0
Contemporary Reviews in Sleep Medicine |

OSA and Pulmonary HypertensionOSA and Pulmonary Hypertension: Time for a New Look FREE TO VIEW

Khalid Ismail, MD; Kari Roberts, MD; Patrick Manning, MD; Christopher Manley, MD; Nicholas S. Hill, MD, FCCP
Author and Funding Information

From Tufts Medical Center, Boston, MA.

CORRESPONDENCE TO: Khalid Ismail, MD, Tufts Medical Center, 800 Washington St, Box #369, Boston, MA 02111; e-mail: kismail@tuftsmedicalcenter.org


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(3):847-861. doi:10.1378/chest.14-0614
Text Size: A A A
Published online

OSA is a common yet underdiagnosed disorder encountered in everyday practice. The disease is a unique physiologic stressor that contributes to the development or progression of many other disorders, particularly cardiovascular conditions. The pulmonary circulation is specifically affected by the intermittent hypoxic apneas associated with OSA. The general consensus has been that OSA is associated with pulmonary hypertension (PH), but only in a minority of OSA patients and generally of a mild degree. Consequently, there has been no sense of urgency to screen for either condition when evaluating the other. In this review, we explore available evidence describing the interaction between OSA and PH and seek to better understand underlying pathophysiology. We describe certain groups of patients who have a particular preponderance of OSA and PH. Failure to recognize the mutual additive effects of these disorders can lead to suboptimal patient outcomes. Among patients with PH and OSA, CPAP, the mainstay treatment for OSA, may ameliorate pulmonary pressure elevations, but has not been studied adequately. Conversely, among patients with OSA, PH significantly limits functional capacity and potentially shortens survival; yet, there is no routine screening for PH in patients with OSA. We think it is time to study the interaction between OSA and PH more carefully to identify high-risk subgroups. These would be screened for the presence of combined disorders, facilitating earlier institution of therapy and improving outcomes.

Figures in this Article

OSA, defined as intermittent upper-airway obstructions that result in an apnea/hypopnea index (AHI) ≥ 5/h, has been linked to multiple comorbidities, including cardiovascular disease, metabolic derangements, and neurocognitive impairment.1-3 Pulmonary hypertension (PH) frequently coexists with OSA and may sometimes be a direct consequence of the disease.4 Despite efforts to better define this interaction, it remains elusive. Studies consisting of small and diverse patient populations, as well as variable definitions of sleep apnea and PH preclude firm conclusions. In this review, we discuss the currently available evidence on the prevalence, proposed pathophysiologic mechanisms, and diagnostic approaches associated with OSA and PH, and suggest areas for future research.

In preparation for this narrative review, we searched the medical literature using Medline and PubMed, using obstructive sleep apnea, sleep-disordered breathing, obesity hypoventilation, pulmonary hypertension and pulmonary arterial hypertension as key words. We selected articles in English published over the past 2 decades that had a specific definition of PH with clearly defined diagnostic methods and a well-described studied patient population.

Prevalence of OSA in Adults

The prevalence of OSA syndrome (AHI ≥ 5/h with daytime sleepiness) in middle-aged (30-60 years) men and women has been traditionally described as 4% and 2%, respectively.5 However, these numbers soar if we consider asymptomatic patients with an AHI ≥ 5/h: up to 24% in men and 9% in women.5 Prevalence rates rise in association with male sex, increasing age, and postmenopausal status.6,7 The problem is further magnified by the estimated 80% of individuals with moderate to severe OSA who remain undiagnosed or untreated despite adequate access to health care.8,9 With the ongoing obesity epidemic and the known association between obesity and OSA, there is reason to believe that these numbers will continue to rise for the foreseeable future.10 In fact, a more recent look at the Wisconsin Sleep Cohort by Peppard et al11 finds the prevalence of asymptomatic AHI ≥ 5/h in men and women 30 to 70 years old to be 34% and 17%, respectively.

Prevalence of PH in Patients With OSA

The reported prevalence of PH among patients with OSA has varied between 17% and 70%12,13 (Table 1). This remarkably broad range can be attributed to the different patient populations studied, the retrospective nature of some studies, the definition of PH as a mean pulmonary artery pressure (mPAP) > 20 mm Hg (as opposed to the current definition of mPAP ≥ 25 mm Hg) and the failure to control for the presence of concurrent heart and lung disease.

Table Graphic Jump Location
TABLE 1 ]  Prevalence of PH Among Patients With Established OSA

AHI = apnea-hypopnea index; AI = apnea index; LV = left ventricular; mPAP = mean pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; PFT = pulmonary function test; PH = pulmonary hypertension; PSG = polysomnography; RDI = respiratory disturbance index; RHC = right-sided heart catheterization; Sao2 = arterial oxygen saturation; TTE = transthoracic echocardiogram; VC = vital capacity.

In one of the larger prospective trials by Chaouat et al,14 220 consecutive patients diagnosed with OSA underwent right-sided heart catheterization (RHC). PH was diagnosed in 17%, but the mPAP in the PH group was only mildly elevated at 26 ± 6 mm Hg. PH strongly correlated with a higher daytime Paco2, lower daytime Pao2, obstructive dysfunction on spirometry, and lower mean nocturnal oxygen saturation (Sao2). BMI was significantly higher in the PH group compared with the non-PH group.

In another prospective cohort of 44 patients with OSA that excluded obstructive airway dysfunction but included heavier patients than the Chaouat cohort, Bady et al15 found PH in 27%. The mPAP in the PH group was 28.5 ± 6 mm Hg. Once again, PH was strongly linked to a higher mean BMI and a lower daytime Pao2.

In a more recent retrospective study by Minai et al,13 83 subjects with OSA underwent RHC within 6 months of polysomnography (PSG). The occurrence of PH was 70% (mPAP, 40.3 ± 11 mm Hg). Correlates of PH included female sex, age < 49 years, BMI ≥ 26, and RVSP ≥ 30 mm Hg on echocardiogram. The strikingly high prevalence of PH in this study may have reflected referral bias (all patients were referred for a RHC because of high clinical suspicion for PH), inclusion of patients with elevated pulmonary capillary wedge pressure (PCWP) > 15 mm Hg (if excluded, prevalence drops from 70% to 22%), and incomplete exclusion of patients with other pulmonary disorders.

The higher prevalence of PH in women with OSA is intriguing and reflects the female preponderance in various other forms of pulmonary arterial hypertension (PAH), including idiopathic and that associated with collagen vascular diseases such as scleroderma. Potential explanations include genetic predisposition, the role of estrogen, and the increased prevalence of autoimmune disease in women.

In summary, available evidence indicates that in patients with OSA, the presence of obesity, daytime hypoxia and hypercapnia, abnormal pulmonary function testing, and nocturnal oxygen desaturation strongly correlate with PH. When present, PH is usually mild but can be severe, as suggested by the Minai et al13 study. Given the wide variations between studies, large prospective trials are still needed to tease out the effects of specific risk factors and more accurately define the prevalence of PH in patients with isolated OSA.

Prevalence of OSA in Patients With PH

Sleep-disordered breathing (SDB), which comprises not only OSA, but also central sleep apnea (CSA), periodic breathing, and oxygen desaturation related to sleep, is associated with PH (Table 2). Rafanan et al25 found that although apneas and hypopneas measured during PSG were rare, 10 of the 13 patients with severe idiopathic PAH (IPAH) (mPAP, 60.8 ± 15 mm Hg) had nocturnal oxygen desaturations. In addition, Schulz et al24 observed no OSA among 20 patients with IPAH, but six had Cheyne-Stokes respiration (CSR), associated with higher mPAP and reduced right ventricular function. In a more recent study including 23 patients with PAH and 15 with chronic thromboembolic pulmonary hypertension (CTEPH),23 45% had CSA/CSR, while OSA was present in 11%.

Table Graphic Jump Location
TABLE 2 ]  Prevalence of SDB Among Patients With Established PH

CI = cardiac index; CO = cardiac output; CSA = central sleep apnea; CSR = Cheyne-Stokes respiration; IPAH = idiopathic pulmonary arterial hypertension; NR = not reported; PVR = pulmonary vascular resistance; RVEF = right ventricular ejection fraction; SDB = sleep-disordered breathing; TST = total sleep time; WHO = World Health Organization. See Table 1 legend for expansion of other abbreviations.

