Cor pulmonale has a well-described association with chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and interstitial lung diseases.1 This association is felt to be the result of chronic hypoxic pulmonary vasoconstriction as well as a complex interaction of molecular pathways culminating in pulmonary vascular remodeling. The WHO clinical classification of pulmonary hypertension (PH) includes these patients in WHO Class III (PH associated with lung diseases and/or hypoxemia), which also incorporates patients with sleep disordered breathing.2 Obstructive sleep apnea (OSA)/hypopnea syndrome is the most widely studied of all sleep disordered breathing syndromes, occurring in approximately 10% of adult men and 5% of middleaged women.3 It is becoming increasingly clear that, in addition to excessive daytime sleepiness and snoring, OSA is associated with a variety of chronic cardiovascular sequelae, including hypertension, stroke, coronary artery disease, and sudden death.4 Pulmonary hypertension is a less appreciated complication of the physiologic changes associated with OSA.5 6 7 8 Patients with OSA have been shown to have transient, sometimes severe, elevations in pulmonary arterial pressures (PAP) during sleep;9 however, daytime, fixed PH has received less attention. Several factors associated with OSA may produce PH,10 11 12 13 including chronic hypoxia, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, intermittent intrathoracic pressure changes, and associated comorbidities. This review is devoted to permanent, daytime PH in patients with OSA.
Pulmonary hypertension is defined by the presence of resting mean PAP (mPAP) >25 mmHg during right heart catheterization (RHC).14 15 However, previous studies on PH in patients with COPD and OSA have defined PH as mPAP >20 mm Hg. Pulmonary arterial hypertension (PAH) is a subgroup further defined by the presence of pulmonary capillary wedge pressure (PCWP) ≤15 mm Hg and both PAH (PCWP ≤15 mm Hg) and pulmonary venous hypertension (PVH; PCWP >15 mm Hg) have been reported in patients with OSA.16 17 18 Severe PH remains poorly defined andthe suggested definition of resting mPAP ≥40 mm Hg has several limitations.19 20
Several hemodynamic alterations have been described in association with normal sleep, including a decrease in systemic blood pressure and heart rate.21 However, limited data suggest that normal sleep has minimal impact on pulmonary hemodynamics.22 23 This relationship is dramatically altered during episodes of apnea. Several studies have described significant increases in PAP from the middle of the apnea to the end of the apnea, which reaches a maximum during the first few breaths once the obstruction is relieved (postapneic hyperventilation).24 25 26 27 28 These acute changes are more pronounced during rapid eye movement (REM) sleep than in non-REM sleep,29 30 31 32 33 and are felt to be related to acute changes in intrathoracic pressure, hypoxia, and reflex mechanisms. Repeated apneic episodes with attendant hypoxia can produce a sustained augmentation of the pressor response of the pulmonary arterial system, which escalates progressively during the night.34 35 36 It may be that the marked oxygen desaturation in REM sleep augments progressive increase in PAP without time to recover to baseline in the event of consecutive prolonged apneic episodes with short interapneic intervals.37
Similar to patients with chronic lung diseases, PH in the setting of OSA generally appears to be mild to moderate,38 39 with severe PH being less common.40 41 42 Largely as a result of concern over the invasive nature of RHC, the true prevalence of PH in OSA is not known due to a lack of large, population-based studies. Prevalence data on resting, awake PH in OSA is based primarily on retrospective case series or prospective cohort studies with poorly defined entry criteria (Table 1).43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 This literature is further confounded by several limitations—the most important among which are a lack of consistency in defining PH, the varying methods used to detect its presence, and the lack of exclusion of other secondary causes with proper evaluation. It is generally accepted that measurement of PH in obese patients with OSA is especially prone to error when performed by Doppler echocardiography (DE),63 64 65 66 and although DE estimates of right ventricular systolic pressure (RVSP) correlate strongly with systolic PAP measured by RHC, there is large variation among individual patients (Figure 1).67 Despite these limitations of DE in making a diagnosis of PH in this population,68 69 several studies have used this methodology (Table 1). In addition, several comorbidities including left-sided cardiac disease, COPD, and obesity may have an impact on the occurrence of PH and were not always excluded.
