Impact of sleep apnea and treatments on cardiovascular disease

Cardiovascular diseases (CVDs) are the leading causes of mortality worldwide, accounting for nearly 18 million deaths per year. Among other considerations, treating CVDs requires better understanding their risk factors. Sleep-disordered breathing, especially obstructive sleep apnea (OSA), is a likely contributor to several CVDs. We review key epidemiological data that addresses the link between OSA and cardiovascular outcomes such as hypertension, atrial fibrillation (AF), stroke, atherosclerosis, and heart failure (HF), and proposed pathophysiological mechanisms underlying this association. There are several biological pathways linking OSA and an increased propensity to cardiovascular diseases, and we discuss the evidence on the benefits of treatments of OSA on the prevalence of cardiovascular complications.

Sleep Apnea - Obstructive - Hypertension - Stroke - Atrial Fibrillation - Continuous Positive Airway Pressure - Weight Loss

INTRODUCTION

Obstructive sleep apnea (OSA) is the most common type of sleep-disordered breathing, and is characterized by repetitive partial or complete collapse of the upper airways during sleep[1]. This phenomenon reduces or prevents airflow and causes frequent arousals, and has several metabolic and physiological consequences[2],[3]. The diagnosis of OSA is ideally made using overnight polysomnography (PSG) with 12 recording channels and specialized professional observation and data analysis, although there are lower cost alternatives, such as portable monitoring devices, that are also validated diagnostic methods[4]. The severity of OSA is determined by the number of apneas and hypopneas per hour of sleep and is quantitated using the apnea-hypopnea index (AHI) (see [Table 1]).

Table 1

Classification of the severity of OSA.

Apnea/hypopnea index (AHI)
AHI score	Classification
<5 events/hour	Normal
5-15 events/hour	Mild
16-30 events/hour	Moderate
>30 events/hour	Severe

Cardiovascular diseases (CVDs) are the leading causes of mortality worldwide, accounting for nearly 18 million deaths per year. Common CVDs include functional abnormalities in the cardiac and vascular system that can result in heart failure, strokes, arrhythmias, atherosclerosis, hypertension, and cardiac ischemia[5]. Although the comorbidities and risk factors for these conditions are numerous and diverse, OSA frequently occurs in patients with CVDs, in part, due to the global epidemic of obesity[6]-[8]. The metabolic syndrome (MS) is one of the most important risk factors for the development of OSA (OR=2.87/95%CI=2.41 3.42)[8]. The MS is an umbrella term describing a constellation of conditions, such as obesity, hypertension, insulin resistance, and hyperlipidemia that not only increases the risk of OSA but also of CVDs[9].

Even though OSA and cardiovascular outcomes often present in partnership, their association can reflect either a cause/effect relationship or as different endpoints having similar risk factors. The coexistence of these conditions does not prove causality, and potential confounding variables should be considered. In addition, treating OSA can also effect the prevalence of CVDs. This review summarizes our current understanding of the relationship between sleep apnea and CVDs based on current evidence.

Pathophysiological mechanisms linking OSA and cardiovascular diseases

OSA is associated with a multitude of cardiovascular pathological mechanisms (see [Figure 1]). Sleep apnea is related to oscillations in intrathoracic pressure caused by repeated inspiratory efforts against a collapsed upper airway[10]. Intrathoracic pressure becomes very negative during apneas, and increases right heart volume due to a greater venous return[11]. The substantial changes in ventricular transmural pressure increases cardiac wall stress (afterload) and atrial enlargement, leading to cardiac remodeling and arrhythmias[12]-[16].

Figure 1 Pathophysiological mechanisms underlying the development of CVDs in OSA.Abbreviations: CVDs = Cardiovascular diseases; SNS = Sympathetic nervous system; RAAS = Renin-angiotensin-aldosterone system.

OSA is also associated with increases in oxidative stress, which contributes to atrial remodeling and arrhythmic pathologies. Sleep apnea promotes the production of systemic inflammatory proteins and the activation of the sympathetic nervous system by cyclical arousals, leading to swings in blood pressure (BP) and heart rate in patients with OSA[17]-[20]. This phenomenon generates shear stress and, combined with hypoxia, leads to dysfunction of the vascular endothelium[10]. The combination of hypoxia and enhanced sympathetic nerve activity increases myocardial oxygen demand, cardiac ischemia and atrial fibrillation[21],[22].

The augmented sympathetic nerve discharge increases BP in individuals with OSA during sleep, which is in contrast to nocturnal decreases that usually occur in those without OSA[23],[24]. However, activation of the sympathetic nervous system and increases in blood pressure in patients with OSA are not restricted to the sleep state, but can also occur during wakefulness, and can trigger left ventricular systolic dysfunction[25]-[27]. These OSA induced stressors generate long-t erm electrical and mechanical remodeling of both atria and ventricles, and eventually can lead to heart failure[28]-[31], although the onset of heart failure can also increase vulnerability to OSA[31]. Patients with heart failure accumulate fluid in the lower limbs during the day while in an upright position; this increases venous return when they lay down to sleep, resulting in rostral fluid redistribution and neck edema that exacerbates OSA[10].

Atherosclerosis is an important cause of myocardial infarction that can also lead to heart failure. OSA can contribute to atherosclerosis via multiple mechanisms such as increased oxidative stress, systemic inflammation, vascular smooth cell/lymphocyte activation, augmented adhesion molecule expression, enhanced lipid accumulation by macrophages, and endothelial dysfunction[32]. Consequently, OSA also predisposes cerebrovascular accidents, as many of the risk factors for stroke (such as hypertension, autonomic dysfunction, oxidative stress, endothelial dysfunction, atherosclerosis, arrhythmias, and hypercoagulability) are increased in OSA patients[33].

An added factor is that intermittent hypoxia increases insulin resistance due to decreases in the phosphorylation of tyrosine kinases and the effectiveness and sensitivity of insulin receptors[34],[35]. The overactivation of the sympathetic system leads to reduced secretion of insulin and hyperglycemia as well, especially due to a reduction of pancreatic P-cell metabolism[34],[35].

Importantly, the irregular and incomplete sleep patterns of OSA patients causes drowsiness during the day, weight gain, deposition of adipose tissue and ectopic fat, besides decreased activity and energy expenditure. These alterations exacerbate obesity, so aggravating dyslipidemia, insulin resistance and hyperglycemia, increasing the risk of developing cardiovascular diseases[35],[36].