In contrast, among 46 patients with IPAH or CTEPH, Jilwan et al21 found OSA in 89% of patients, while only four patients had CSA. These results are in agreement with those of Prisco et al22 on 28 patients with varying etiologies of PH (World Health Organization groups I, IV, and V) among whom obstructive events predominated over central. However, these latter studies included older patients who were predominantly male and had higher BMIs, likely predisposing to a higher prevalence of OSA.

In summary, despite scarce data, it appears that SDB is common in patients with PH. CSA/CSR prevails in younger patients with severe PH and right-sided heart failure, while OSA predominates in older patients with PH, especially if studied populations include more men with higher BMI. Clearly, larger and better defined studies are needed to more accurately describe the prevalence of SDB in different subtypes of patients with PH.

Hemodynamic Changes Associated With OSA

In 1971, the Bologna Sleep Laboratory (University of Bologna, Italy) was the first to directly measure systemic and pulmonary arterial (PA) pressures and alveolar ventilation in normal subjects during different stages of sleep.26 They demonstrated a significant rise in mPAP during sleep compared with wakefulness, but without significant change from one sleep stage to the next. At the same time, alveolar ventilation fell significantly during sleep compared with wakefulness, with diminished ventilatory responses to hypoxic and hypercapnic stimuli.

Unlike normal subjects, patients with OSA experience progressive PA pressure increases throughout sleep stages 1 to 3, with an upswing during rapid eye-movement sleep.27 Alveolar ventilation follows an opposite pattern, declining in slow-wave sleep and dropping even further during rapid eye-movement sleep. Tracheostomy (the only effective treatment of OSA at the time) was associated with a decrease in PA pressure and return of alveolar ventilation to normal28 (Fig 1).

Figure Jump LinkFigure 1 –  Pulmonary artery pressure and arterial blood gas analysis in five patients with OSAS. A, Pulmonary artery pressure and alveolar hypoventilation increase progressively and significantly from wakefulness (W) through sleep stages 1, 2, 3-4, and then REM sleep. B, Two years after tracheostomy, pulmonary artery pressure remains higher than physiologic levels during wakefulness and increases only slightly during sleep. The arterial blood gases and pH remain within physiologic limits in both wakefulness and sleep. Mn = minimum; Mx = maximum; OSAS = OSA syndrome; Pulm.Art.Press = pulmonary artery pressure; REM = rapid eye movement; St = stage. (Reprinted with permission from Coccagna et al.28)Grahic Jump Location

Recurrent upper airway obstruction with accompanying apneas presents a distinct physiologic challenge to the cardiovascular system (Fig 2). Pulmonary vasoconstriction occurs in response to alveolar hypoxia, increasing pulmonary vascular resistance and contributing to an increase in precapillary PA pressure. Simultaneously, intrathoracic pressure swings intensify with increasing respiratory efforts against a closed upper airway. Negative intrathoracic pressure during obstructive events can reach −80 cm H2O.29 The associated increase in venous return leads to increased right ventricular preload and stroke volume, in turn increasing pulmonary blood flow.30

Figure Jump LinkFigure 2 –  Pathophysiologic mechanisms involved in the development of apnea-related increased pulmonary artery pressure. At the endovascular level (magnified enclosure), endothelial dysfunction, heightened inflammation, and procoagulation play an additional role. CRP = C-reactive protein; RA = right atrium; RV = right ventricle; SV = stroke volume; PA = pulmonary artery; PV = pulmonary vein; LA = left atrium; LV = left ventricle; P = pressure; VEGF = vascular endothelial growth factor.Grahic Jump Location

Increased venous return also shifts the interventricular septum to the left, which reduces left ventricular (LV) compliance. In addition, negative intrathoracic pressure, by increasing LV transmural pressure, elevates LV afterload.31 Both factors impede LV function and contribute to a relative increase in pulmonary venous pressure.32 Pulmonary systolic pressures as high as 80 mm Hg and diastolic pressures as high as 54 mm Hg have been reported toward the end of an apneic event.33

Given these pathophysiologic changes, one would expect daytime PH to be universally present in patients with OSA. However, individuals vary considerably in their pulmonary vasoconstrictor responses to hypoxia. In their Doppler echocardiogram study on 32 patients with severe OSA (mean AHI, 36/h), Sajkov et al17 found an exaggerated increase in pulmonary artery pressure (Ppa) in response to hypoxia, and a marked rise in Ppa during dobutamine-induced increase in blood flow in patients with PH compared with control subjects. This suggests that a subset of patients with OSA may be more susceptible to vascular remodeling, another area in need of further research.

Vascular Endothelial Dysfunction Associated With OSA

In addition to the discussed hemodynamic changes, accumulating evidence indicates that endothelial dysfunction, oxidative stress, heightened inflammation, as well as a procoagulant state also contribute to OSA-induced PH (Fig 2). Impaired vasodilation to endothelium-dependent vasodilators such as acetylcholine has been observed in systemic vessels of patients with OSA.34 Ip et al35 demonstrated that 4 weeks of CPAP reverses that process. Further, endothelin-1, the potent long-acting vasoconstrictor peptide synthetized by endothelium, is elevated in OSA and decreases with CPAP therapy.36 Vascular endothelial growth factor expression is also increased in relation to the degree of nocturnal oxygen desaturation with OSA.37 Other mediators that have been linked to endothelial dysfunction, including leukocyte adhesion molecules, are also elevated in patients with OSA.38,39

In addition, a heightened inflammatory state exists, as suggested by elevated levels of C-reactive protein (CRP) and IL-6 levels, both of which decrease with CPAP therapy.40 Increased release of oxygen free radicals similar to that seen in hypoxia/reperfusion injury has also been detected, to the extent that some believe OSA to be an “oxidative stress disorder.”41

Finally, the occurrence of a procoagulant state is well documented. Elevated hypoxia-induced erythropoietin production has been observed by Cahan et al.42 CPAP treatment lowered erythropoietin levels in these patients.43 Serum fibrinogen levels are elevated and fibrinolytic activity is reduced secondary to elevated plasminogen activator inhibitor.44,45 In addition, patients with OSA have increased platelet activation and aggregation, and both return to normal with CPAP treatment.46 Weak but growing evidence has also implicated OSA as a risk factor47,48 for DVT and pulmonary embolism, even after correcting for other risk factors like obesity. To our knowledge, OSA has not been linked to CTEPH, but additional research is needed to explore the possibility.

PH as a Cause for OSA

An equally interesting but even less researched aspect of the OSA/PH interaction is how PH and, eventually, right-sided heart failure, can contribute to the development of OSA. Fluid retention and rostral redistribution have been suggested to worsen OSA in patients with end-stage renal disease.49 In a cohort of 40 patients with hypertension, Friedman et al50 studied rostral fluid shifts by measuring calf and neck circumference before and after sleep during PSG. AHI strongly correlated with the amount of leg fluid volume displaced. These findings were reproduced by Jafari and Mohsenin51 in a cohort of patients with OSA. Patients with PH, especially those with right-sided heart failure, are frequently fluid overloaded and one can expect similar redistributive changes during sleep that could exacerbate upper airway edema and OSA. This possible relationship, as well as potential therapeutic effect of fluid removal and treatment of right-sided heart failure on OSA, has not been specifically studied.

Screening for PH in Patients With OSA

Typically, even patients with severe sleep apnea are not routinely screened for PH. In fact, American College of Chest Physicians (CHEST) evidence-based guidelines12 recommend against routine evaluation for PH in patients with OSA. PH can be suspected clinically, but signs and symptoms are neither sensitive nor specific. Evidence of increased pulmonary artery diameter on chest radiographs, or right ventricular strain on ECG would support a diagnosis of PH or right-sided heart dysfunction, but are not routinely obtained in patients with OSA.

B-type natriuretic peptide (BNP) level, which correlates with left or right ventricular dysfunction and a cardiogenic etiology of dyspnea, can also be helpful in detecting PH and right-sided heart failure. In one study, plasma BNP levels correlated with mPAP, right atrial pressure, right ventricular end-diastolic pressure, and pulmonary vascular resistance.52 In another study, elevated BNP levels seemed to reflect an increased likelihood of LV hypertrophy in patients with severe sleep apnea.53 Therefore, plasma BNP may be elevated in patients with OSA but without PH and its sensitivity and specificity for detection of PH have not been established.

