Introduction

Obstructive sleep apnea (OSA) is a breathing disorder where normal ventilation is impaired during sleep due to upper airway narrowing [1•]. Initially noted by scholars centuries ago as episodes of snoring and suffocating gasps coupled with perpetual drowsiness and difficulty in arousal [2], OSA is now diagnosed by polysomnography. The severity of OSA on polysomnography is designated using the apnea-hypopnea index (AHI). Based on this metric, The Wisconsin Sleep Cohort, a longitudinal population-based study established over two decades ago, estimated the prevalence of OSA to be 9% in women and 24% in men [3]. Since the Wisconsin Sleep Cohort’s inception, there has been a dramatic relative increase in prevalence of OSA over time. Extrapolating Wisconsin Sleep Cohort estimates to the US population using data from the National Health and Nutrition Examination Survey (NHANES) adjusted for sex, age, and body mass index (BMI), the prevalence of OSA in 2007–2010 compared with 1988–1994 increased by 14–55%, depending on the subgroup analyzed [4, 5].

The increase in prevalence of OSA has been linked to rising rates of obesity over the past several decades [6]. Obesity, central body fat distribution, and large neck girth are well-established risk factors for OSA (Fig. 1). Additional risk factors that have been linked to OSA include older age, male sex, craniofacial and upper airway abnormalities, and nighttime nasal congestion [7,8,9]. OSA has been associated with multiple adverse cardiovascular effects including hypertension, ischemic heart disease, stroke, and arrhythmias [10,11,12,13, 14••, 15•] as well as metabolic disorders including diabetes mellitus, lipid profile derangements, and non-alcoholic fatty liver disease [15•, 16,17,18,19]. These chronic sequelae are mediated by several pathophysiologic mechanisms that are upregulated in OSA, including elevated sympathetic nervous system activity, renin-angiotensin aldosterone system activity, endothelial dysfunction, inflammation, and metabolic dysregulation. Various treatment modalities are available for OSA, comprising lifestyle modifications, medical treatments, and surgical intervention [20]. Due to its increasing prevalence and significant adverse effects, untreated OSA has an appreciable economic burden, estimated between $34 and $69 billion annually worldwide [21].

Fig. 1
figure 1

Pathophysiologic drivers of hypertension and cardiovascular disease in obstructive sleep apnea. Obesity and large neck girth are strong independent risk factors for OSA. OSA can also increase the risk of obesity due to inactivity and neurohormonal dysregulation. OSA and obesity both result in elevated sympathetic nervous system activity, renin-angiotensin system activity, endothelial dysfunction, inflammation, and metabolic dysregulation that, in turn, increase the risk of developing hypertension and cardiovascular disease

Full size image

Risk Factors for Obstructive Sleep Apnea

Several anatomic and functional factors predispose patients to developing OSA. Anatomically, patients with OSA have been found to have craniofacial differences including smaller pharyngeal airways, larger volume of soft tissue surrounding their upper airway, lower placement of the hyoid bone, and larger volume of the lateral pharyngeal wall [7]. When awake, these patients are able to compensate by increasing upper airway muscle activity to maintain a patent airway [22]. During sleep, however, upper airway muscles relax and are dyssynchronous, likely contributing to airway obstruction [23]. While OSA occurs across a breadth of body sizes, many of these anatomic abnormalities occur more frequently in obesity and among individuals with large neck girths, contributing to the higher rates of OSA in obesity.

Upper airway patency is also influenced by functional factors such as leptin. In experimental models, leptin has been found to influence sleep architecture and upper airway resistance [24]. Leptin is a peptide produced by adipose tissue that affects satiety and plays a role in metabolic regulation including glucose and fatty acid metabolism as well as insulin resistance [25]. Leptin has also been suggested as a marker of cardiovascular disease risk [26]. Patients with OSA have elevated levels of leptin, with a positive correlation observed between leptin levels and severity of OSA [24]. Furthermore, Phillips et al. found that leptin levels were higher among 32 obese men with OSA compared with 32 matched obese controls without OSA, suggesting that OSA may play a role in leptin resistance [27]. The presence of leptin resistance in individuals with obesity and OSA likely hinders losing weight and contributes to worsening of OSA.

Epidemiology of Hypertension in Obstructive Sleep Apnea

The high prevalence of hypertension in individuals with OSA is well-established [14••], and there seems to be a dose-response relationship between OSA and blood pressure [28, 29]. OSA has been found to be particularly common in resistant and refractory hypertension [30, 31]. In a large cross-sectional study (n = 2677), the odds of HTN increased by 1% for every episode of apnea per hour of sleep and up to 13% for every 10% decrease in oxygen saturation [29] In The Sleep Heart Health Study, a cohort of 6132 patients, the prevalence of hypertension was found to be 59%, 62%, and 67% in mild, moderate, and severe sleep apnea, respectively [32]. The association of obstructive sleep apnea and hypertension was no longer significant in participants aged 60 years and older [33]. In the Wisconsin Sleep Cohort, there was a linear increase in blood pressure with increasing severity of sleep apnea, independent of age, sex, and BMI [28].