Hypertension

The association between OSA and systemic arterial hypertension is a subject of intense investigation. OSA and hypertension often coexist, with the prevalence of OSA in hypertensive patients varying between 30-50%[37],[38]. In patients with drug-resistant hypertension this number increases to 70%, with OSA being by far the most common secondary associated condition[37],[38]. A longitudinal study that analyzed data from the Wisconsin sleep cohort study concluded that sleep-disordered breathing increased the risk of developing hypertension by ~3fold, even when confounding factors such as age, gender, body habitus, smoking, alcohol use, education, and physical activity were accounted for. Having higher AHI values strengthens the association between OSA and hypertension[39]. A recent systematic review and meta-analysis reported a significant association of essential hypertension with mild (OR=1.18, 95%CI=1.09-1.27, p<0.05), moderate (OR=1.32, 95%CI=1.20-1.43, p<0.05) and severe OSA (OR=1.56, 95%CI=1.29-1.84, p<0.05)[40]. For studies comparing OSA and non-OSA participants, the pooled OR was 1.80 (95%CI=1.54-2.06, p<0.05)[39]. Finally, there is a pooled OR of 2.84 (95%CI=1.70-3.98, p<0.05) in six studies that explored the association between OSA and resistant hypertension[40].

It is important to note that no significant association was reported between hypertension and OSA in patients aged 60 years, although the reasons for this are unclear. It could be related to a selection bias and the cross-sectional nature of the studies[1],[41]. Two alternative hypotheses could be the different phenotypic expression of sleep apnea related to the proportion of mixed and central apneas, which can impact the underlying pathophysiology, and the co-existence of other medical conditions affecting the interaction between OSA and systemic hypertension in the elderly[41],[42].

Atrial fibrillation

Atrial fibrillation (AF) occurs frequently in patients with OSA[15],[18],[43],[44], as both conditions share several risk factors such hypertension, congestive heart failure, and coronary artery disease, hampering the determination causal relationships[44]. Multivariate analysis reports a strong independent association between the odds of having OSA and developing AF (OR=2.2)[45]. A multicenter cohort study reports that the chances of developing cardiac arrhythmias are three times greater in patients with OSA compared to patients with no sleep-disordered breathing (OR=4.02, 95%IC=1.03-15.74)[46]. The strength of the proposed causal link is strengthened by a meta-analysis indicating that AF is prevalent in OSA patients (OR=2.12, 95%CI=1.85-2.44, p<0.001)[47].

Higher AHI scores increase the susceptibility to AF, with an odds ratio of 2.91 in men with an established OSA diagnosis[48]. Reversal of AF reversal is associated with an increased risk of recurrence of AF after one year (82% vs. 42%, p=0.01) in those untreated for OSA[49].

The higher prevalence of OSA in patients with AF also suggests that sleep apnea could initiate and perpetuate arrhythmias[15],[18],[43]. A recent prospective cohort study of patients with AF reported an OSA prevalence of 85%, which is significantly higher than the prevalence of 18.2 % reported in other studies[50],[51]. One reason for these differences in prevalence of AF may be that OSA may be under-recognized in some arrhythmic patient groups, as patients with cardiac arrhythmias are not routinely screened for OSA[50],[51].

Cerebrovascular disease

Recent studies propose OSA as an independent risk factor for cerebrovascular diseases, and it is estimated that 3070% of people who have suffered a stroke also have OSA[52]-[55]. A meta-analysis of 12 prospective cohort studies (25,760 subjects) suggests an increased risk (2.15 greater) of incident fatal and non-fatal strokes in patients with severe OSA[56]. Another meta- -analysis also supports this assertion, even after adjustment for confounding factors such as age, sex, BMI, diabetes, hypertension, coronary artery disease, previous coronary artery intervention, heart failure, smoking, alcohol use and dyslipidemia (RR=1.94; 95%CI=1.31-2.89; p=0.001)[55].

The relationship between OSA and stroke was also highlighted by a meta-analysis of 10 prospective studies showing that OSA was associated with a ~2.1-fold higher risk for fatal or non-fatal stroke, increasing to a ~6.4-fold higher risk in untreated patients (AHI>10 events/hour) over a median of 6.8 years of follow-up[57]. Taken together, these results indicate an enhanced risk of stroke in patients with OSA that occurs independently of other risk factors and which is related to OSA severity. The absence of effective OSA treatments can have a detrimental effect on stroke risk[57].

Atherosclerosis

Coronary computed tomography angiography images indicate that the severity of OSA increases both non-calcified/ mixed coronary plaques and total arterial stenosis scores. Patients with severe OSA have 3.8- times (95%CI=1.46-10.40; p=0.01) greater risk of non-calcified/mixed plaques independent of other risk factors, so increasing their vulnerability to acute coronary syndrome[58].

Early markers of atherosclerosis in hypertensive and OSA groups suggest that carotid intima-media thickness and carotid diameter is increased in individuals with either OSA or hypertension, but that these were exaggerated in patients with both OSA and hypertension, where there was also decreased carotid distensibility[59]. These results suggest additive effects OSA and hypertension on the progression of atherosclerosis and that OSA is independently associated with carotid intimamedia thickness[59].

Heart failure

Patients with heart failure (HF) frequently report sleepdisordered breathing, and pathophysiological links between these conditions lead to decompensation of heart failure in OSA patients[60]. However, some suggest that the high prevalence of OSA in patients with HF may be related to demographic criteria (age, sex, ethnicity, and race), similar risk factors (obesity and comorbid conditions), AHI cutoff, and severity of HF[61],[62].

A cross-sectional analysis of 6,424 adults from the Sleep Heart Health Study indicates that OSA is associated with a 2.38 increase in the relative odds of presenting with HF[61]. This association is reinforced by two different studies of patients with OSA confirmed by polysomnography[60],[63]. These studies report that 21% of individuals with HF and preserved ejection fraction (HFpEF) have OSA, 11% of individuals with HF and reduced ejection fraction (HFrEF) have OSA, and 7.7% of all OSA patients have left ventricular ejection fraction <50%[60],[63]. Despite the positive findings proposing a strong association between OSA and HF, large RCTs with longer follow-up periods have not been reported.

Influence of OSA treatment on cardiovascular consequences

The current gold-standard treatment for OSA is the continuous positive airway pressure (CPAP) device, which consists in a mask that is attached to a pump that forces air into the upper airways through the nasal passages. The continuous pressure during both inspiration and expiration must be sufficient to overcome the structural obstruction in the upper airways. The majority of studies of OSA treatment is based on interventions with CPAP (see [Table 2]), although there are also other approaches such as lifestyle changes (e.g., reduction of BMI, avoidance of alcohol and sedatives before bedtime), surgical procedures (specially uvulopalatopharyngoplasty - UPPP), oral appliances, and other devices for enlargement of nostril orifices (see [Table 3]).

Table 2

Evidence of CPAP effects in cardiovascular diseases.