The prevalence of PH determined by RHC or DE in patients with OSA, in studies excluding cardiopulmonary disease, ranges from 17% to 41% (Table 1). In the largest series published to date, 17% of a sample of 220 patients with OSA met diagnostic criteria for PH.70 71 The true gender distribution of PH in OSA patients is unknown. Female preponderance has been described in several other forms of PH and has been attributed to genetic predisposition, the role of estrogen, and higher prevalence of autoimmune disease in females.72 Two recent studies of PH in patients with OSA have reported a higher prevalence of PH among females than males.73 74 The accuracy and significance of this finding, if any, requires larger studies in view of the predominantly male nature of the OSA population.
Coexistence of underlying chronic lung disease increases the risk of developing PH, and most studies showing a >50% prevalence of PH in patients with OSA have not excluded patients with chronic cardiopulmonary disease.75 76 77 78 Studies have indicated that the presence of obstructive79 80 81 or restrictive82 ventilatory defects on spirometry indicate a group at higher risk. On the other hand, even studies of patients without significant cardiopulmonary disease have included patients with small airway abnormalities83 or mild hypoxemia.84 85 In a European population with lower body mass index (BMI) (32±6 kg/m2),86 a lower prevalence of PH was reported than an Australian population with a higher BMI (37 [range 24-54 kg/m2]).87 Other studies have reported no association between the prevalence or severity of PH and BMI in patients with OSA.88 89
Exercise-induced PH has also been described in patients with OSA.90 91 92 93 In a cohort of 49 consecutive patients with OSA, Hetzel et al94 found that 6 (12%) patients had resting PH (mPAP >20 mm Hg), whereas 39 (80%) patients had PH during exercise (mPAP >30 mm Hg). All patients had normal pulmonary vascular resistance, and the main contributors to PH were elevated BMI, total lung capacity, and elevated PCWP.
Early studies in patients with OSA reported on the occurrence of clinical cor pulmonale.95 96 However, it is not clear that cor pulmonale equates to RV systolic failure in this population since RV diastolic dysfunction and solute and water retention may produce similar clinical findings. O’Hearn et al and Whyte et al97 98 found lower extremity edema to be a highly specific indicator of right heart failure in OSA patients with a BMI >40 kg/m2. Unlike patients with PAH who have chronic RV pressure overload and markedly elevated pulmonary vascular resistance, OSA patients may have chronic volume overload with milder elevation in pulmonary vascular resistance, suggesting that these patients may not have a large decrease in the cross-sectional area of the pulmonary vasculature.99 100
Cineradiographic observation in humans has demonstrated a progressive enlarging of the heart size throughout apnea.101 Thus, RV hypertrophy and dilation could stem from the mechanical effect of long-term, recurrent upper airway obstruction.102 The Framingham Heart Study found a small but significant increase in RV wall thickness using DE, suggestive of elevated PAP, in patients with severe OSA.103 Thickness of the RV wall was independently and positively correlated with the severity of OSA. The prevalence of RV abnormalities has varied widely between 0% and 71% among studies (Table 2).104 105 106 107 108 109 110 111 112 113 The validity and clinical significance of this observation remains poorly defined given the obvious limitations of DE in imaging the RV in morbidly obese patients with OSA.