Suspicion of PH or right-sided heart failure in a patient with SDB should lead to a trans-thoracic echocardiogram. However, echocardiography, especially in the obese or those with concomitant lung disease, has its limitations. Fisher et al54 prospectively tested the accuracy of Doppler echocardiography in estimating PA pressure in 65 consecutive patients with various forms of PH (the majority had PAH) referred for RHC. Only 48% of the echocardiographic estimates were within 10 mm Hg of catheterization values. Moreover, 38% of pressure overestimates and 80% of pressure underestimates exceeded 20 mm Hg. Other studies also questioned the accuracy of echocardiography for estimation of PA pressure in patients with advanced lung disease, especially emphysema.55

In summary, because symptoms of PH are not specific, and tools used to detect PH have not been validated in the OSA population, specific recommendations cannot be made on screening patients with OSA for PH. Nevertheless, the lack of accurate screening tools should not be interpreted as a lack of necessity to screen for PH in patients with OSA, as will be discussed later.

Screening for SDB in Patients With PH

Current CHEST evidence-based guidelines endorse assessment of SDB when evaluating patients with PH and, if suspected, PSG is recommended.12 In practice, this raises a vital question: How is SDB assessed in patients with PH? Even in non-PH populations undergoing sleep evaluation, the answer is not straightforward. Snoring, in a retrospective analysis of 250 consecutive patients referred to a sleep center, had a positive predictive value (PPV) and negative predictive value (NPV) for OSA of only 0.63 and 0.56, respectively.56 In another study of 380 patients referred for PSG, witnessed apneas with hypersomnia had a PPV and NPV for OSA in the range of 0.40 and 0.60.57 The Epworth Sleepiness Scale is a notoriously poor discriminative tool for OSA.58 Even overall clinical impression of experienced clinicians appears to have a sensitivity and specificity of 52% and 70%, respectively.59

In the PH population, several studies suggest that even typical symptoms like snoring and excessive daytime sleepiness, are not reliable in the evaluation of SDB21-23 Sleep questionnaires developed to help overcome some of these uncertainties include the Berlin questionnaire, which assesses risk factors for OSA, wake-time sleepiness or fatigue, and the presence of obesity or hypertension. An evaluation of its accuracy in identifying patients with OSA in the primary care setting revealed a sensitivity of 0.86, specificity of 0.77, PPV of 0.89, and a likelihood ratio of 3.79.60 To our knowledge, sleep questionnaires have not been validated for use in the PH population.

Clinical prediction models combining clinical data with objective measurements like craniofacial measurements, BMI, and oximetry also hold some promise to identify patients at risk for OSA more accurately. One study tested a model using upper airway and body measurements in 300 patients, and showed a PPV of 100% and a NPV of 88.5%.61 Thus, in summary, sleep questionnaires and prediction models seem to perform better than single clinical predictors in identifying patients with OSA, but a standardized screening method awaits validation in the PH population.

Certain disorders have a strong predilection for both OSA and PH, and the presence of one disease should be a signal to screen for the other.

Obesity Hypoventilation Syndrome

Obesity hypoventilation syndrome (OHS) is the combination of obesity (BMI > 30 kg/m2) and hypoventilation (awake Paco2 > 45 mm Hg), after the exclusion of other disorders associated with hypoventilation.62 The majority of patients also have associated OSA (up to 90%).63 The typical patient is middle aged, extremely obese (BMI > 40 kg/m2), and a hypersomnolent loud snorer with dyspnea, lower extremity edema, oxygen desaturation, and elevated serum bicarbonate.64

Cohort studies show a remarkably high occurrence of PH in OHS. In two different studies, the prevalence of PH was 58%65 and 88%66 (mPAP > 20 mm Hg). The prevalence of severe PH (mPAP > 40 mm Hg) was 31%.66 If OHS is left untreated, cor pulmonale usually develops.67 The prevalence of OHS is almost certainly underestimated in the general population, as arterial blood gases are not routinely analyzed in obese patients, but in patients with OSA, available epidemiologic data suggest a prevalence of OHS in the range of 10% to 20%, and even higher in patients with extreme obesity (BMI > 40 kg/m2).64 There is currently no recommendation for intensified screening of patients with OHS for OSA or PH, although the strong concurrence of both would seem to justify it.

Overlap Syndrome

Coined by Flenley68 to describe the association of COPD and OSA, the Overlap Syndrome has an estimated prevalence of 11% to 15% in consecutive patients with OSA.69,70 This coexistence was initially thought to be based on a common pathophysiologic linkage, but is now thought to occur by chance, according to epidemiologic evidence from the Sleep Heart Health Study database,71 since both are relatively common disorders in the adult population.

Characteristically, patients with Overlap Syndrome have more daytime hypoxemia, hypercapnea, and PH than expected with either disease alone.69 Furthermore, these changes develop in patients with milder airway obstruction and less severe OSA than would be expected.70 Again, there is currently no recommendation to screen for PH in patients with the Overlap Syndrome.

The Bariatric Patient

Morbidly obese patients being evaluated for bariatric surgery present a unique opportunity for screening. Obesity, by far, is the strongest risk factor for OSA.72 It has also been suggested as a strong predictor of PH in patients with OSA.13-15 Nocturnal oxygen desaturation related to apneic events can be more prolonged and severe in the morbidly obese,73 mainly due to reduction in expiratory reserve volume, especially when lying supine.74

In addition to the large percentage of patients with OHS who appear to be underdiagnosed, there is also a higher prevalence of the cardiomyopathy of obesity, chronic thromboembolic disease, and prior anorexigen use, that may contribute to the increased incidence of PH.75 The additional burden of PH on morbid obesity can greatly impair the functional capacity of these patients and increase their risk for perioperative complications. Some bariatric surgery programs routinely screen every patient for OSA, but few routinely screen for PH. Presently, evidence does not support more aggressive screening, but the question has not been adequately investigated.

Clinical Implications of the Diagnosis of PH in Patients With OSA

Should we be more determined to diagnose PH in patients with OSA? Would it impact relevant clinical outcomes? In the previously described study by Minai et al,13 patients with OSA and PH showed trends toward a shorter 6-min walk distance and greater Borg dyspnea and fatigue scores. In addition, and for the first time, they showed increased mortality in patients with OSA and PH at 1, 4, and 8 years (Fig 3).13

Figure Jump LinkFigure 3 –  Kaplan-Meier survival estimates in 83 patients with OSA with and without PH. The survival rate at 1, 4, and 8 y was 100%, 90%, and 76% in the non-PH group and 93%, 75%, and 43% in the PH group, respectively. PH = pulmonary hypertension. (Reprinted with permission from Minai et al.13)Grahic Jump Location

The knowledge that PH is present would enable us to intensify the focus on controlling reversible factors, such as optimal therapy of OSA, systemic hypertension, fluid overload, and diabetes mellitus. It would also address the potential causal role PH might play in the development of upper airway edema and obstruction. However, current data do not answer the question of whether specific PH therapy improves outcomes in PH associated with OSA.

Clinical Implication of the Diagnosis of OSA in Patients With PH

Should we be more conscientious about excluding OSA as a cause or comorbidity in a patient with PH? Does it impact quality of life? Can undiagnosed OSA hinder the response to advanced PH therapy? The evidence to address these questions has been scant.

Ulrich et al,23 in their cohort of 38 patients with PH, found that the 50% of patients with SDB reported a worse quality of life in physical domains assessed by different questionnaires. Another unanswered question is whether CSR/CSA in patients with PH translates into a poorer prognosis, as it does in left-sided heart failure.76

CPAP is a well-established treatment of patients with OSA and can reverse the pathophysiology that ultimately may lead to the development of PH. By eliminating recurrent episodes of upper airway obstruction, positive pressure therapy dampens the swings in intrathoracic pressure and their effects on right ventricular function. Hypoxemia, for the most part, is corrected at the optimum CPAP level. In addition, positive pressure, as has been well documented, reduces LV afterload and improves LV function.

Several studies have reported improvements in pulmonary hemodynamics after initiation of CPAP therapy in patients with OSA (Table 3). Sajkov et al79 used Doppler echocardiography before and after CPAP treatment in 20 patients with OSA, after excluding patients with cardiac disease, systemic hypertension, and abnormal lung functions. After 4 months of CPAP, estimated mPAPs decreased from 16.8 ± 1.2 mm Hg to 13.9 ± 0.6 mm Hg (P < .05), with the greatest decline seen in the five patients with PH at baseline. Interestingly, the pulmonary vascular response to hypoxia also decreased after CPAP, possibly related to improved pulmonary endothelial function.