Cardiovascular disease	Observations made based on CPAP therapeutical effects
Hypertension	Minimum CPAP use of at least 4 hours is able to reduce BP pressure in all profiles of hypertension[64] CPAP also reduces BP in resistant hypertension patients, with a better response proportional to OSA severity[65]-[72].
Atrial fibrillation	CPAP reduces AF development risk in 42% and its recurrence (42% vs. 82%)[73]-[76]. CPAP also reduces the risk of progression to permanent AF (HR=0.66)[76],[77].
Cerebrovascular disease	A recent RCT indicates that patients who were adherent to CPAP therapy had a lower risk for stroke (HR=0.56) and for composite endpoint of cerebral events (HR=0.52)[78]. These results were not adjusted for multiple testing, and post hoc CPAP dose-response analysis showed no significant associations[78]. A different RCT suggests no benefit of CPAP treatment on cerebrovascular risk reduction[79].
Atherosclerosis	A RCT showed that CPAP treatment reverses markers of atherosclerosis, decreases carotid intima-media thickness, pulse-wave velocity, C-reactive protein, and catecholamines after 4 months[80]. It is also shown a reduction in tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6)[81]. Withdrawal of CPAP treatment exacerbates endothelial dysfunction in patients with minimally symptomatic OSA[82],[83].
Heart failure	CPAP usage shows some positive outcomes, such as improvements in LVEF and pulmonary pressure in 12 weeks. Among patients with LVEF lower than 45%, CPAP led to an improvement in LVEF from 25 to 35% (p<0.001) and reduction in systolic blood pressure by 10mmHg (p=0.03) after a month of treatment[84]-[86]. Nonetheless, this treatment reduces biochemical markers of HF (sympathetic activity)[87]. There are still some questions about the effects of CPAP on the survival rate. Some studies show improvement, as the risk for death and hospitalization was increased in the untreated group (HR=2.03) and in less compliant CPAPtreated patients (HR=4.02) when compared to the compliant CPAP-treated group[88]. Meanwhile, other studies don’t show improvements in this matter[84],[89]. Still, HF patients with OSA treated with CPAP continue to experience rostral fluid shifts during sleep, increasing neck circumference[31].

Abbreviations: CPAP = Continuous positive airway pressure; BP = Blood pressure; OSA = Obstructive sleep apnea; AF = Atrial fibrillation; HR = Hazard ratio; RCT = Randomized controlled trial; LVEF = Left ventricular ejection fraction; HF = Heart failure.

Table 3

Evidence of alternative OSA treatments.

Treatment	Description	Observations made on its therapeutical effects
Lifestyle changes	A combination of behavioral interventions, aiming weight loss (through dietary changes and exercising), sleep hygiene and avoidance of alcohol and tobacco consumption.	Several meta-analysis and systematic reviews indicate that lifestyle changes can improve OSA primary outcomes, such as AHI, oxygen desaturation, and excessive daytime drowsiness[94]-[99]. A recent RCT shows reductions of BP, independently and associated with CPAP therapy, being stronger in the combined approach[100]. Additionally, growing evidence supports weight loss can reduce AF burden and arrhythmia related complications[18],[101],[102]. Weight loss and frequent exercises are also related to reducing platelet reactivity and aggregation, reducing atherosclerosis and stroke risk[103].
Oral appliance therapy (OAT)	Oral appliances to treat OSA fall into two broad categories: tongue retaining devices and mandibular advancement splints (MAS). MAS are extensively used and the predominant category. The appliance aims to slightly advance the mandible forward and enlarge the upper airway. It also prevents the collapse of the throat passage. There are several designs and the selection of the most appropriate model, besides its degree of advancement and fitting, require a special training and a qualified professional.	Hypertension: two different studies reported that oral appliances led to slight reductions in mean 24-hour and awake BP, measured with 24-hour ambulatory blood pressure monitoring (ABPM), restricted to hypertensive patients[104],[105]. Andrén et al. (2013)[108] replicated the same results, however the ameliorations were observed only in moderate-severe OSA patients, after 3 months of treatment[107]. Contrariwise, Trzepizur et al. (2009)[109] did not find any changes in blood pressure (measured with a finger monitor) after 2 months with either oral appliance or CPAP therapy in treated hypertensive patients[110]. Atrial fibrillation: to date, there is a lack of good quality data assessing the effect of OAT on cardiac arrhythmias. Cerebrovascular disease: Anandam et al. (2013) reported a reduction in cardiovascular mortality, including stroke, after treatment with OAT[110]. However, the fatal events were a composite endpoint (stroke, myocardial infarction, sudden cardiac arrest and arrhythmias) and independent results for stroke were not available. Atherosclerosis: A recent RCT found no significant changes in most oxidative stress parameters after 1 month of oral appliances for moderate OSA patients[109]. Parallelly, a different study found that inflammatory markers (high sensitivity C-reactive protein, and fibrinogen) were reduced after 3 months, and 1 year of treatment with oral devices in mild to moderate OSA patients[110]. It is also shown that oral appliances resulted in a significant improvement in endothelial function after a treatment period of 2 months, and significant reductions in arterial stiffness after 1 month of oral appliance and CPAP therapy[105],[107]. Heart failure: Two studies assessed left ventricular mass and did not find any effect of oral appliance on this heart function parameter after 3 months of treatment. No further results were found[111],[112].
UPPP	The most common OSA surgical procedure is uvulopalatopharyngoplasty (UPPP). The surgery consists in removing excess of tissue from the back of the throat (tonsils, uvula, and part of the soft palate).	The benefits of UPPP on reducing OSA parameters and improving CVDs are extremely limited and no consistent data was found for the majority of conditions. For hypertension, a systematic review was found describing reductions in blood pressure in 5 studies (two as a primary outcome and 3 as a second)[113].

Abbreviations: OSA = Obstructive sleep apnea; AHI = Apnea/hypopnea index; RCT = Randomized controlled trial; BP = Blood pressure; CPAP = Continuous positive airway pressure; AF = Atrial fibrillation; CVDs = Cardiovascular diseases.

Continuous positive airway pressure (CPAP)

There is much evidence that CPAP reduces blood pressure and AF progression/recurrence in patients with OSA, but the benefits of CPAP in stroke (risk and/or progression) is unclear[74],[79]. There are many advantages of CPAP treatment in preventing atherosclerosis, although RCT studies and metaanalysis are needed to investigate changes in blood pressure and inflammatory markers by CPAP.

Most studies on the impact of CPAP on LVEF and other cardiac markers in HF are 1-3m onths in duration[87],[90],[91]. The reported amelioration of HF in RCTs should thus be evaluated with caution. The improvements noticed with CPAP therapy were assessed by measuring fatigue, drowsiness and humor, with no analysis of exercise capacity or shortness of breath (dyspnea). Improvements in the latter markers would better characterize improvements in cardiac insufficiency resulting from HF in OSA.