Following the Framingham Heart Study, several studies reported decreased RV contractility and RV failure in patients with severe OSA.114 115 116 Right ventricular dysfunction, however, appears to be less common compared to PH alone and is frequently associated with coexisting left heart or chronic lung diseases with daytime hypoxemia.117 118 119 Echocardiographic studies in OSA patients without significant pulmonary comorbidities found elevated awake arterial partial pressure of carbon dioxide (PaCO2), apnea-hypopnea index (AHI) >40,120 and obesity to be important risk factors for reduced RV ejection fraction.121Mild abnormalities in RV function have been reported in the absence of daytime, resting PAH and may presumably occur as a consequence of the nocturnal hypoxia and attendant hemodynamic alterations. Current evidence, however, suggests that the occurrence of RV systolic failure in OSA requires the presence of additional comorbidities such as chronic lung disease or left ventricular dysfunction.122 123 124
Patients with OSA have normal gas exchange when awake andonly become hypoxemic during sleep.125 Animal experiments have shown that intermittent hypoxia (4-8 hours per day) is sufficient to induce a sustained rise in PAP and RV hypertrophy.126 127 128 129 130 Coccagna and colleagues131 have demonstrated occurrence of PAP elevation with sleep-related hypoxemia, and acute rise in PAP during obstructive events has been shown to correlate inversely with the degree of oxygen desaturation.132 133 134 The mild increase in PAP during a respiratory event is due to an interplay of multiple factors including hypoxic pulmonary vasoconstriction, mechanically induced negative intrathoracic pressure from heightened inspiratory muscle response against an occluded airway, and direct effect on the vasculature from reflex mechanisms inducing variations in heart rate, cardiac output, and increased left-sided filling pressures. However, most studies have reported no association between severity of OSA (as measured by AHI) and the presence or severity of PH.135 136 137 138 139 140
It is well established that chronic daytime hypoxia can lead to PH and cor pulmonale.141 Hypoxic pulmonary vasoconstriction improves ventilation-perfusion matching by shunting blood to betterventilated lung zones and induces a rise in PAP.142 The deleterious effects of episodic hypoxia on pulmonary hemodynamics have been extensively described;143 144 145 146 however, the mechanisms by which chronic hypoxia leads to pulmonary vascular remodeling are complex and poorly understood. In addition to causing vasoconstriction and shear stress, chronic hypoxia exerts its effect on the vascular endothelium and smooth muscle cells (mainly the small muscular pulmonary arteries and nonmuscular precapillary arterioles) to release vasoconstrictive, pro-proliferative, and mitogenic mediators. Several mediators including endothelin-1, vascular endothelial growth factor, angiotensin II, nitric oxide, endothelial apoptotic factors, angiotensin converting enzyme, inflammatory mediators (IL-8, IL-6), reactive oxygen species, and various transcription factors such as hypoxia-inducible factor-1 have been implicated in this process.147 These events lead to angiogenesis,promote muscle and fibroblast proliferation, produce extension of smooth muscle into nonmuscularized vessels, and increase vascularity.148 The pathologic features of hypoxic vasculopathy include concentric intimal thickening secondary to proliferation of endothelial cells, smooth muscle cells, and myofibroblasts, medial hypertrophy with longitudinally oriented smooth muscle bundles of the muscular pulmonary arteries, adventitial proliferation, and abnormal extracellular matrix deposition.149 150 151 There is muscularization of the arterioles, with well-developed distinct elastic laminae and medial muscle layer extending to the smaller vessels. Extreme capillary proliferation may also be seen in some patients with severe OSA and RV hypertrophy.152
Controversy remains over whether intermittent hypoxia (such as that produced by apneic events during sleep) is adequate to produce pulmonary vascular remodeling resulting in awake, resting PH. Individual variation in ventilatory responsiveness to hypoxia demonstrated in awake OSA patients153 could also modulate the magnitude of PAP changes,154 although its role in PH remains controversial. So far it has not been convincingly demonstrated that a reduced chemosensitivity, possibly secondary to repetitive nighttime hypoxemic and hypercapnic episodes, can lead to daytime hypoxemia or PH.155 156 Although hypercapnia is known to potentiate the hypoxic response, evidence does not support it being a major factor for OSA-associated PAP changes. Whether the repetitive upper airway collapse and large intrathoracic negative pressure swings with nocturnal oxygen desaturation and hypercapnia leading to marked variation in PAP underlies the chronic PAP elevation in OSA requires further study.157 158 159 160 161 162
The hypothesis that isolated nocturnal hypoxemia may lead to permanent PH is supported by studies demonstrating PH in patients with normal daytime PaO2163 or very slight hypoxemia.164 A decrease in PAP after 3-6 months of nighttime continuous positive airway pressure (CPAP) therapy without an associated improvement in spirometry or awake blood gases165 166 167 further strengthens this hypothesis.
