The potential links between SDB and cardiac disease are illustrated in Fig. 77–4.
Schematic of pathophysiologic components of obstructive sleep apnea (SA), activation of cardiovascular disease mechanisms, and consequent development of cardiovascular disease. Modified with permission from 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. J Am Coll Cardiol. 2008 Aug 19;52(8):686-717.18
Observational studies of clinic-based patients have reported that patients with SDB have a higher risk of death and that treatment with continuous positive airway pressure (CPAP) therapy may reduce this risk.32,138,139,140,141,142,143,144,145,146,147,148,149 Many of these studies were small and did not fully consider confounding factors such as obesity, hypertension, and CVD, and changes in other treatment. However, three larger population-based cohort studies have confirmed that after attempting to account for such confounders, SDB appears to be independently associated with all-cause mortality.150,151,152
The Australian Busselton Study of 397 participants followed for a mean period of 13.4 years reported an adjusted hazard ratio for mortality of 4.4 to 6.2 for moderate-to-severe SDB (AHI ≥ 15).150 The Wisconsin Sleep Cohort Study involving 1522 participants, with follow-up over a period of 18 years, demonstrated no significant increase in all-cause mortality in individuals with an AHI between 15 and 30, but demonstrated a significant hazard ratio of 2.7 to 3.8 for severe SDB (AHI ≥ 30).152 In the much larger Sleep Heart Health Study, which included 6441 middle-aged and older adults with an average follow-up time of 8.2 years from several US communities, SDB was associated with increased all-cause and CVD-related mortality (Fig. 77–5). The association was strongest in men aged 40 to 70 years with severe disease (AHI ≥ 30), with an adjusted hazard ratio of approximately 2.151
Kaplan-Meier survival curves across categories of sleep disordered breathing in 6441 men and women in the Sleep Heart Health Study. Modified with permission from Punjabi NM, Caffo BS, Goodwin JL, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med. 2009 Aug;6(8):e1000132.151
Animal studies suggest a central role of hypoxemia occurring with upper airway obstruction in the pathogenesis of hypertension,84,153 whereas a human study suggests a critical role of upper airway-associated arousal.154 Increases in blood pressure and heart rate occur approximately 5 to 7 seconds after the termination of an apnea or hypopnea, coincident with arousal, peak ventilation, and the nadir of oxygen saturation.155,156 The hemodynamic profile of blood pressure patterns in SDB is characterized by a nondipping blood pressure pattern,153 a profile also associated with an increase in CVD.157
Repetitive upper airway obstruction-associated sympathetic nervous system activation, intermittent negative intrathoracic pressure swings, sleep deprivation, and recurrent episodes of hypoxemia and hypercapnia resulting in arterial chemoreceptor activation and increased sympathetic activity, which individually or interactively may result in acute blood pressure increases, may also contribute to sustained sympathetic activation and chronically elevated blood pressure even during nonsleep periods.
Abundant cross-sectional data support an association between SDB and hypertension independent of obesity,34,158,159,160,161,162,163,164,165 including data from large cohorts such as the Wisconsin Sleep Cohort Study and the Sleep Heart Health Study. In a cross-sectional analysis of 709 Wisconsin Sleep Cohort participants, an independent association between blood pressure and SDB (AHI ≥ 5) was observed.34 In a Pennsylvania-based study involving 1741 participants, a dose-response pattern was observed for SDB and hypertension (ie, the ORs for hypertension were 6.8, 2.3, and 1.6 for moderate or severe SDB, mild SDB, and snoring, respectively). Additionally, this association was strongest among individuals who were young and of normal weight.166 In a cross-sectional analysis of data from 6132 participants in the Sleep Heart Health Study, mean systolic and diastolic blood pressure and prevalence of hypertension increased significantly with increasing severity of SDB, measured by the AHI and percentage of sleep time spent below 90% oxygen saturation, and a 40% to 50% increased adjusted odds of hypertension was observed for those with an AHI ≥ 30 or upper quartile of hypoxemia.165
In a sample of 2677 adults referred to a sleep clinic with suspected SDB, the mean blood pressure level and prevalence of hypertension were reported to increase linearly with severity of SDB; each additional apneic event per hour of sleep was estimated to increase the odds of hypertension by approximately 1%, and each 10% decrease in nocturnal oxygen saturation increased the odds by 13%.163 Overall, these studies demonstrate associations between SDB and hypertension even with mild levels of SDB, show dose-response relationships between hypertension and increasing SDB severity, and demonstrate persistence of statistical significance of these associations even after taking into account measures of obesity.