Despite some positive results, additional studies are still needed to access the benefits of CPAP on preventing CVD development and progression. Results may vary in their findings of CPAP benefits, likely due to differences in sample sizes, study designs, confounding variables, gender, OSA diagnostic methods, and variability in the duration and compliance of the CPAP treatments[70].

The sleep apnea cardiovascular endpoints (SAVE) study, an international, multicenter, randomized trial evaluated the long-term benefits of CPAP on cardiovascular events in 2,717 OSA patients. CPAP and control groups were matched for age, gender and BMI. The SAVE study reported that CPAP treatment failed to improve cardiovascular outcomes and did not prevent progression to more chronic conditions such as heart failure[78]. These results suggest that CPAP therapy should not be used as a primary treatment for protection against CV events or reducing mortality[78], and also supported by a more recent systematic review of the poor efficacy of CPAP therapy in reducing cardiovascular risk[92]. Nevertheless, it is important to note that there are other benefits of CPAP therapy, such as improvements in sleep quality and daytime function, in patients with cardiovascular diseases[93]. In addition, it must be recognized that the patients in the SAVE study were in general not sleepy and CPAP adherence was low; these may have also contributed to the null results[94],[95].

Alternative strategies

The literature describing the effects of lifestyle changes on cardiovascular outcomes and OSA is scarce and inconclusive. Despite overall favorable improvements in measures of sleep apnea, possible benefits of CVD in OSA are unclear except for reductions in blood pressure in such patients. Studies of the comparative, additive or independent benefits of weight loss and lifestyle modifications in obese OSA patients with cardiovascular comorbidities are unavailable. It is likely that improvements were likely related to the direct effects of lifestyle modifications on CVD outcomes rather than on reducing the impact of OSA on cardiovascular pathologies. Nevertheless, the clinical benefits of reductions of blood pressure and OSA parameters (AHI, daytime sleepiness, and O2 desaturation) due to lifestyle modifications have not been reported in RCTs with long follow-up periods.

Studies on the effects of uvulopalatopharyngoplasty (UPPP) on blood pressure report mixed results[113]. Potential reasons for this may be that some studies failed to adjust for the use of antihypertensive medications, had differences in outcomes such as UPPP success rates and frequency of blood pressure measurement (office-based blood pressure measurements were predominantly used, rather than home or ambulatory measurements). Importantly, the majority of studies were case reports or cohort studies with limited sample sizes.

Several recent publications report some benefits of surgical procedures on AF[18],[115]. Renal sympathetic denervation (RSD) shows promising effects on reducing AF[18],[115], possibly due to reductions of arrhythmogenic atrial autonomic, structural and electrical remodeling; RSD is as efficient as combined therapy with beta-blockers and angiotensin receptor blockers[116]. These findings are mostly from isolated pre-clinical animal studies; clinical studies in OSA populations are needed to establish RSD as an alternative approach.

The positive outcomes of oral appliance therapy (OAT) in the treatment of OSA are mostly inconclusive. Comparative studies on cardiovascular outcomes using different therapies for OSA are relatively scarce[116], although a cohort study reports that oral appliances are as effective as CPAP in reducing cardiovascular death (HR=1.08)[108], although this is inconsistent with other findings that show that CPAP does not alter cardiovascular mortality[78],[92].

Although small reductions in blood pressure are important (every 5mmHg reduction in the mean systolic BP reduces cardiovascular risk by 17%), the minor reductions observed in many studies using alternate therapies for OSA (ranging from-0.07 to-0.77mmHg) may have limited clinical impact[105]-[107],[109],[117]-[119], as they were based on the findings using relatively short follow-up periods (1-3 months) with small patient sample sizes[105]-[107],[109].

Two studies reported improvements in arterial stiffness and endothelium function with OAT[106],[107]. Only few studies evaluated the effects of OAT circulating cardiovascular biomarkers of OSA[110],[111],[119]; these studies were generally underpowered and evaluated a variety of outcomes, such as oxidative stress parameters (thiobarbituric acid reactive substances, erythrocyte superoxide dismutase activity, uric acid, homocysteine, folate, and vitamins B12 and E dosages) and inflammatory markers (high sensitivity C-reactive protein, and fibrinogen). More extensive studies are needed to elucidate the effects of OAT on circulating cardiovascular biomarkers of OSA and their clinical relevance to atherosclerosis and cerebrovascular disease. The evidence describing the therapeutic potential of OAT on CVD outcomes in OSA is still at its infancy. Additional studies directly comparing cardiovascular event rates are important, but will probably require RCTs with large patient groups and also long-term follow-up studies.

CONCLUSION

Our understanding of OSA and its association with CVDs continues to evolve. This brief survey of the literature indicates that OSA both predisposes to and aggravates hypertension, atrial fibrillation, and cerebrovascular disease. The relationship between OSA and atherosclerosis and HF, while being plausible, needs more extensive investigation. It is difficult to establish a causal effect of OSA on CVDs, as these are related in a multidirectional manner. Future studies should focus on risk stratification of OSA patients related to adverse cardiovascular outcomes. Studies to identify new OSA-specific biomarkers of cardiovascular risk are needed.

Additionally, there is a need for large-scale, randomized, well-controlled studies on the effects of CPAP on cardiovascular diseases such as hypertension, atrial fibrillation, stroke, atherosclerosis, and heart failure that are unhindered by issues of poor compliance.

There are only a few studies on the modest benefits of alternative therapies for OSA on reducing CVDs in OSA. The clinical benefits of surgical treatment of OSA on CVD in OSA are unclear. Lifestyle changes can improve sleep-apnea parameters and hypertension. However, the degree of their influence (additive or independent) and whether these changes are clinically relevant is unclear. Oral appliances likely reduce blood pressure, atherosclerosis and stroke in OSA, but more rigorous large scale RCTS are needed. Long-term populational studies that directly compare cardiovascular event rates with different management protocols of OSA would be informative.

Conflict of Interests

The authors have no conflict of interests to declare.