Several studies have shown that OSA patients with PH often have concomitant cardiac or pulmonary disease, leading to the speculation that such comorbidities are a prerequisite for the development of significant PH and RV failure in OSA. It has been suggested that PH in association with OSA is mainly precapillary in nature;168 however, given the prevalence of morbid obesity, hypertension, and left ventricular systolic and diastolic dysfunction in this population, it is likely that postcapillary factors169 170 171 172 173 174 175 play an important role. Diastolic dysfunction and left ventricular hypertrophy with elevated PCWP have been demonstrated in OSA patients without any other evidence of underlying cardiac disease and may contribute to the diagnosis of PH during rest and exercise.176 177 178 179 Diastolic dysfunction can produce elevated PCWP in severely obese OSA patients with normal left ventricular function. 180 181 182 Chaouat et al183 demonstrated a rise in mPAP from 26.0±5.8 to 46.7±12 mm Hg during submaximal steady-state exercise, partly explained by an exercise-induced rise in PCWP. Two other studies have reported similar findings, suggesting that PVH due to diastolic dysfunction is an important factor in patients with OSA.184 185 Whether exercise-induced PH identifies a subgroup of OSA patients at higher risk of developing resting PH requires further study.
Patients with both COPD and OSA (also known as “overlap syndrome”) are at a higher risk of developing PH than patients with either condition alone. Chronic obstructive pulmonary disease is often the primary cause of alveolar hypoventilation in OSA.186 Studies have clearly demonstrated that presence of airway obstruction predicts hypoxemia-hypercapnia and PH.187 188 189 190 191 192 193 194 In these patients with PH, bronchial obstruction is usually mild-moderate, and the degree of blood gas disturbances may not be severe.195
The likelihood of PH in morbid obesity is increased considerably when OSA is present.196 197 Bady et al demonstrated that the severity of obesity and the associated changes in lung function play an important role in the pathogenesis of PH in patients with OSA.198 Another study showed that greater age and increased BMI distinguished OSA patients with mild PH from those without PH.199 However, other studies200 201 202 have not found a significant difference in body weight in OSA patients with and without PH. Discrepancies in the findings among the series in the literature could be accounted for by the differences in the prevalence of severe obesity in each series and across continents where these studies were conducted.203 Obesity hypoventilation syndrome, which is defined by a clinical triad of obesity, awake chronic hypercapnia, and OSA, is associated with a higher prevalence of PH and greater PAP levels.204 205 Whether obesity confers an added risk for PH over and above that due to OSA and the associated comorbidities needs to be better defined.
The effect of humoral factors on awake PAP remains speculative. Increased natriuretic peptides and decreased nitric oxide have been found in OSA patients206 and levels improved with CPAP treatment.207 Both circulating humoral substances and genetic factors could influence individual responsiveness to hypoxia and therefore the levels of PAP reached after obstructive events causing similar degree of oxygen desaturations.208 Clearly we are in need of studies to better define the role of pulmonary vasoconstriction, vascular remodeling, and preclinical changes in pulmonary circulation and the impact of genetic factors on changes in pulmonary hemodynamics due to OSA.
The presence of comorbidities such as COPD and left-sided cardiac disease increases the likelihood of PH in patients with OSA. Studies have shown that the development of PH is correlated with lower daytime baseline arterial oxygen tension (PaO2) and longer duration of nocturnal hypoxemia (SaO2 <90%), which are important surrogate markers of severity in OSA.209 210 211 212 In a recent study, younger age, female gender, obesity, and increased duration of nocturnal desaturation were found to be associated with the presence of PH.213 However, presumably because of the small sample size and the relatively low prevalence of PH in this population, no prediction models based on demographics and polysomnographic variables had been reported until recently.