Table Graphic Jump Location
TABLE 3 ]  Effects of Treatment With CPAP in Patients With OSA

CRP = C-reactive protein; PASP = systolic pulmonary artery pressure; RVSP = right ventricular systolic pressure. See Table 1 legend for expansion of other abbreviations

In another trial by Alchanatis et al,80 consisting of 29 patients with OSA and PH but no other cardiac or lung dysfunction, and 12 patients with OSA but without PH, Doppler-estimated mPAP decreased in both the PH and the non-PH groups after 6 months of CPAP therapy

Last, Arias et al78 randomized 23 otherwise healthy patients with OSA and 10 healthy control subjects to receive either sham or effective CPAP therapy for 6 months with crossover at the end of 3 months. Ten of the 23 patients with OSA and none of the control subjects had PH at baseline, as determined by echocardiography (PA systolic pressure > 30 mm Hg). CPAP significantly reduced PA systolic pressure in the OSA group, with the greatest reduction occurring in patients with PH or LV diastolic dysfunction at baseline (Fig 4).78

Figure Jump LinkFigure 4 –  Individual values for the PASP after both sham and effective CPAP treatment in patients with OSA. Black bar represents mean PASP, changing from baseline 28.9 ± 8.6 mm Hg to 24.0 ± 5.8 mm Hg after 12 wk of CPAP (P = .0001). PASP = pulmonary artery systolic pressure. (Reprinted with permission from Arias et al.78)Grahic Jump Location

A separate but equally important benefit of CPAP therapy is its effect on pathways of vascular endothelial injury and platelet dysfunction. As mentioned, endothelin-1 is elevated in OSA and decreases with CPAP therapy.36 Patients with OSA have lower levels of circulating metabolites of nitric oxide compared with healthy subjects; these levels readily return to normal with CPAP.81 Elevated markers of inflammation are observed in OSA, namely CRP and IL-6, and both decrease with CPAP therapy.40 Finally, increased platelet activation and aggregation normalize with CPAP treatment.46

The universal concern with CPAP nonadherence, which may discourage a more aggressive screening or treatment approach to OSA, seems to be unfounded in the PH population, at least based on the interventional trials discussed here. Adherence ranged from 77% (5.1 ± 0.3 h/night) in the Sajkov trial,79 to 87% (mean, 5.4 h/night) in the Alchanatis trial,80 and 91% (mean, 6 ± 1.4 h/night) in the Arias trial.78 Perhaps knowledge of underlying PH promotes enhanced adherence, or possibly the clinical response is more consistently positive in this patient population, encouraging routine use of CPAP.

In summary, despite the paucity of clinical trials, available evidence supports an ameliorative effect of CPAP therapy on PA pressure. It appears that patients who stand to gain the most are the ones with more significant PH with already compromised vascular endothelial function. These findings support a more aggressive approach to the detection of OSA in patients with PH, and institution of effective CPAP therapy as early as possible.

As emphasized in this review, it is difficult to draw firm conclusions about the interplay between OSA and PH as far as prevalence, causation, and response to therapy, especially specific PAH regimens. Nevertheless, this discussion highlights the need for further research to more accurately characterize the interaction between these two entities. In patients with OSA, we need to better define and predict who is at risk for clinically significant PH, create better screening tools, understand the impact PH has on quality of life and other outcomes, and develop more effective therapeutic approaches. Similarly, perhaps before a diagnosis of idiopathic PH is made, we need to develop a standard evaluation for OSA, recognize the consequences of untreated disease, and establish the additional benefits CPAP might offer to the management of this patient population.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Hill has received research grants from Actelion, Bayer, Gilead, Novartis AG, and United Therapeutics Corporation. He has also served on medical advisory boards for Bayer and Gilead. Drs Ismail, Roberts, Manning, and Manley have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: We thank Hajar Delshad, PA-C, at Boston Children’s Hospital, for assistance with tables, figures, and editing of the manuscript. We also thank Carolyn D’Ambrosio, MD, at Tufts Medical Center for reviewing the manuscript and providing helpful advice.

AHI

apnea-hypopnea index

BNP

B-type natriuretic peptide

CRP

C-reactive protein

CSA

central sleep apnea

CSR

Cheyne-Stokes respiration

CTEPH

chronic thromboembolic pulmonary hypertension

IPAH

idiopathic pulmonary arterial hypertension

LV

left ventricular

mPAP

mean pulmonary artery pressure

NPV

negative predictive value

OHS

obesity hypoventilation syndrome

PA

pulmonary arterial

PAH

pulmonary arterial hypertension

PCWP

pulmonary capillary wedge pressure

PH

pulmonary hypertension

Ppa

pulmonary artery pressure

PPV

positive predictive value

PSG

polysomnography

RHC

right-sided heart catheterization

RVSP

right ventricular systolic pressure

Sao2

oxygen saturation

SDB

sleep-disordered breathing

Somers VK, White DP, Amin R, 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. Circulation. 2008;118(10):1080-1111. [CrossRef] [PubMed]
 
Aronsohn RS, Whitmore H, Van Cauter E, Tasali E. Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes. Am J Respir Crit Care Med. 2010;181(5):507-513. [CrossRef] [PubMed]
 
Lal C, Strange C, Bachman D. Neurocognitive impairment in obstructive sleep apnea neurocognitive impairment. Chest. 2012;141(6):1601-1610. [CrossRef] [PubMed]
 
Sajkov D, McEvoy RD. Obstructive sleep apnea and pulmonary hypertension. Prog Cardiovasc Dis. 2009;51(5):363-370. [CrossRef] [PubMed]
 
Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230-1235. [CrossRef] [PubMed]
 
Bixler EO, Vgontzas AN, Lin HM, et al. Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med. 2001;163(3 pt 1):608-613. [CrossRef] [PubMed]
 
Durán J, Esnaola S, Rubio R, Iztueta A. Obstructive sleep apnea-hypopnea and related clinical features in a population-based sample of subjects aged 30 to 70 yr. Am J Respir Crit Care Med. 2001;163(3 pt 1):685-689. [CrossRef] [PubMed]
 
Kapur V, Strohl KP, Redline S, Iber C, O’Connor G, Nieto J. Underdiagnosis of sleep apnea syndrome in U.S. communities. Sleep Breath. 2002;6(2):49-54. [CrossRef] [PubMed]
 
Young T, Evans L, Finn L, Palta M. Estimation of the clinically diagnosed proportion of sleep apnea syndrome in middle-aged men and women. Sleep. 1997;20(9):705-706. [PubMed]
 
Lee W, Nagubadi S, Kryger MH, Mokhlesi B. Epidemiology of obstructive sleep apnea: a population-based perspective. Expert Rev Respir Med. 2008;2(3):349-364. [CrossRef] [PubMed]
 
Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006-1014. [CrossRef] [PubMed]
 
Atwood CW Jr, McCrory D, Garcia JG, Abman SH, Ahearn GS; American College of Chest Physicians. Pulmonary artery hypertension and sleep-disordered breathing: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(1_ suppl):72S-77S. [CrossRef] [PubMed]
 
Minai OA, Ricaurte B, Kaw R, et al. Frequency and impact of pulmonary hypertension in patients with obstructive sleep apnea syndrome. Am J Cardiol. 2009;104(9):1300-1306. [CrossRef] [PubMed]
 
Chaouat A, Weitzenblum E, Krieger J, Oswald M, Kessler R. Pulmonary hemodynamics in the obstructive sleep apnea syndrome. Results in 220 consecutive patients. Chest. 1996;109(2):380-386. [CrossRef] [PubMed]
 
Bady E, Achkar A, Pascal S, Orvoen-Frija E, Laaban JP. Pulmonary arterial hypertension in patients with sleep apnoea syndrome. Thorax. 2000;55(11):934-939. [CrossRef] [PubMed]
 
Niijima M, Kimura H, Edo H, et al. Manifestation of pulmonary hypertension during REM sleep in obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 1999;159(6):1766-1772. [CrossRef] [PubMed]
 
Sajkov D, Wang T, Saunders NA, Bune AJ, Neill AM, Mcevoy RD. Daytime pulmonary hemodynamics in patients with obstructive sleep apnea without lung disease. Am J Respir Crit Care Med. 1999;159(5 pt 1):1518-1526. [CrossRef] [PubMed]
 
Sanner BM, Doberauer C, Konermann M, Sturm A, Zidek W. Pulmonary hypertension in patients with obstructive sleep apnea syndrome. Arch Intern Med. 1997;157(21):2483. [CrossRef] [PubMed]
 