• REFERENCES

• 1 Sarkar P, Mukherjee S, Chai-Coetzer CL, McEvoy RD. The epidemiology of obstructive sleep apnoea and cardiovascular disease. J Thorac Dis. 2018 Dec;10(Suppl 34):S4189-S200.
• 2 Sânchez-de-la-Torre M, Campos-Rodriguez F, Barbé F. Obstructive sleep apnoea and cardiovascular disease. Lancet Respir Med. 2013 Mar;1(1):61-72.
• 3 Kohler M, Stradling JR. Mechanisms of vascular damage in obstructive sleep apnea. Nat Rev Cardiol. 2010 Dec;7(12):677-85.
• 4 Canadian Agency for Drugs and Technologies in Health (CADTH). Portable monitoring devices for diagnosis of obstructive sleep apnea at home: review of accuracy, cost- effectiveness, guidelines, and coverage in Canada. CADTH Technol Overv. 2010 Dec;1(4):e0123.
• 5 World Health Organization (WHO). Cardiovascular diseases [Internet]. Geneva: WHO; 2017; [access in 2019 Nov 26]. Available from: https://www. who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
• 6 Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000 May;342(19):1378-4.
• 7 Ramar K, Caples SM. Cardiovascular consequences of obese and nonobese obstructive sleep apnea. Med Clin North Am. 2010 May;94(3):465-78.
• 8 Gottlieb DJ, Yenokyan G, Newman AB, O’Connor GT, Punjabi NM, Quan FS, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation. 2010 Jul;122(4):352-60.
• 9 Xu S, Wan Y, Xu M, Ming J, Xing Y, An F, et al. The association between obstructive sleep apnea and metabolic syndrome: a systematic review and meta-analysis. BMC Pulm Med. 2015;15:105.
• 10 Selim BJ, Ramar K. Management of sleep apnea syndromes in heart failure. Sleep Med Clin. 2017 Mar;12(1):107-21.
• 11 Stowhas AC, Namdar M, Biaggi P, Russi EW, Bloch KE, Stradling JR, et al. The effect of simulated obstructive apnea and hypopnea on aortic diameter and BP. Chest. 2011 Sep;140(3):675-80.
• 12 Virolainen J, Ventila M, Turto H, Kupari M. Effect of negative intrathoracic pressure on left ventricular pressure dynamics and relaxation. J Appl Physiol (1985). 1995 Aug;79(2):455-60.
• 13 Orban M, Bruce CJ, Pressman GS, Leinveber P, Romero-Corral A, Korinek J, et al. Dynamic changes of left ventricular performance and left atrial volume induced by the Mueller maneuver in healthy young adults and implications for obstructive sleep apnea, atrial fibrillation, and heart failure. Am J Cardiol. 2008 Dec;102(11):1557-61.
• 14 Haïssaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998 Sep;339(10):659-66.
• 15 Caples SM, Somers VK. Sleep disordered breathing and atrial fibrillation. Progress in cardiovascular diseases. 2009 Mar/Apr;51(5):411.
• 16 Bradley TD, Hall MJ, Ando SI, Floras JS. Hemodynamic effects of simulated obstructive apneas in humans with and without heart failure. Chest. 2001 Jun;119(6):1827-35.
• 17 Korantzopoulos P, Kolettis TM, Galaris D, Goudevenos JA. The role of oxidative stress in the pathogenesis and perpetuation of atrial fibrillation. Int J Cardiol. 2007 Feb;115(2):135-43.
• 18 Goudis CA, Ketikoglou DG. Obstructive sleep and atrial fibrillation: pathophysiological mechanisms and therapeutic implications. Int J Cardiol. 2017 Mar;230:293-300.
• 19 Chung MK, Martin DO, Sprecher D, Wazni O, Kanderian A, Carnes CA, et al. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation. 2001 Dec;104(24):2886-91.
• 20 Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso V, et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation. 2002 May;105(21):2462-4.
• 21 Skalidis EI, Hamilos MI, Karalis IK, Chlouverakis G, Kochiadakis GE, Vardas PE. Isolated atrial microvascular dysfunction in patients with lone recurrent atrial fibrillation. J Am Coll Cardiol. 2008;51(21):2053-7.
• 22 Pepin JL, Levy P. Pathophysiology of cardiovascular risk in sleep apnea syndrome. Rev Neurol. 2002 Sep;158(8-9):785-97.
• 23 Tkacova R, Hall MJ, Rutherford R, Floras JS, Bradley TD. Effect of continuous positive airway pressure on nocturnal blood pressure in patients with heart failure and obstructive sleep apnea. Circulation. 1996;94:I340.
• 24 Tsai CT, Chiang FT, Tseng CD, Hwang JJ, Kuo KT, Wu CK, et al. Increased expression of mineralocorticoid receptor in human atrial fibrillation and a cellular model of atrial fibrillation. J Am Coll Cardiol. 2010 Feb;55(8):758-70.
• 25 Spaak J, Egri ZJ, Kubo T, Yu E, Ando SI, Kaneko Y, et al. Muscle sympathetic nerve activity during wakefulness in heart failure patients with and without sleep apnea. Hypertension. 2005 Dec;46(6):1327-32.
• 26 Goldberger JJ, Cain ME, Hohnloser SH, Kadish AH, Knight BP, Lauer MS, et al. American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society Scientific Statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death. Circulation. 2008 Sep;118(14):1497-518.
• 27 Floras JS. Should sleep apnoea be a specific target of therapy in chronic heart failure? Heart. 2009;95(13):1041-6.
• 28 Fung JW, Li TS, Choy DK, Yip GWK, Ko FWS, Sanderson JE, et al. Severe obstructive sleep apnea is associated with left ventricular diastolic dysfunction. Chest. 2002 Feb;121(2):422-9.
• 29 Laaban JP, Pascal-Sebaoun S, Bloch E, Orvoen-Frija E, Oppert JM, Huchon G. Left ventricular systolic dysfunction in patients with obstructive sleep apnea syndrome. Chest. 2002 Oct;122(4):1133-8.
• 30 Oliveira W, Campos O, Lira-Filho EB, Cintra FD, Vieira M, Ponchirolli A, et al. Left atrial volume and function in patients with obstructive sleep apnea assessed by real-time three-dimensional echocardiography. J Am Soc Echocardiogr. 2008 Dec;21(12):1355-61.
• 31 Yumino D, Redolfi S, Ruttanaumpawan P, Su MC, Smith S, Newton GE, et al. Nocturnal rostral fluid shift: a unifying concept for the pathogenesis of obstructive and central sleep apnea in men with heart failure. Circulation. 2010 Apr;121(14):1598-605.
• 32 Lorenzi-Filho G, Drager LF. Obstructive sleep apnea and atherosclerosis: a new paradigm. Am J Respir Crit Care Med. 2007 Jun;175(12):1219-21.
