011; 17: 1391-1401.Crossref
- 121.
- Troncoso Brindeiro CM, da Silva AQ, Allahdadi KJ, et al. Reactive oxygen species contribute to sleep apnea-induced hypertension in rats. Am J Physiol Heart Circ Physiol. 2007; 293: H2971-H2976.Crossref
- 122.
- Zhan G, Serrano F, Fenik P, et al. NADPH oxidase mediates hypersomnolence and brain oxidative injury in a murine model of sleep apnea. Am J Respir Crit Care Med. 2005; 172: 921-929.Crossref
- 123.
- Lira AB, de Sousa Rodrigues CF. Evaluation of oxidative stress markers in obstructive sleep apnea syndrome and additional antioxidant therapy: a review article. Sleep Breath. 2016; 20: 1155-1160.Crossref
- 124.
- Farías JG, Herrera EA, Carrasco-Pozo C, et al. Pharmacological models and approaches for pathophysiological conditions associated with hypoxia and oxidative stress. Pharmacol Ther. 2016; 158: 1-23.Crossref
- 125.
- Mandal S, Kent BD. Obstructive sleep apnoea and coronary artery disease. J Thorac Dis. 2018; 10: S4212-S4220.Crossref
- 126.
- Resano-Barrio MP, Arroyo-Espliguero R, Viana-Llamas MC, Mediano O. Obstructive sleep apnoea syndrome: continuous positive airway pressure therapy for prevention of cardiovascular risk. Eur Cardiol. 2020; 15: e65.Crossref
- 127.
- Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005; 365: 1046-1053.Crossref
- 128.
- Doherty LS, Kiely JL, Swan V, McNicholas WT. Long-term effects of nasal continuous positive airway pressure therapy on cardiovascular outcomes in sleep apnea syndrome. Chest. 2005; 127: 2076-2084.Crossref
- 129.
- Barbé F, Durán-Cantolla J, Sánchez-de-la-Torre M, et al. Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial. JAMA. 2012; 307: 2161-2168.Crossref
- 130.
- Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet. 2002; 359: 204-210.Crossref
- 131.
- Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003; 362: 1527-1535.Crossref
- 132.
- de Oliveira AC, Martinez D, Massierer D, et al. The antihypertensive effect of positive airway pressure on resistant hypertension of patients with obstructive sleep apnea: a randomized, double-blind, clinical trial. Am J Respir Crit Care Med. 2014; 190: 345-347.Crossref
- 133.
- Pépin JL, Tamisier R, Barone-Rochette G, et al. Comparison of continuous positive airway pressure and valsartan in hypertensive patients with sleep apnea. Am J Respir Crit Care Med. 2010; 182: 954-960.Crossref
- 134.
- Campos-Rodriguez F, Grilo-Reina A, Perez-Ronchel J, et al. Effect of continuous positive airway pressure on ambulatory BP in patients with sleep apnea and hypertension: a placebo-controlled trial. Chest. 2006; 129: 1459-1467.Crossref
- 135.
- Robinson GV, Smith DM, Langford BA, et al. Continuous positive airway pressure does not reduce blood pressure in nonsleepy hypertensive OSA patients. Eur Respir J. 2006; 27: 1229-1235.Crossref
- 136.
- Peker Y, Glantz H, Eulenburg C, et al. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea. The RICCADSA randomized controlled trial. Am J Respir Crit Care Med. 2016; 194: 613-620.Crossref
- 137.
- McEvoy RD, Antic NA, Heeley E, et al. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med. 2016; 375: 919-931.Crossref
- 138.
- Stepnowsky C, Sarmiento KF, Bujanover S, et al. Comorbidities, health-related quality of life, and work productivity among people with obstructive sleep apnea with excessive sleepiness: findings from the 2016 US National Health and Wellness Survey. J Clin Sleep Med. 2019; 15: 235-243.Crossref
- 139.
- Mazzotti DR, Keenan BT, Lim DC, et al. Symptom subtypes of obstructive sleep apnea predict incidence of cardiovascular outcomes. Am J Respir Crit Care Med. 2019; 200: 493-506.Crossref
- 140.
- Deegan PC, McNicholas WT. Predictive value of clinical features for the obstructive sleep apnoea syndrome. Eur Respir J. 1996; 9: 117-124.Crossref
- 141.
- Arnardottir ES, Bjornsdottir E, Olafsdottir KA, et al. Obstructive sleep apnoea in the general population: highly prevalent but minimal symptoms. Eur Respir J. 2016; 47: 194-202.Crossref
- 142.
- Escourrou P, Grote L, Penzel T, et al. The diagnostic method has a strong influence on classification of obstructive sleep apnea. J Sleep Res. 2015; 24: 730-738.Crossref
- 143.
- Randerath W, Bassetti CL, Bonsignore MR, et al. Challenges and perspectives in obstructive sleep apnoea: report by an ad hoc working group of the Sleep Disordered Breathing Group of the European Respiratory Society and the European Sleep Research Society. Eur Respir J. 2018; 52: 1702616.Crossref
- 144.
- Stone KL, Blackwell TL, Ancoli-Israel S, et al. Sleep disordered breathing and risk of stroke in older community-dwelling men. Sleep. 2016; 39: 531-540.Crossref
- 145.
- Carberry JC, Amatoury J, Eckert DJ. Personalized management approach for OSA. Chest. 2018; 153: 744-755.Crossref
- 146.
- Saaresranta T, Hedner J, Bonsignore MR, et al. Clinical phenotypes and comorbidity in european sleep apnoea patients. PLoS One. 2016; 11: e0163439.Crossref
- 147.
- Zinchuk AV, Jeon S, Koo BB, et al. Polysomnographic phenotypes and their cardiovascular implications in obstructive sleep apnoea. Thorax. 2018; 73: 472-480.Crossref
- 148.
- Eckert DJ, White DP, Jordan AS, et al. Defining phenotypic causes of obstructive sleep apnea. identification of novel therapeutic targets. Am J Respir Crit Care Med. 2013; 188: 996-1004.Crossref
- 149.
- Blackman A, Foster GD, Zammit G, et al. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial. Int J Obes (Lond). 2016; 40: 1310-1319.Crossref
- 150.
- Schütz SG, Dunn A, Braley TJ, et al. New frontiers in pharmacologic obstructive sleep apnea treatment: a narrative review. Sleep Med Rev. 2021; 57: 101473.Crossref
- 151.
- Carberry JC, Grunstein RR, Eckert DJ. The effects of zolpidem in obstructive sleep apnea - an open-label pilot study. J Sleep Res. 2019; 28: e12853.Crossref
- 152.
- He B, Al-Sherif M, Nido M, et al. Domiciliary use of transcutaneous electrical stimulation for patients with obstructive sleep apnoea: a conceptual framework for the TESLA home programme. J Thorac Dis. 2019; 11: 2153-2164.Crossref