Laks L, Lehrhaft B, Grunstein R, Sullivan C. Pulmonary hypertension in obstructive sleep apnoea. Eur Respir J. 1995;8(4):537-541. [PubMed]
 
Krieger J, Sforza E, Apprill M, Lampert E, Weitzenblum E, Ratomaharo J. Pulmonary hypertension, hypoxemia, and hypercapnia in obstructive sleep apnea patients. Chest. 1989;96(4):729-737. [CrossRef] [PubMed]
 
Jilwan FN, Escourrou P, Garcia G, Jaïs X, Humbert M, Roisman G. High occurrence of hypoxemic sleep respiratory disorders in precapillary pulmonary hypertension and mechanisms. Chest. 2013;143(1):47-55. [CrossRef] [PubMed]
 
Prisco DL, Sica AL, Talwar A, et al. Correlation of pulmonary hypertension severity with metrics of comorbid sleep-disordered breathing. Sleep Breath. 2011;15(4):633-639. [CrossRef] [PubMed]
 
Ulrich S, Fischler M, Speich R, Bloch KE. Sleep-related breathing disorders in patients with pulmonary hypertension. Chest. 2008;133(6):1375-1380. [CrossRef] [PubMed]
 
Schulz R, Baseler G, Ghofrani HA, Grimminger F, Olschewski H, Seeger W. Nocturnal periodic breathing in primary pulmonary hypertension. Eur Respir J. 2002;19(4):658-663. [CrossRef] [PubMed]
 
Rafanan AL, Golish JA, Dinner DS, Hague LK, Arroliga AC. Nocturnal hypoxemia is common in primary pulmonary hypertension. Chest. 2001;120(3):894-899. [CrossRef] [PubMed]
 
Coccagna G, Lugaresi E. Haemodynamics during sleep: old results and new perspectives. J Sleep Res. 1995;4(S1):2-7. [CrossRef] [PubMed]
 
Coccagna G, Mantovani M, Brignani F, Parchi C, Lugaresi E. Continuous recording of the pulmonary and systemic arterial pressure during sleep in syndromes of hypersomnia with periodic breathing. Bull Physiopathol Respir (Nancy). 1972;8(5):1159-1172. [PubMed]
 
Coccagna G, Mantovani M, Brignani F, Parchi C, Lugaresi E. Tracheostomy in hypersomnia with periodic breathing. Bull Physiopathol Respir (Nancy). 1972;8(5):1217-1227. [PubMed]
 
Saunders NA, Sullivan CE. Sleep and Breathing. New York, NY: M. Dekker; 1984.
 
Guyton AC, Lindsey AW, Abernathy B, Richardson T. Venous return at various right atrial pressures and the normal venous return curve. Am J Physiol. 1957;189(3):609-615. [PubMed]
 
Robotham JL, Rabson J, Permutt S, Bromberger-Barnea B. Left ventricular hemodynamics during respiration. J Appl Physiol. 1979;47(6):1295-1303. [PubMed]
 
Buda AJ, Pinsky MR, Ingels NB Jr, Daughters GT II, Stinson EB, Alderman EL. Effect of intrathoracic pressure on left ventricular performance. N Engl J Med. 1979;301(9):453-459. [CrossRef] [PubMed]
 
Guilleminault C, Cummiskey J, Dement WC. Sleep apnea syndrome: recent advances. Adv Intern Med. 1980;26:347-372. [PubMed]
 
Kato M, Roberts-Thomson P, Phillips BG, et al. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation. 2000;102(21):2607-2610. [CrossRef] [PubMed]
 
Ip MS, Tse HF, Lam B, Tsang KW, Lam WK. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med. 2004;169(3):348-353. [CrossRef] [PubMed]
 
Phillips BG, Narkiewicz K, Pesek CA, Haynes WG, Dyken ME, Somers VK. Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens. 1999;17(1):61-66. [CrossRef] [PubMed]
 
Schulz R, Hummel C, Heinemann S, Seeger W, Grimminger F. Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe nighttime hypoxia. Am J Respir Crit Care Med. 2002;165(1):67-70. [CrossRef] [PubMed]
 
Chin K, Nakamura T, Shimizu K, et al. Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome. Am J Med. 2000;109(7):562-567. [CrossRef] [PubMed]
 
Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med. 2002;165(7):934-939. [CrossRef] [PubMed]
 
Yokoe T, Minoguchi K, Matsuo H, et al. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation. 2003;107(8):1129-1134. [CrossRef] [PubMed]
 
Lavie L. Obstructive sleep apnoea syndrome—an oxidative stress disorder. Sleep Med Rev. 2003;7(1):35-51. [CrossRef] [PubMed]
 
Cahan C, Decker MJ, Arnold JL, et al. Diurnal variations in serum erythropoietin levels in healthy subjects and sleep apnea patients. J Appl Physiol (1985). 1992;72(6):2112-2117. [PubMed]
 
Cahan C, Decker MJ, Arnold JL, Goldwasser E, Strohl KP. Erythropoietin levels with treatment of obstructive sleep apnea. J Appl Physiol (1985). 1995;79(4):1278-1285. [PubMed]
 
Chin K, Ohi M, Kita H, et al. Effects of NCPAP therapy on fibrinogen levels in obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 1996;153(6 pt 1):1972-1976. [CrossRef] [PubMed]
 
Rångemark C, Hedner JA, Carlson JT, Gleerup G, Winther K. Platelet function and fibrinolytic activity in hypertensive and normotensive sleep apnea patients. Sleep. 1995;18(3):188-194. [PubMed]
 
Bokinsky G, Miller M, Ault K, Husband P, Mitchell J. Spontaneous platelet activation and aggregation during obstructive sleep apnea and its response to therapy with nasal continuous positive airway pressure. A preliminary investigation. Chest. 1995;108(3):625-630. [CrossRef] [PubMed]
 
Chou KT, Huang CC, Chen YM, et al. Sleep apnea and risk of deep vein thrombosis: a non-randomized, pair-matched cohort study. Am J Med. 2012;125(4):374-380. [CrossRef] [PubMed]
 
Epstein MD, Segal LN, Ibrahim SM, Friedman N, Bustami R. Snoring and the risk of obstructive sleep apnea in patients with pulmonary embolism. Sleep. 2010;33(8):1069-1074. [PubMed]
 
Elias RM, Bradley TD, Kasai T, Motwani SS, Chan CT. Rostral overnight fluid shift in end-stage renal disease: relationship with obstructive sleep apnea. Nephrol Dial Transplant. 2012;27(4):1569-1573. [CrossRef] [PubMed]
 
Friedman O, Bradley TD, Chan CT, Parkes R, Logan AG. Relationship between overnight rostral fluid shift and obstructive sleep apnea in drug-resistant hypertension. Hypertension. 2010;56(6):1077-1082. [CrossRef] [PubMed]
 
Jafari B, Mohsenin V. Overnight rostral fluid shift in obstructive sleep apnea: does it affect the severity of sleep-disordered breathing? Chest. 2011;140(4):991-997. [CrossRef] [PubMed]
 
Yap LB, Mukerjee D, Timms PM, Ashrafian H, Coghlan JG. Natriuretic peptides, respiratory disease, and the right heart. Chest. 2004;126(4):1330-1336. [CrossRef] [PubMed]
 
Usui Y, Tomiyama H, Hashimoto H, et al. Plasma B-type natriuretic peptide level is associated with left ventricular hypertrophy among obstructive sleep apnoea patients. J Hypertens. 2008;26(1):117-123. [CrossRef] [PubMed]
 
Fisher MR, Forfia PR, Chamera E, et al. Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med. 2009;179(7):615-621. [CrossRef] [PubMed]
 
Fisher MR, Criner GJ, Fishman AP, et al; NETT Research Group. Estimating pulmonary artery pressures by echocardiography in patients with emphysema. Eur Respir J. 2007;30(5):914-921. [CrossRef] [PubMed]
 
Deegan PC, McNicholas WT. Predictive value of clinical features for the obstructive sleep apnoea syndrome. Eur Respir J. 1996;9(1):117-124. [CrossRef] [PubMed]
 
Hessel NS, de Vries N. Diagnostic work-up of socially unacceptable snoring. II. Sleep endoscopy. Eur Arch Otorhinolaryngol. 2002;259(3):158-161. [CrossRef] [PubMed]
 