• 33 Lyons OD, Clodagh MR. Sleep apnea and stroke. Can J Cardiol. 2015;31(7):918-27.
• 34 Lévy P, Pépin JL, Arnaud C, Tamisier R, Borel JC, Dematteis M, et al. Intermittent hypoxia and sleep-disordered breathing: current concepts and perspectives. Eur Respir J. 2008 Oct;32(4):1082-95.
• 35 Min LI, Xiaoying LI, Yan LU. Obstructive sleep apnea syndrome and metabolic diseases. Endocrinology. 2018 Jul;159(7):2670-5.
• 36 Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A, Lin HM, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab. 2000 Mar;85(3):1151-8.
• 37 Pedrosa RP, Drager LF, Gonzaga CC, Hopper K, Lotsikas A, Lin HM, et al. Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension. 2011 Nov;58(5):811-7.
• 38 Goncalves SC, Martinez D, Gus M, Abreu-Silva EO, Bertoluci C, Dutra I, et al. Obstructive sleep apnea and resistant hypertension: a casecontrol study. Chest. 2007 Dec;132(6):1858-62.
• 39 Young T, Palta M, Dempsey J, Peppard PE, Nieto FJ, Hla KM. Burden of sleep apnea: rationale, design, and major findings of the Wisconsin Sleep Cohort study. WMJ. 2009 Aug;108(5):246-9.
• 40 Hou H, Zhao Y, Yu W, Dong H, Xue X, Ding J, et al. Association of obstructive sleep apnea with hypertension: a systematic review and meta-analysis. J Glob Health. 2018 Jun;8(1):010405.
• 41 Haas DC, Foster GL, Javier Nieto F, Redline S, Resnick HE, Robbins JA, et al. Age-dependent associations between sleep-disordered breathing and hypertension: importance of discriminating between systolic/diastolic hypertension and isolated systolic hypertension in the Sleep Heart Health Study. Circulation. 2005 Feb;111(5):614-21.
• 42 Glasser M, Bailey N, McMillan A, Goff E, Morrell MJ. Sleep apnoea in older people. Breathe. 2011;7:248-56.
• 43 Gami AS, Pressman G, Caples SM, Kanagala R, Gard JJ, Davison DE, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation. 2004 Jul;110(4):364-7.
• 44 Uchôa CHG, Danzi-Soares NJ, Nunes FS, Souza AAL, Nerbass FB, Pedrosa RP, et al. Impact of OSA on cardiovascular events after coronary artery bypass surgery. Chest. 2015 May;147(5):1352-60.
• 45 Wolk R, Kara T, Somers VK. Sleep-disordered breathing and cardiovascular disease. Circulation. 2003 Jul;108(1):9-12.
• 46 Mehra R, Benjamin EJ, Shahar E, Gottlieb DJ, Nawabit R, Kirchner HL, et al. Association of nocturnal arrhythmias with sleep disordered breathing: the sleep heart health study. Am J Respir Crit Care Med. 2006 Apr;173(8):910-6.
• 47 Youssef I, Kamran H, Yacoub M, Patel N, Goulbourne C, Kumar S, et al. Obstructive sleep apnea as a risk factor for atrial fibrillation: a metaanalysis. J Sleep Disord Ther. 2018;7(1):282.
• 48 Lorenzi Filho G, Genta PR, Pedrosa RP, Drager LF, Martinez D. Cardiovascular consequences of obstructive sleep apnea syndrome. J Bras Pneumol. 2010;36(Suppl 2):38-42.
• 49 Mehra R, Stone KL, Varosy PD, Hoffman AR, Marcus GM, Blackwell T, et al. Nocturnal arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study. Arch Intern Med. 2009 Jun;169(12):1147-55.
• 50 Holmqvist F, Guan N, Zhu Z, Kowey PR, Allen LA, Fonarow GC, et al. Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in patients with atrial fibrillation: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Am Heart J. 2015;169(5):647.e2-54.e2.
• 51 Abumuamar AM, Dorian P, Newman D, Shapiro CM. The prevalence of obstructive sleep apnea in patients with atrial fibrillation. Clin Cardiol. 2018 May;41(5):601-7.
• 52 Benjafield AV, Ayas NT, Eastwood PR, Heinzer R, Ip MSM, Morell MJ, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature based analysis. Lancet Respir Med. 2019 Aug;7(8):687-98.
• 53 Dong R, Dong Z, Liu H, Shi F, Du J. Prevalence, risk factors, outcomes, and treatment of obstructive sleep apnea in patients with cerebrovascular disease: a systematic review. J Stroke Cerebrovasc Dis. 2018 Jun;27(6):1471-80.
• 54 Johnson KG, Johnson DC. Frequency of sleep apnea in stroke and TIA patients: a meta-analysis. J Clin Sleep Med. 2010 Apr;6(2):131-7.
• 55 Wu Z, Chen F, Yu F, Wang Y, Guo Z. A meta-analysis of obstructive sleep apnea in patients with cerebrovascular disease. Sleep Breath. 2018 Sep;22(3):729-42.
• 56 Wang X, Ouyang Y, Wang Z, Zhao G, Liu L, Bi Y. Obstructive sleep apnea and risk of cardiovascular disease and all-cause mortality: a meta-analysis of prospective cohort studies. Int J Cardiol. 2013 Nov;169(3):207-14.
• 57 Li M, Hou W, Zhang X, Tang Z. Obstructive sleep apnea and risk of stroke: a meta- analysis of prospective studies. Int J Cardiol. 2014 Mar;172(2):466-9.
• 58 Somuncu MU, Bulut U, Karakurt H, Utkusavas A, Akbay E, Kilinc FK. The relationship between obstructive sleep apnea and coronary plaque: a coronary computed tomographic angiography study. Acta Cardiol Sin. 2019;35(3):325-34.
• 59 Drager LF, Bortolotto LA, Krieger EM, Lorenzi-Filho G. Additive effects of obstructive sleep apnea and hypertension on early markers of carotid atherosclerosis. Hypertension. 2009 Jan;53(1):64-9.
• 60 Chadda KR, Fazmin IT, Ahmad S, Valli H, Edling CE, Haung CLH, et al. Arrhythmogenic mechanisms of obstructive sleep apnea in heart failure patients. Sleep. 2018 Sep;41(9):zsy136.
• 61 Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med. 2001 Jan;163(1):19-25.
• 62 Khattak HK, Hayat F, Pamboukian SV, Hahn HS, Schwartz BP, Stein PK. Obstructive sleep apnea in heart failure: review of prevalence, treatment with continuous positive airway pressure, and prognosis. Tex Heart Inst J. 2018 Jun;45(3):151-61.
• 63 Wachter R, Lüthje L, Klemmstein D, Lüers C, Stahrenberg R, Edelmann F, et al. Impact of obstructive sleep apnoea on diastolic function. Eur Respir J. 2012 Feb;41(2):376-83.
• 64 Martínez-García M, Capote F, Campos-Rodriguez F, Lloberes P, Díaz MJ, Somoza M, et al. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA. 2013 Dec;310(22):2407-15.