Evidence suggests that hypertension is a sequela of OSA [34], although the temporal relationship between OSA and hypertension is somewhat elusive. In a longitudinal analysis of The Sleep Heart Health Study, after excluding individuals who had hypertension at baseline, O’Connor et al. found a significant association between severity of OSA and risk of developing hypertension [35]. This association was no longer significant after adjusting for BMI. Similarly, in the Victoria Sleep Cohort, a longitudinal study of 2148 Spanish subjects followed for 7.5 years, Cano-Pumarega et al. demonstrated a significant association between severity of OSA and subsequent risk of incident hypertension, which dissipated after univariate adjustment for age, as well as adjustment for sex, BMI, fitness level, and several health behaviors [36]. Nonetheless, pooled meta-analytic results across prospective studies estimate a 48% increased risk of hypertension among individuals with OSA (pooled hazard ratio 1.48, 95% confidence interval 1.04–1.91) [14••].

Epidemiology of Cardiovascular Disease in OSA

The frequent concurrence of hypertension and OSA likely drives the increased risk of cardiovascular disease observed in patients with OSA. OSA is independently associated with carotid intima-media thickness, a marker of atherosclerosis [37]. OSA is also associated with increased risk of atrial fibrillation, with a dose-response relationship observed between severity of OSA and magnitude of the risk of developing atrial fibrillation [13]. In the Wisconsin Sleep Cohort Study, more severe OSA was significantly associated with adverse cardiac remodeling, including worsening of both left and right ventricular function [38•]. Consequently, OSA has been linked with an increased risk of incident heart failure [39, 40]. Meta-analyses of longitudinal studies demonstrate an increased risk of coronary artery disease and cardiovascular mortality among individuals with moderate-to-severe OSA [10, 11, 15•]. Several studies have also shown a 2-fold increased risk of stroke among individuals with OSA compared with those without OSA [10,11,12].

Pathophysiology of Hypertension and Cardiovascular Disease in Obstructive Sleep Apnea

There are multiple interrelated pathophysiologic mechanisms that contribute to hypertension and cardiovascular disease in obstructive sleep apnea. In a human experimental model, exposure to intermittent hypoxia leads to a measurable increase in mean arterial pressure, cerebral vascular resistance, and pressor response [41]. Correspondingly, in OSA, recurrent episodes of apnea result in intermittent hypoxia which causes various autonomic, hemodynamic, and biochemical changes contributing to the pathophysiology of hypertension and cardiovascular disease.

Sympathetic Nervous System Activity

During most normal sleep, there is increased parasympathetic and decreased sympathetic activity which contributes to physiologic nocturnal “dipping” in blood pressure and heart rate [42]. In OSA, several pathophysiologic mechanisms lead to a persistent increase in sympathetic drive. Negative pressure against obstruction and repetitive intermittent hypoxia are thought to cause renal, adrenal, and peripheral chemoreceptor activation. This generates an increase in circulating hormones such as catecholamines, renin, angiotensin II, and enthothelin-1 and downregulation of nitric oxide synthesis, resulting in increased sympathetic nervous system activity [43]. In 1988, Hedner et al. directly measured muscle sympathetic nerve activity in patients with OSA, demonstrating that these patients had progressively increasing sympathetic activity during apneic events [44]. Measurement of muscle sympathetic nerve activity also revealed that patients with OSA have persistently elevated sympathetic activity even when they are awake [45]. This suggests that the effects of sympathetic drive are persistent even after withdrawal of the hypoxic stimulus. Accordingly, urinary catecholamine levels are positivity correlated with the severity of OSA [46]. With regard to chemoreceptors, the carotid body, an oxygen sensing receptor, is stimulated by hypoxia, resulting in increased sympathetic activation. A persistent increase in sympathetic drive ultimately leads to an increase in vascular resistance and vascular remodeling, which also contributes to the observed increase in blood pressure [47].

Renin-Angiotensin System Activity

The sympathetic nervous system closely interacts with the kidney whereby renal sympathetic nerves activate the renin-angiotensin system, resulting in sodium retention, impaired natriuresis, and increased blood pressure. Thus, patients with OSA have higher angiotensin II and aldosterone levels compared with non-OSA controls [48]. In a small randomized double-blind placebo controlled cross-over study, intermittent hypoxia was found to increase both systolic and diastolic blood pressure; this relationship was diminished by exposure to a type 1 angiotensin II receptor blocker [49].