Pouliot Z, Peters M, Neufeld H, Kryger MH. Using self-reported questionnaire data to prioritize OSA patients for polysomnography. Sleep. 1997;20(3):232-236. [PubMed]
 
Viner S, Szalai JP, Hoffstein V. Are history and physical examination a good screening test for sleep apnea? Ann Intern Med. 1991;115(5):356-359. [CrossRef] [PubMed]
 
Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP. Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med. 1999;131(7):485-491. [CrossRef] [PubMed]
 
Kushida CA, Efron B, Guilleminault C. A predictive morphometric model for the obstructive sleep apnea syndrome. Ann Intern Med. 1997;127(8 pt 1):581-587. [CrossRef] [PubMed]
 
Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep. 1999;22(5):667-689. [PubMed]
 
Mokhlesi B, Tulaimat A, Faibussowitsch I, Wang Y, Evans AT. Obesity hypoventilation syndrome: prevalence and predictors in patients with obstructive sleep apnea. Sleep Breath. 2007;11(2):117-124. [CrossRef] [PubMed]
 
Mokhlesi B, Tulaimat A. Recent advances in obesity hypoventilation syndrome. Chest. 2007;132(4):1322-1336. [CrossRef] [PubMed]
 
Kessler R, Chaouat A, Schinkewitch P, et al. The obesity-hypoventilation syndrome revisited: a prospective study of 34 consecutive cases. Chest. 2001;120(2):369-376. [CrossRef] [PubMed]
 
Sugerman HJ, Baron PL, Fairman RP, Evans CR, Vetrovec GW. Hemodynamic dysfunction in obesity hypoventilation syndrome and the effects of treatment with surgically induced weight loss. Ann Surg. 1988;207(5):604-613. [CrossRef] [PubMed]
 
Ahmed Q, Chung-Park M, Tomashefski JF Jr. Cardiopulmonary pathology in patients with sleep apnea/obesity hypoventilation syndrome. Hum Pathol. 1997;28(3):264-269. [CrossRef] [PubMed]
 
Flenley DC. Sleep in chronic obstructive lung disease. Clin Chest Med. 1985;6(4):651-661. [PubMed]
 
Chaouat A, Weitzenblum E, Krieger J, Ifoundza T, Oswald M, Kessler R. Association of chronic obstructive pulmonary disease and sleep apnea syndrome. Am J Respir Crit Care Med. 1995;151(1):82-86. [CrossRef] [PubMed]
 
Weitzenblum E, Chaouat A, Kessler R, Canuet M. Overlap syndrome: obstructive sleep apnea in patients with chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5(2):237-241. [CrossRef] [PubMed]
 
Sanders MH, Newman AB, Haggerty CL, et al; Sleep Heart Health Study. Sleep and sleep-disordered breathing in adults with predominantly mild obstructive airway disease. Am J Respir Crit Care Med. 2003;167(1):7-14. [CrossRef] [PubMed]
 
Vgontzas AN, Tan TL, Bixler EO, Martin LF, Shubert D, Kales A. Sleep apnea and sleep disruption in obese patients. Arch Intern Med. 1994;154(15):1705-1711. [CrossRef] [PubMed]
 
Sériès F, Cormier Y, La Forge J. Role of lung volumes in sleep apnoea-related oxygen desaturation. Eur Respir J. 1989;2(1):26-30. [PubMed]
 
Ray CS, Sue DY, Bray G, Hansen JE, Wasserman K. Effects of obesity on respiratory function. Am Rev Respir Dis. 1983;128(3):501-506. [PubMed]
 
Friedman SE, Andrus BW. Obesity and pulmonary hypertension: a review of pathophysiologic mechanisms. J Obes. 2012;2012:505274. [CrossRef] [PubMed]
 
Lanfranchi PA, Braghiroli A, Bosimini E, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation. 1999;99(11):1435-1440. [CrossRef] [PubMed]
 
Colish J, Walker JR, Elmayergi N, et al. Obstructive sleep apnea: effects of continuous positive airway pressure on cardiac remodeling as assessed by cardiac biomarkers, echocardiography, and cardiac MRI. Chest. 2012;141(3):674-681. [CrossRef] [PubMed]
 
Arias MA, García-Río F, Alonso-Fernández A, Martínez I, Villamor J. Pulmonary hypertension in obstructive sleep apnoea: effects of continuous positive airway pressure: a randomized, controlled cross-over study. Eur Heart J. 2006;27(9):1106-1113. [CrossRef] [PubMed]
 
Sajkov D, Wang T, Saunders NA, Bune AJ, Mcevoy RD. Continuous positive airway pressure treatment improves pulmonary hemodynamics in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2002;165(2):152-158. [CrossRef] [PubMed]
 
Alchanatis M, Tourkohoriti G, Kakouros S, Kosmas E, Podaras S, Jordanoglou JB. Daytime pulmonary hypertension in patients with obstructive sleep apnea: the effect of continuous positive airway pressure on pulmonary hemodynamics. Respiration. 2001;68(6):566-572. [CrossRef] [PubMed]
 
Ip MS, Lam B, Chan LY, et al. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med. 2000;162(6):2166-2171. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Pulmonary artery pressure and arterial blood gas analysis in five patients with OSAS. A, Pulmonary artery pressure and alveolar hypoventilation increase progressively and significantly from wakefulness (W) through sleep stages 1, 2, 3-4, and then REM sleep. B, Two years after tracheostomy, pulmonary artery pressure remains higher than physiologic levels during wakefulness and increases only slightly during sleep. The arterial blood gases and pH remain within physiologic limits in both wakefulness and sleep. Mn = minimum; Mx = maximum; OSAS = OSA syndrome; Pulm.Art.Press = pulmonary artery pressure; REM = rapid eye movement; St = stage. (Reprinted with permission from Coccagna et al.28)Grahic Jump Location
Figure Jump LinkFigure 2 –  Pathophysiologic mechanisms involved in the development of apnea-related increased pulmonary artery pressure. At the endovascular level (magnified enclosure), endothelial dysfunction, heightened inflammation, and procoagulation play an additional role. CRP = C-reactive protein; RA = right atrium; RV = right ventricle; SV = stroke volume; PA = pulmonary artery; PV = pulmonary vein; LA = left atrium; LV = left ventricle; P = pressure; VEGF = vascular endothelial growth factor.Grahic Jump Location
Figure Jump LinkFigure 3 –  Kaplan-Meier survival estimates in 83 patients with OSA with and without PH. The survival rate at 1, 4, and 8 y was 100%, 90%, and 76% in the non-PH group and 93%, 75%, and 43% in the PH group, respectively. PH = pulmonary hypertension. (Reprinted with permission from Minai et al.13)Grahic Jump Location
Figure Jump LinkFigure 4 –  Individual values for the PASP after both sham and effective CPAP treatment in patients with OSA. Black bar represents mean PASP, changing from baseline 28.9 ± 8.6 mm Hg to 24.0 ± 5.8 mm Hg after 12 wk of CPAP (P = .0001). PASP = pulmonary artery systolic pressure. (Reprinted with permission from Arias et al.78)Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Prevalence of PH Among Patients With Established OSA

AHI = apnea-hypopnea index; AI = apnea index; LV = left ventricular; mPAP = mean pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; PFT = pulmonary function test; PH = pulmonary hypertension; PSG = polysomnography; RDI = respiratory disturbance index; RHC = right-sided heart catheterization; Sao2 = arterial oxygen saturation; TTE = transthoracic echocardiogram; VC = vital capacity.