• 65 Montesi SB, Edwards BA, Malhotra A, Bakker JP. The effect of continuous positive airway pressure treatment on blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Clin Sleep Med. 2012 Oct;8(5):587-96.
• 66 Liu L, Cao Q, Guo Z, Dai Q. Continuous positive airway pressure in patients with obstructive sleep apnea and resistant hypertension: a meta-analysis of randomized controlled trials. J Clin Hypertens. 2016 Feb;18(2):153-8.
• 67 Iftikhar IH, Valentine CW, Bittencourt LR, Cohen DL, Fedson AC, Gíslason T, et al. Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: a metaanalysis. J Hypertens. 2014 Dec;32(12):2341-50.
• 68 Haentjens P, Van Meerhaeghe A, Moscariello A, Weerdt S, Poppe K, Dupont A, et al. The impact of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea syndrome: evidence from a meta-analysis of placebo-controlled randomized trials. Arch Intern Med. 2007 Apr;167(8):757-64.
• 69 Fava C, Dorigoni S, Vedove DF, Danese E, Montagnana M, Guidi GC, et al. Effect of CPAP on blood pressure in patients with OSA/hypopnea: a systematic review and meta-analysis. Chest. 2014 Apr;145(4):762-71.
• 70 Durán-Cantolla J, Aizpuru F, Martínez-Null C, Barbé-Illa F. Obstructive sleep apnea/hypopnea and systemic hypertension. Sleep Med Rev. 2009 Oct;13(5):323-31.
• 71 Bakker JP, Edwards BA, Gautam SP, Montesi SB, Durân-Cantolla J, Barandiarân FA, et al. Blood pressure improvement with continuous positive airway pressure is independent of obstructive sleep apnea severity. J Clin Sleep Med. 2014 Apr;10(4):365-9.
• 72 Pedrosa RP, Drager LF, Paula LK, Amaro ACS, Bortolotto LA, Lorenzi- Filho G. Effects of OSA treatment on BP in patients with resistant hypertension: a randomized trial. Chest. 2013 Nov;144(5):1487-94.
• 73 Qureshi WT, Nasir UB, Alqalyoobi S, O’Neal WT, Mawri S, Sabbagh S, et al. Meta- analysis of continuous positive airway pressure as a therapy of atrial fibrillation in obstructive sleep apnea. Am J Cardiol. 2015 Dec;116(11):1767-73.
• 74 Bradley TD, Hall MJ, Ando SI, Floras JS. Hemodynamic effects of simulated obstructive apneas in humans with and without heart failure. Chest. 2001 Jun;119(6):1827-35.
• 75 Kanagala R, Murali NS, Friedman PA, Naser A, Gersh BJ, Ballman KV, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003 May;107(20):2589-94.
• 76 Tung P, Anter E. Atrial fibrillation and sleep apnea: Considerations for a dual epidemic. J Atr Fibrillation. 2016 Apr/May;8(6):1283.
• 77 Marulanda-Londoño E, Chaturvedi E. The interplay between obstructive sleep apnea and atrial fibrillation. Front Neurol. 2017 Dec;8:668.
• 78 McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, et al. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Eng J Med. 2016 Sep;375(10):919-31.
• 79 Hsu CY, Vennelle M, Li HY, Engleman HM, Dennis MS, Douglas NJ. Sleep-disordered breathing after stroke: a randomised controlled trial of continuous positive airway pressure. J Neurol Neurosurg Psychiatry. 2006 oct;77(10):1143-9.
• 80 Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, Lorenzi GF. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med. 2007 Oct;176(7):706-12.
• 81 Baessler A, Nadeem R, Harvey M, Madbouly E, Younus A, Sajid H, et al. Treatment for sleep apnea by continuous positive airway pressure improves levels of inflammatory markers - a meta-analysis. J Inflamm (Lond). 2013 Mar;10:13.
• 82 Kohler M, Craig S, Pepperell JC, Nicoll D, Bratton DJ, Nunn AJ, et al. CPAP improves endothelial function in patients with minimally symptomatic OSA: results from a subset study of the MOSAIC trial. Chest. 2013 Sep;144(3):896-902.
• 83 Kohler M, Stoewhas AC, Ayers L, Senn O, Bloch KE, Russi EW, et al. Effects of continuous positive airway pressure therapy withdrawal in patients with obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med. 2011 Nov;184(10):1192-9.
• 84 Kaneko Y, Floras JS, Usui K, Plante J, Tkacova R, Kubo T, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med. 2003 Mar;348(13):1233-41.
• 85 Shim CY, Kim D, Park S, Lee CJ, Cho HJ, Ha JW, et al. Effects of continuous positive airway pressure therapy on left ventricular diastolic function: a randomised, sham-controlled clinical trial. Eur Respir J. 2018 Jan;51(2):1701774.
• 86 Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, et al. Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for high blood pressure research professional education committee, council on clinical cardiology, stroke council, and council on cardiovascular nursing. J Am Coll Cardiol. 2008 Aug;52(8):686-717.
• 87 Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005 Nov;353(19):2034-41.
• 88 Kasai T, Narui K, Dohi T, Yanagisawa N, Ishiwata S, Ohno M, et al. Prognosis of patients with heart failure and obstructive sleep apnea treated with continuous positive airway pressure. Chest. 2008 Mar;133(3):690-6.
• 89 Naughton MT, Kee K. Sleep apnoea in heart failure: to treat or not to treat? Respirology. 2017 Feb;22(2):217-29.
• 90 Mansfield DR, Gollogly NC, Kaye DM, Richardson M, Bergin P, Naughton MT. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med. 2004 Feb;169(3):361-6.
• 91 Wang H, Parker JD, Newton GE, Floras JS, Mak S, Chiu KL, et al. Influence of obstructive sleep apnea on mortality in patients with heart failure. J Am Coll Cardiol. 2007 Apr;49(15):1625-31.
• 92 Labarca G, Dreyse J, Drake L, Jorquera J, Barbe F. Efficacy of continuous positive airway pressure (CPAP) in the prevention of cardiovascular events in patients with obstructive sleep apnea: systematic review and meta-analysis. Sleep Med Rev. 2020 Aug;52:101312.
• 93 Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, et al. HFSA 2010 comprehensive heart failure practice guideline. J Card Fail. 2010 Jun;16(6):e1-e194.