Endothelial Dysfunction

In an experimental model, intermittent hypoxia was shown to increase endothelial dysfunction [50•]. In a large cohort of older adults, flow-mediated dilation showed a statistically significant relationship between arterial diameter and the severity of hypoxia [51]. Compared with healthy controls, Gjørup et al. found that individuals with OSA had increased plasma levels of endothelin-1, and that mean nocturnal levels of endothelin correlated with the severity of OSA and with increased ambulatory blood pressure [52]. Ip et al. demonstrated that serum nitrites and nitrates were lower in patents with OSA [53]. Several studies have also showed an improvement in endothelial function with successful treatment of OSA [54,55,56].

Inflammation

OSA has been described as a low-grade chronic inflammatory disease [57]. Patients with OSA have higher circulating levels of inflammatory markers including high sensitivity CRP, interleukin-6, interleukin-8, TNF alpha, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 [58, 59]. While systemic inflammation has been linked to hypertension, atherosclerosis, and cardiovascular disease, its role in OSA may be confounded by obesity [60].

Metabolic Dysregulation

The Sleep Heart Health Study showed an association between OSA and impaired fasting glucose, glucose tolerance, and diabetes [61]. These associations were similar in magnitude in both obese and non-obese patients with OSA. In a meta-regression analysis of over eighteen thousand pooled subjects, patients with OSA were found to have higher levels of total cholesterol, triglycerides, and low-density lipoprotein and lower levels of high-density lipoprotein; the degree of dyslipidemia correlated with the severity of OSA [16]. Recent studies have also shown a relationship between OSA and hepatic steatosis, fibrosis, and non-alcoholic fatty liver disease [17], as well as chronic kidney disease [15, 62].

Treatment of Obstructive Sleep Apnea

Surgical intervention for OSA is uncommon, employed mainly for patients with morbid obesity requiring bariatric surgery [63, 64] and patients who do not tolerate conservative treatment [65]. Non-surgical approaches to managing OSA include a variety of behavioral measures, among them the avoidance of alcohol, sedatives, and tobacco and the adjusting sleep positioning (e.g., adding pillows, oral appliances) [66]. The mainstays of treatment, however, are medically supervised weight loss and nightly use of continuous positive airway pressure (CPAP). CPAP provides pneumatic splinting of the upper airway leading to significant improvement in the apnea-hypopnea index [65]. Lowering of the apnea-hypopnea index is significantly correlated with improvement in the symptoms of OSA, which include daytime sleepiness and disturbed cognition and mood. The associations of OSA with both physiologic disturbances and with cardiovascular risk factors have reinforced the proposal that treatment with CPAP may prevent life-threatening cardiovascular events [65, 67]. Such an effect has proven difficult to demonstrate, partly due to the complex, multidirectional relationships between OSA, hypertension, and obesity.

The Impact of Treatment for Obstructive Sleep Apnea on Blood Pressure

In patients with normal blood pressure or moderate hypertension, treatment of OSA with CPAP produces a very modest decline in blood pressure. Hu et al., for example, found both systolic and diastolic blood pressure fell by 2–3 mmHg after CPAP was administered to patients with hypertension of mixed severity [68]. Twenty-four-hour ambulatory monitoring in other studies demonstrated a similar modest decline in systolic blood pressure, diastolic blood pressure, and blood pressure variability when CPAP was initiated [34, 69,70,71]. The small decrements in blood pressure in moderately hypertensive patients have shifted attention to the potential benefits of CPAP for OSA patients with severe hypertension [72]. The anti-hypertensive effect of CPAP in such patients is indeed slightly greater, with systolic and diastolic blood pressure typically declining about 6–7 mmHg and 4–5 mmHg, respectively [70, 73]. In randomized trials, CPAP alone did not reduce the incidence of new onset hypertension [74].

The Impact of Treatment for Obstructive Sleep Apnea on Cardiovascular Risk

A few observational studies have supported speculation that the association of OSA with hypertension and obesity—both cardiovascular risk factors—means that treatment with CPAP may prevent cardiovascular events [75, 76]. This hypothesis remains unconfirmed. The Sleep Apnea Cardiovascular Endpoints (SAVE) study randomly assigned over 2500 patients with OSA and a history of cardiovascular disease to usual care plus CPAP versus usual care alone [77••]. While CPAP improved daytime sleepiness and health-related quality of life, it did not reduce the number of serious cardiovascular events during a mean follow-up of 3.7 years [77••]. Similarly negative findings have been replicated across multiple large, randomized, multicenter studies [74, 78,79,80,81, 82••]. Poor patient adherence across studies complicates the interpretation of these findings.