Table Graphic Jump Location
TABLE 2 ]  Prevalence of SDB Among Patients With Established PH

CI = cardiac index; CO = cardiac output; CSA = central sleep apnea; CSR = Cheyne-Stokes respiration; IPAH = idiopathic pulmonary arterial hypertension; NR = not reported; PVR = pulmonary vascular resistance; RVEF = right ventricular ejection fraction; SDB = sleep-disordered breathing; TST = total sleep time; WHO = World Health Organization. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 3 ]  Effects of Treatment With CPAP in Patients With OSA

CRP = C-reactive protein; PASP = systolic pulmonary artery pressure; RVSP = right ventricular systolic pressure. See Table 1 legend for expansion of other abbreviations

References

Somers VK, White DP, Amin R, 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. Circulation. 2008;118(10):1080-1111. [CrossRef] [PubMed]
 
Aronsohn RS, Whitmore H, Van Cauter E, Tasali E. Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes. Am J Respir Crit Care Med. 2010;181(5):507-513. [CrossRef] [PubMed]
 
Lal C, Strange C, Bachman D. Neurocognitive impairment in obstructive sleep apnea neurocognitive impairment. Chest. 2012;141(6):1601-1610. [CrossRef] [PubMed]
 
Sajkov D, McEvoy RD. Obstructive sleep apnea and pulmonary hypertension. Prog Cardiovasc Dis. 2009;51(5):363-370. [CrossRef] [PubMed]
 
Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230-1235. [CrossRef] [PubMed]
 
Bixler EO, Vgontzas AN, Lin HM, et al. Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med. 2001;163(3 pt 1):608-613. [CrossRef] [PubMed]
 
Durán J, Esnaola S, Rubio R, Iztueta A. Obstructive sleep apnea-hypopnea and related clinical features in a population-based sample of subjects aged 30 to 70 yr. Am J Respir Crit Care Med. 2001;163(3 pt 1):685-689. [CrossRef] [PubMed]
 
Kapur V, Strohl KP, Redline S, Iber C, O’Connor G, Nieto J. Underdiagnosis of sleep apnea syndrome in U.S. communities. Sleep Breath. 2002;6(2):49-54. [CrossRef] [PubMed]
 
Young T, Evans L, Finn L, Palta M. Estimation of the clinically diagnosed proportion of sleep apnea syndrome in middle-aged men and women. Sleep. 1997;20(9):705-706. [PubMed]
 
Lee W, Nagubadi S, Kryger MH, Mokhlesi B. Epidemiology of obstructive sleep apnea: a population-based perspective. Expert Rev Respir Med. 2008;2(3):349-364. [CrossRef] [PubMed]
 
Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006-1014. [CrossRef] [PubMed]
 
Atwood CW Jr, McCrory D, Garcia JG, Abman SH, Ahearn GS; American College of Chest Physicians. Pulmonary artery hypertension and sleep-disordered breathing: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(1_ suppl):72S-77S. [CrossRef] [PubMed]
 
Minai OA, Ricaurte B, Kaw R, et al. Frequency and impact of pulmonary hypertension in patients with obstructive sleep apnea syndrome. Am J Cardiol. 2009;104(9):1300-1306. [CrossRef] [PubMed]
 
Chaouat A, Weitzenblum E, Krieger J, Oswald M, Kessler R. Pulmonary hemodynamics in the obstructive sleep apnea syndrome. Results in 220 consecutive patients. Chest. 1996;109(2):380-386. [CrossRef] [PubMed]
 
Bady E, Achkar A, Pascal S, Orvoen-Frija E, Laaban JP. Pulmonary arterial hypertension in patients with sleep apnoea syndrome. Thorax. 2000;55(11):934-939. [CrossRef] [PubMed]
 
Niijima M, Kimura H, Edo H, et al. Manifestation of pulmonary hypertension during REM sleep in obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 1999;159(6):1766-1772. [CrossRef] [PubMed]
 
Sajkov D, Wang T, Saunders NA, Bune AJ, Neill AM, Mcevoy RD. Daytime pulmonary hemodynamics in patients with obstructive sleep apnea without lung disease. Am J Respir Crit Care Med. 1999;159(5 pt 1):1518-1526. [CrossRef] [PubMed]
 
Sanner BM, Doberauer C, Konermann M, Sturm A, Zidek W. Pulmonary hypertension in patients with obstructive sleep apnea syndrome. Arch Intern Med. 1997;157(21):2483. [CrossRef] [PubMed]
 
Laks L, Lehrhaft B, Grunstein R, Sullivan C. Pulmonary hypertension in obstructive sleep apnoea. Eur Respir J. 1995;8(4):537-541. [PubMed]
 
Krieger J, Sforza E, Apprill M, Lampert E, Weitzenblum E, Ratomaharo J. Pulmonary hypertension, hypoxemia, and hypercapnia in obstructive sleep apnea patients. Chest. 1989;96(4):729-737. [CrossRef] [PubMed]
 
Jilwan FN, Escourrou P, Garcia G, Jaïs X, Humbert M, Roisman G. High occurrence of hypoxemic sleep respiratory disorders in precapillary pulmonary hypertension and mechanisms. Chest. 2013;143(1):47-55. [CrossRef] [PubMed]
 
Prisco DL, Sica AL, Talwar A, et al. Correlation of pulmonary hypertension severity with metrics of comorbid sleep-disordered breathing. Sleep Breath. 2011;15(4):633-639. [CrossRef] [PubMed]
 
Ulrich S, Fischler M, Speich R, Bloch KE. Sleep-related breathing disorders in patients with pulmonary hypertension. Chest. 2008;133(6):1375-1380. [CrossRef] [PubMed]
 
Schulz R, Baseler G, Ghofrani HA, Grimminger F, Olschewski H, Seeger W. Nocturnal periodic breathing in primary pulmonary hypertension. Eur Respir J. 2002;19(4):658-663. [CrossRef] [PubMed]
 
Rafanan AL, Golish JA, Dinner DS, Hague LK, Arroliga AC. Nocturnal hypoxemia is common in primary pulmonary hypertension. Chest. 2001;120(3):894-899. [CrossRef] [PubMed]
 
Coccagna G, Lugaresi E. Haemodynamics during sleep: old results and new perspectives. J Sleep Res. 1995;4(S1):2-7. [CrossRef] [PubMed]
 
Coccagna G, Mantovani M, Brignani F, Parchi C, Lugaresi E. Continuous recording of the pulmonary and systemic arterial pressure during sleep in syndromes of hypersomnia with periodic breathing. Bull Physiopathol Respir (Nancy). 1972;8(5):1159-1172. [PubMed]
 
Coccagna G, Mantovani M, Brignani F, Parchi C, Lugaresi E. Tracheostomy in hypersomnia with periodic breathing. Bull Physiopathol Respir (Nancy). 1972;8(5):1217-1227. [PubMed]
 
Saunders NA, Sullivan CE. Sleep and Breathing. New York, NY: M. Dekker; 1984.
 
Guyton AC, Lindsey AW, Abernathy B, Richardson T. Venous return at various right atrial pressures and the normal venous return curve. Am J Physiol. 1957;189(3):609-615. [PubMed]
 
Robotham JL, Rabson J, Permutt S, Bromberger-Barnea B. Left ventricular hemodynamics during respiration. J Appl Physiol. 1979;47(6):1295-1303. [PubMed]
 
Buda AJ, Pinsky MR, Ingels NB Jr, Daughters GT II, Stinson EB, Alderman EL. Effect of intrathoracic pressure on left ventricular performance. N Engl J Med. 1979;301(9):453-459. [CrossRef] [PubMed]
 
Guilleminault C, Cummiskey J, Dement WC. Sleep apnea syndrome: recent advances. Adv Intern Med. 1980;26:347-372. [PubMed]
 
Kato M, Roberts-Thomson P, Phillips BG, et al. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation. 2000;102(21):2607-2610. [CrossRef] [PubMed]
 
Ip MS, Tse HF, Lam B, Tsang KW, Lam WK. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med. 2004;169(3):348-353. [CrossRef] [PubMed]
 
Phillips BG, Narkiewicz K, Pesek CA, Haynes WG, Dyken ME, Somers VK. Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens. 1999;17(1):61-66. [CrossRef] [PubMed]
 
Schulz R, Hummel C, Heinemann S, Seeger W, Grimminger F. Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe nighttime hypoxia. Am J Respir Crit Care Med. 2002;165(1):67-70. [CrossRef] [PubMed]
 
Chin K, Nakamura T, Shimizu K, et al. Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome. Am J Med. 2000;109(7):562-567. [CrossRef] [PubMed]
 
Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med. 2002;165(7):934-939. [CrossRef] [PubMed]
 
Yokoe T, Minoguchi K, Matsuo H, et al. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation. 2003;107(8):1129-1134. [CrossRef] [PubMed]
 
Lavie L. Obstructive sleep apnoea syndrome—an oxidative stress disorder. Sleep Med Rev. 2003;7(1):35-51. [CrossRef] [PubMed]
 
Cahan C, Decker MJ, Arnold JL, et al. Diurnal variations in serum erythropoietin levels in healthy subjects and sleep apnea patients. J Appl Physiol (1985). 1992;72(6):2112-2117. [PubMed]
 
Cahan C, Decker MJ, Arnold JL, Goldwasser E, Strohl KP. Erythropoietin levels with treatment of obstructive sleep apnea. J Appl Physiol (1985). 1995;79(4):1278-1285. [PubMed]
 