• 94 Mokhlesi B, Ayas NT. Cardiovascular events in obstructive sleep apnea - can CPAP therapy SAVE lives? N Engl J Med. 2016 Sep;375(10):994-6.
• 95 Pack AI, Magalang UJ, Singh B, Kuna ST, Keenan BT, Maislin G. Randomized clinical trials of cardiovascular disease in obstructive sleep apnea: understanding and overcoming bias. Sleep. 2021 Feb;44(2):zsaa229. https://doi.org/10.1093/sleep/zsaa229
• 96 Aiello KD, Caughey WG, Nelluri B, Sharma A, Mookadam F, Mookadam M. Effect of exercise training on sleep apnea: a systematic review and meta-analysis. Respir Med. 2016 Jul;116:85-92.
• 97 Araghi MH, Chen YF, Jagielski A, Choudhury S, Banerjee D, Hussain S, et al. Effectiveness of lifestyle interventions on obstructive sleep apnea (OSA): systematic review and meta-analysis. Sleep. 2013 Oct;36(10):1553-62.
• 98 Iftikhar IH, Bittencourt L, Youngstedt SD, Ayas N, Cistulli P, Schwab R, et al. Comparative efficacy of CPAP, MADs, exercise-training, and dietary weight loss for sleep apnea: a network meta-analysis. Sleep Med. 2017 Feb;30:7-14.
• 99 Mitchell LJ, Davidson ZE, Bonham M, O’Driscoll DM, Hamilton GS, Truby H. Weight loss from lifestyle interventions and severity of sleep apnoea: a systematic review and meta-analysis. Sleep Med. 2014 Oct;15(10):1173-83.
• 100 Ng WL, Stevenson CE, Wong E, Tanamas S, Boelsen-Robinson T, Shaw JE, et al. Does intentional weight loss improve daytime sleepiness? A systematic review and meta- analysis. Obes Rev. 2017 Apr;18(4):460-75.
• 101 Thomasouli MA, Brady EM, Davies MJ, Hall AP, Khunti K, Morris DH, et al. The impact of diet and lifestyle management strategies for obstructive sleep apnoea in adults: a systematic review and meta-analysis of randomised controlled trials. Sleep Breath. 2013 Sep;17(3):925-35.
• 102 Chirinos JA, Gurubhagavatula I, Teff K, Rader DJ, Wadden TA, Townsend R, et al. CPAP, weight loss, or both for obstructive sleep apnea. N Engl J Med. 2014 Jun;370(24):2265-75.
• 103 Abed HS, Wittert GA, Leong DP, Shirazi MG, Bahrami B, Middeldorp ME, et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial. JAMA. 2013 Nov;310(19):2050-60.
• 104 Pathak RK, Middeldorp ME, Meredith M, Mehta AB, Mahajan R, Wong CX, et al. Long-term effect of goal-directed weight management in an atrial fibrillation cohort: a long-term follow-up study (LEGACY). J Am Coll Cardiol. 2015 May;65(20):2159-69.
• 105 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 Jun;127(6):2076-84.
• 106 Andrén A, Hedberg P, Walker-Engström ML, Wahlén P, Tegelberg A. Effects of treatment with oral appliance on 24-h blood pressure in patients with obstructive sleep apnea and hypertension: a randomized clinical trial. Sleep Breath. 2013 May;17(2):705-12.
• 107 Gotsopoulos H, Kelly JJ, Cistulli PA. Oral appliance therapy reduces blood pressure in obstructive sleep apnea: a randomized, controlled trial. Sleep. 2004 Aug;27(5):934-41.
• 108 Trzepizur W, Gagnadoux F, Abraham P, Rousseau P, Meslier N, Saumet J, et al. Microvascular endothelial function in obstructive sleep apnea: Impact of continuous positive airway pressure and mandibular advancement. Sleep Med. 2009 Aug;10(7):746-52.
• 109 Phillips CL, Grunstein RR, Darendeliler MA, Mihailidou AS, Srinivasan VK, Yee BJ, et al. Health outcomes of continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med. 2013 Apr;187(8):879-87.
• 110 Anandam A, Patil M, Akinnusi M, Jaoude P, El-Solh AA. Cardiovascular mortality in obstructive sleep apnoea treated with continuous positive airway pressure or oral appliance: an observational study. Respirology. 2013 Nov;18(8):1184-90.
• 111 Dal-Fabbro C, Garbuio S, D’Almeida V, Cintra FD, Tufik S, Bittencourt L. Mandibular advancement device and CPAP upon cardiovascular parameters in OSA. Sleep Breath. 2014 Dec;18(4):749-59.
• 112 Galic T, Bozic J, Ivkovic N, Gunjaca G, Ticinovic TK, Dogas Z. Effects of mandibular advancement device treatment on arterial stiffness and glucose metabolism in patients with mild to moderate obstructive sleep apnea: a prospective 1 year study. Sleep Breath. 2016;20(1):69-77.
• 113 Barnes M, McEvoy RD, Banks S, Tarquinio N, Murray CG, Vowles N, et al. Efficacy of positive airway pressure and oral appliance in mild to moderate obstructive sleep apnea. Am J Respir Crit Care Med. 2004;170(6):656-64.
• 114 Hoekema A, Voors AA, Wijkstra PJ, Stegenga B, Van Der Hoeven JH, Tol CG, et al. Effects of oral appliances and CPAP on the left ventricle and natriuretic peptides. Int J Cardiol. 2008 Aug;128(2):232-9.
• 115 Halle TR, Oh MS, Collop NA, Quyyumi AA, Bliwise DL, Dedhia RC. Surgical treatment of OSA on cardiovascular outcomes: a systematic review. Chest. 2017 Dec;152(6):1214-29.
• 116 Huang B, Liu H, Scherlag BJ, Sun L, Xing S, Xu J, et al. Atrial fibrillation in obstructive sleep apnea: Neural mechanisms and emerging therapies. Trends Cardiovasc Med. 2020 Feb;31(2):127-32.
• 117 Linz D, Hohl M, Nickel A, Mahfoud F, Wagner M, Ewen M, et al. Effect of renal denervation on neurohumoral activation triggering atrial fibrillation in obstructive sleep apnea. Hypertension. 2013 Oct;62(4):767-74.
• 118 Van Haesendonck G, Dieltjens M, Kastoer C, Shivalkar B, Vrints C, Van De Heyning CM, et al. Cardiovascular benefits of oral appliance therapy in obstructive sleep apnea: a systematic review. J Dent Sleep Med. 2015 Jan;2(1):9-14.
• 119 Hermida RC, Ayala DE, Fernández JR, Mojón A. Sleep-time blood pressure: prognostic value and relevance as a therapeutic target for cardiovascular risk reduction. Chronobiol Int. 2013 Mar;30(1-2):68-86.
• 120 Vries GE, Wijkstra PJ, Houwerzijl EJ, Kerstjen HA, Hoekema A. Cardiovascular effects of oral appliance therapy in obstructive sleep apnea: a systematic review and meta-analysis. Sleep Med Rev. 2018 Aug;40:55-68.

Publication History

Received: 25 June 2021

Accepted: 01 November 2021

Article published online:
01 December 2023