The Impact of Adherence on the Relationship Between CPAP and Cardiovascular Risk

Approximately 30% of patients placed on CPAP never actually initiate treatment [83]. Among those patients who do initiate CPAP, 25% abandon it within 1 year. The SAVE study demonstrated that cardiovascular events were reduced for the small number of patients using CPAP more than 4 h per night [77••]. To more definitively elucidate the relationship between CPAP treatment and cardiovascular outcomes, future studies will need to systematically assess adherence (e.g., using in-center polysomnography and other objective measures of adherence), requiring a minimum of 4 h per night of CPAP use.

Weight Loss as a Treatment for Obstructive Sleep Apnea

Weight gain, like hypertension, is closely linked to OSA [72, 84]. In a longitudinal study of normal-weight subjects, 10% weight gain was associated with a sixfold increased risk of OSA [85]. Conversely, 10% weight loss produced a 26% decline in the apnea-hypopnea index. As with hypertension, the association between obesity and OSA is mutually reinforcing. For example, obesity is associated with chronic subclinical inflammation which has been hypothesized to predispose individuals to OSA, but OSA is, itself, a pro-inflammatory stimulus [86]. Similarly, obesity is both a risk factor for OSA—reflecting architectural changes to the airway, impaired breathing mechanics—and a consequence of OSA—perhaps due to inactivity and altered neurohumoral status [87]. Nonetheless, a meta-analysis of over 3000 OSA patients reported that treatment with CPAP was associated with a mean weight gain of 0.4 kg [87]. The authors speculate that a by-product of improved slow-wave sleep may be a higher level of weight gain-inducing anabolic hormones. Acknowledging the relationship of OSA and obesity, The American Thoracic Society guidelines encourage a calorie restriction for all patients with OSA and a body mass index greater than 25 kg/m2. The committee notes, however, a “very low certainty” that symptoms or cardiovascular risk will be altered by diet alone [88•].

The complexity of the relationship between OSA, hypertension, and obesity is highlighted by a randomized controlled trial by Chirinos et al. that compared the anti-hypertensive effects of CPAP and weight loss (by diet and exercise), both alone and in combination [89]. Systolic blood pressure declined by 14.1 mmHg in the dual intervention group. Since this reduction exceeded the summed effect of a regimen limited to either weight loss (6.8 mmHg) or CPAP (3.0 mmHg) alone, the results suggested weight loss and CPAP synergistically contribute to blood pressure control. Chirinos et al. also found a reduction in insulin resistance and triglyceride levels associated with combined weight loss and CPAP. As in other studies, greater adherence to CPAP was associated with greater reduction in blood pressure.

Several studies have demonstrated that surgical weight loss often reduces OSA severity and results in remission of hypertension [90, 91]. In a prospective, multicenter before-and-after study of 132 patients with OSA who underwent laparoscopic Roux-en-Y gastric bypass surgery, Peromaa-Haavisto et al. found that OSA resolved in 45% of patients and improved in another 33% of the patients [91]. However, this magnitude of reduction in OSA prevalence after bariatric surgery is not consistent across studies. A systematic review and meta-analysis by Wong et al. evaluated participant-level data from two RCTs comparing bariatric surgery with intensive lifestyle modifications for weight loss [92]. The analyses demonstrated a greater reduction in severity of sleep apnea and body weight in participants who underwent bariatric surgery compared with those who underwent lifestyle modifications. Nonetheless, 97.5% of participants who underwent surgical weight loss and 100% of participants who underwent lifestyle modifications had persistent OSA at 1 year following the intervention. There is a paucity of evidence specifically evaluating if there is a synergistic or complimentary effect of surgical weight loss on OSA, hypertension, and cardiovascular risk.

Conclusions

The prevalence of OSA has been increasing in recent decades in the setting of rising obesity rates. There is a high incidence and prevalence of hypertension in OSA, promoting vascular injury and ultimately leading to elevated cardiovascular risk in individuals with OSA. Several pathophysiologic mechanisms contribute to the increased risk of hypertension and cardiovascular disease among individuals with OSA, including upregulation of neurohormonal pathways, endothelial dysfunction, and inflammation. The metabolic effects of obesity in OSA likely also contribute to these mechanisms, representing a multifaceted, mutually reinforcing relationship across these disease states. CPAP alone has not been demonstrated to reduce the risk of hypertension and cardiovascular disease in individuals with OSA, only to modestly lower blood pressure. However, generally poor adherence to CPAP likely contributes to its lack of perceived efficacy. The combination of CPAP and weight loss has the greatest promise for cardiovascular risk reduction on OSA. Future research is needed to identify ways to improve patient adherence to CPAP and to clarify the relationship between CPAP and cardiovascular risk in the setting of adequate adherence. Newer therapies should focus on reducing nocturnal hypoxia while minimizing patient burden.