Chin K, Ohi M, Kita H, et al. Effects of NCPAP therapy on fibrinogen levels in obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 1996;153(6 pt 1):1972-1976. [CrossRef] [PubMed]
 
Rångemark C, Hedner JA, Carlson JT, Gleerup G, Winther K. Platelet function and fibrinolytic activity in hypertensive and normotensive sleep apnea patients. Sleep. 1995;18(3):188-194. [PubMed]
 
Bokinsky G, Miller M, Ault K, Husband P, Mitchell J. Spontaneous platelet activation and aggregation during obstructive sleep apnea and its response to therapy with nasal continuous positive airway pressure. A preliminary investigation. Chest. 1995;108(3):625-630. [CrossRef] [PubMed]
 
Chou KT, Huang CC, Chen YM, et al. Sleep apnea and risk of deep vein thrombosis: a non-randomized, pair-matched cohort study. Am J Med. 2012;125(4):374-380. [CrossRef] [PubMed]
 
Epstein MD, Segal LN, Ibrahim SM, Friedman N, Bustami R. Snoring and the risk of obstructive sleep apnea in patients with pulmonary embolism. Sleep. 2010;33(8):1069-1074. [PubMed]
 
Elias RM, Bradley TD, Kasai T, Motwani SS, Chan CT. Rostral overnight fluid shift in end-stage renal disease: relationship with obstructive sleep apnea. Nephrol Dial Transplant. 2012;27(4):1569-1573. [CrossRef] [PubMed]
 
Friedman O, Bradley TD, Chan CT, Parkes R, Logan AG. Relationship between overnight rostral fluid shift and obstructive sleep apnea in drug-resistant hypertension. Hypertension. 2010;56(6):1077-1082. [CrossRef] [PubMed]
 
Jafari B, Mohsenin V. Overnight rostral fluid shift in obstructive sleep apnea: does it affect the severity of sleep-disordered breathing? Chest. 2011;140(4):991-997. [CrossRef] [PubMed]
 
Yap LB, Mukerjee D, Timms PM, Ashrafian H, Coghlan JG. Natriuretic peptides, respiratory disease, and the right heart. Chest. 2004;126(4):1330-1336. [CrossRef] [PubMed]
 
Usui Y, Tomiyama H, Hashimoto H, et al. Plasma B-type natriuretic peptide level is associated with left ventricular hypertrophy among obstructive sleep apnoea patients. J Hypertens. 2008;26(1):117-123. [CrossRef] [PubMed]
 
Fisher MR, Forfia PR, Chamera E, et al. Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med. 2009;179(7):615-621. [CrossRef] [PubMed]
 
Fisher MR, Criner GJ, Fishman AP, et al; NETT Research Group. Estimating pulmonary artery pressures by echocardiography in patients with emphysema. Eur Respir J. 2007;30(5):914-921. [CrossRef] [PubMed]
 
Deegan PC, McNicholas WT. Predictive value of clinical features for the obstructive sleep apnoea syndrome. Eur Respir J. 1996;9(1):117-124. [CrossRef] [PubMed]
 
Hessel NS, de Vries N. Diagnostic work-up of socially unacceptable snoring. II. Sleep endoscopy. Eur Arch Otorhinolaryngol. 2002;259(3):158-161. [CrossRef] [PubMed]
 
Pouliot Z, Peters M, Neufeld H, Kryger MH. Using self-reported questionnaire data to prioritize OSA patients for polysomnography. Sleep. 1997;20(3):232-236. [PubMed]
 
Viner S, Szalai JP, Hoffstein V. Are history and physical examination a good screening test for sleep apnea? Ann Intern Med. 1991;115(5):356-359. [CrossRef] [PubMed]
 
Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP. Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med. 1999;131(7):485-491. [CrossRef] [PubMed]
 
Kushida CA, Efron B, Guilleminault C. A predictive morphometric model for the obstructive sleep apnea syndrome. Ann Intern Med. 1997;127(8 pt 1):581-587. [CrossRef] [PubMed]
 
Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep. 1999;22(5):667-689. [PubMed]
 
Mokhlesi B, Tulaimat A, Faibussowitsch I, Wang Y, Evans AT. Obesity hypoventilation syndrome: prevalence and predictors in patients with obstructive sleep apnea. Sleep Breath. 2007;11(2):117-124. [CrossRef] [PubMed]
 
Mokhlesi B, Tulaimat A. Recent advances in obesity hypoventilation syndrome. Chest. 2007;132(4):1322-1336. [CrossRef] [PubMed]
 
Kessler R, Chaouat A, Schinkewitch P, et al. The obesity-hypoventilation syndrome revisited: a prospective study of 34 consecutive cases. Chest. 2001;120(2):369-376. [CrossRef] [PubMed]
 
Sugerman HJ, Baron PL, Fairman RP, Evans CR, Vetrovec GW. Hemodynamic dysfunction in obesity hypoventilation syndrome and the effects of treatment with surgically induced weight loss. Ann Surg. 1988;207(5):604-613. [CrossRef] [PubMed]
 
Ahmed Q, Chung-Park M, Tomashefski JF Jr. Cardiopulmonary pathology in patients with sleep apnea/obesity hypoventilation syndrome. Hum Pathol. 1997;28(3):264-269. [CrossRef] [PubMed]
 
Flenley DC. Sleep in chronic obstructive lung disease. Clin Chest Med. 1985;6(4):651-661. [PubMed]
 
Chaouat A, Weitzenblum E, Krieger J, Ifoundza T, Oswald M, Kessler R. Association of chronic obstructive pulmonary disease and sleep apnea syndrome. Am J Respir Crit Care Med. 1995;151(1):82-86. [CrossRef] [PubMed]
 
Weitzenblum E, Chaouat A, Kessler R, Canuet M. Overlap syndrome: obstructive sleep apnea in patients with chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5(2):237-241. [CrossRef] [PubMed]
 
Sanders MH, Newman AB, Haggerty CL, et al; Sleep Heart Health Study. Sleep and sleep-disordered breathing in adults with predominantly mild obstructive airway disease. Am J Respir Crit Care Med. 2003;167(1):7-14. [CrossRef] [PubMed]
 
Vgontzas AN, Tan TL, Bixler EO, Martin LF, Shubert D, Kales A. Sleep apnea and sleep disruption in obese patients. Arch Intern Med. 1994;154(15):1705-1711. [CrossRef] [PubMed]
 
Sériès F, Cormier Y, La Forge J. Role of lung volumes in sleep apnoea-related oxygen desaturation. Eur Respir J. 1989;2(1):26-30. [PubMed]
 
Ray CS, Sue DY, Bray G, Hansen JE, Wasserman K. Effects of obesity on respiratory function. Am Rev Respir Dis. 1983;128(3):501-506. [PubMed]
 
Friedman SE, Andrus BW. Obesity and pulmonary hypertension: a review of pathophysiologic mechanisms. J Obes. 2012;2012:505274. [CrossRef] [PubMed]
 
Lanfranchi PA, Braghiroli A, Bosimini E, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation. 1999;99(11):1435-1440. [CrossRef] [PubMed]
 
Colish J, Walker JR, Elmayergi N, et al. Obstructive sleep apnea: effects of continuous positive airway pressure on cardiac remodeling as assessed by cardiac biomarkers, echocardiography, and cardiac MRI. Chest. 2012;141(3):674-681. [CrossRef] [PubMed]
 
Arias MA, García-Río F, Alonso-Fernández A, Martínez I, Villamor J. Pulmonary hypertension in obstructive sleep apnoea: effects of continuous positive airway pressure: a randomized, controlled cross-over study. Eur Heart J. 2006;27(9):1106-1113. [CrossRef] [PubMed]
 
Sajkov D, Wang T, Saunders NA, Bune AJ, Mcevoy RD. Continuous positive airway pressure treatment improves pulmonary hemodynamics in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2002;165(2):152-158. [CrossRef] [PubMed]
 
Alchanatis M, Tourkohoriti G, Kakouros S, Kosmas E, Podaras S, Jordanoglou JB. Daytime pulmonary hypertension in patients with obstructive sleep apnea: the effect of continuous positive airway pressure on pulmonary hemodynamics. Respiration. 2001;68(6):566-572. [CrossRef] [PubMed]
 
Ip MS, Lam B, Chan LY, et al. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med. 2000;162(6):2166-2171. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
Guidelines
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543