Pulmonary hypertension can lead to functional decline and poor prognosis in several diseases, including connective tissue diseases, pulmonary fibrosis, and COPD.214 Previous studies of PH in patients with OSA have not addressed this association, largely because of the small numbers of patients with PH and the shortterm nature of these studies.215 A recent report found that OSA patients with PH had lower functional capacity (as measured by 6-minute walk distance) and more dyspnea compared to OSA patients without PH.216 This association did not reach statistical significance largely due to the small sample size. This study further showed that mortality was increased in patients with PH (Figure 3) and that in addition to factors such as age, forced expiratory volume in 1 second, diffusion capacity for carbon monoxide, and AHI, pulmonary hemodynamics were important correlates of increased mortality in patients with OSA.217 The only other report to examine the hemodynamic predictors of mortality in OSA did not find resting mPAP to be a predictor of mortality on multivariate analysis.218
The American College of Chest Physicians consensus panel has recommended that patients with PH should be evaluated for OSA but did not recommend routine screening for PH in patients with OSA.219
Given the likelihood of comorbidities, an important initial step should be to look for and manage comorbidities, including diastolic dysfunction and COPD. In addition, exertional and nocturnal hypoxia should be corrected with oxygen supplementation or CPAP therapy as appropriate. Oxygen supplementation has been shown to reduce PAP in patients with COPD and nocturnal hypoxemia. 220 In dog models of artificially-induced recurrent episodes of obstructive apnea, blunting of PAP elevation results from restoration of arterial oxygen saturation following O2 supplementation.221 222 Tracheostomy has also been shown to cause a dramatic reduction in PAP in OSA patients with sleep-related oxygen desaturation.223 224
Treatment of OSA with CPAP has been shown to lower systolic blood pressure, improve quality of life, and improve arterial oxygen saturation in patients without concomitant COPD. It is unclear whether the mild PH found among OSA patients without concomitant cardiopulmonary diseases requires treatment. In addition to relieving the upper airway obstruction and minimizing the intrathoracic pressure swings, long-term treatment with CPAP can produce significant improvement in daytime arterial oxygenation,225 raising the expectation of improvement or stabilization of PH, similar to that seen in COPD patients receiving long-term oxygen supplementation.226 Studies examining the effect of nasal CPAP treatment on PH in patients with OSA are sparse and have reported conflicting results (Table 3).227 228 229 230 231 232 233 234 235 Prevention of high PAP peak through application of CPAP during sleep was first demonstrated by Marrone et al.236 Studies by Sforza et al and Chaouat et al237 238 did not demonstrate a change in PAP following nasal CPAP use for 1 and 5 years respectively. These studies were limited by the very small subset of patients with PH in the OSA group (N=8 and 4 respectively). Two small, uncontrolled studies addressed the positive impact of CPAP therapy on pulmonary hemodynamics in OSA patients with PH. Collop and coworkers239 showed that treatment of OSA with nasal CPAP reverses PH in morbidly obese women without clinically significant lung disease. A prospective, uncontrolled, single-center case series by Sajkov et al240 showed significant decrease in the daytime PAP and pulmonary vascular response to hypoxia after 4 months of nasal CPAP treatment in 5 of the 20 OSA patients with mild PH. These were followed by larger prospective, controlled trials. Alchanatis et al,241 in a study of OSA patients (N=29) without other pulmonary or cardiac disease, reported a reduction in mPAP in both groups of OSA patients with (N=6) and without PH (N=23) after 6 months of CPAP treatment. Arias and colleagues242 demonstrated a reduction in systolic PAP after CPAP therapy in 10 obese patients in the first placebo-controlled trial of OSA treatment in PH.
Based on the current limited data, we can conclude that CPAP therapy has a modest role in improving pulmonary hemodynamics in OSA and is less likely to normalize the more severe elevations in PAP.243 The role of additional vasomodulatory agents in this setting requires further study. It had been reported that the response of RV function to OSA treatment is better than that of PAP.244 245 246 Right ventricular ejection fraction has been shown to improve significantly after long-term CPAP treatment in both pediatric and adult populations.247 248 249
Dramatic weight reduction brought about by surgical options may also play a role in improving pulmonary hemodynamics in OSA. Matilde et al250 showed a significant improvement in pulmonary hemodynamics following a marked reduction in body weight and resolution of OSA following bariatric surgery. In their study, the PAP completely normalized in 4 out of 28 patients with mPAP ranging from 31 to 80 mm Hg. There was also a significant reduction in mean systolic PAP in the group of obese patients in whom OSA resolved post-surgery (mean systolic PAP 61±16 mm Hg before to 43±9 mm Hg after surgery).
Obstructive sleep apnea modestly increases the risk of PH and causes mild elevation of PAP as compared to PAH. Development of PH is likely multifactorial, involving both precapillary and postcapillary processes. Due to a lack of population-based studies, the true prevalence of PH is not known; however, it is clear that patients with comorbidities are at higher risk. In patients with milder elevations in PAP, CPAP therapy has the potential to improve pulmonary hemodynamics, although the role of adjunctive vasomodulatory therapy should be explored in those with more significant elevations. Longer-term studies of various treatment options with an emphasis on functional improvement, quality of life, and survival are required to properly assess their role.
Key Words—obstructive sleep apnea, pulmonary hypertension, right heart failure, right ventricular hypertrophy
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