A causal association between SDB and hypertension is supported by longitudinal data from the Wisconsin Sleep Cohort Study, which showed significant dose-response relationships, such that relative to the reference category (baseline AHI = 0), the ORs for the presence of hypertension at the 4-year follow-up were 1.42 for an AHI of 0.1 to 4.9, 2.03 for an AHI of 5.0 to 14.9, and 2.89 for an AHI of ≥ 15.0.167 Recent findings from the Sleep Heart Health Study also demonstrated a significant longitudinal relationship between SDB and the development of hypertension among individuals who were normotensive at baseline examination; however, this relationship was attenuated to borderline significance after taking obesity into account.168,169
Randomized clinical trials have assessed the effects of CPAP treatment on OSA in more than 1600 patients with hypertension.170 In the majority of studies, the effect on blood pressure has been favorable. The results of two meta-analyses, including studies that were conducted largely in normotensive patients, suggest that the reduction in blood pressure during CPAP therapy is in the region of 1.5 to 2.5 mm Hg171,172; the magnitude of effect varied from zero up to a 10-mm Hg reduction in blood pressure.173,174 Regression analysis estimated that 24-hour mean blood pressure would decrease by 1.39 mm Hg for each 1-hour increase in effective nightly use of a CPAP device.172
In the most recent meta-analysis of published data, which included 29 randomized controlled trials, mean reductions in daytime systolic and diastolic blood pressures with CPAP (vs no treatment) were 2.6 and 2.0 mm Hg, respectively; corresponding nighttime reductions were 3.8 and 1.8 mm Hg.175 Another interesting finding of this systematic review was that there was an association between the severity of OSA at baseline and the beneficial effects of CPAP on blood pressure: the higher the baseline AHI, the greater the reduction in systolic BP, suggesting that patients with more severe OSA may benefit the most from CPAP therapy in terms of blood pressure reduction.
The greatest benefits of CPAP therapy for OSA have been seen in patients with resistant hypertension.164,176,177,178 In such patients, treatment of OSA with CPAP reduced daytime blood pressure by 6.5 mm Hg, compared with a 3.1-mm Hg increase in untreated patients over the study period.177
It is important to mention that compliance to CPAP therapy by patients with resistant hypertension plays a key role in achieving optimal blood pressure reduction. Decreases in 24-hour blood pressure were documented in patients with resistant hypertension who used CPAP for at least 5.8 hours per night, but not in those with lower usage,178 and another study of CPAP treatment for OSA in patients with resistant hypertension reported a significant correlation between hours of CPAP use and decreases in 24-hour systolic and diastolic blood pressure.179
It may take 3 to 6 months to achieve the maximum reduction in blood pressure associated with CPAP therapy.180,181 OSA is recognized as the most prevalent risk factor contributing to resistant hypertension,182 and an American Heart Association (AHA) scientific statement recommends that OSA in patients with resistant hypertension should be treated with CPAP.183
Bradycardia and Atrioventricular Block
Bradycardia and atrioventricular block are commonly observed in association with SDB and most likely are mediated by vagal stimulation accompanying apneas and hypopneas.184,185 Atrioventricular block has been noted to be frequent in SDB and tends to occur during rapid eye movement sleep and improve with CPAP treatment.186,187
Sleep apnea is highly prevalent in patients with AF. More than 50% of those with persistent AF or with paroxysmal AF with a high AF burden have been shown to have clinically relevant SDB.188 The prevalence of CSA (as opposed to OSA) in patients with AF is not well described. One study has reported a prevalence of 79% for CSA in pacemaker recipients with permanent AF189; this was probably a result of a high prevalence of underlying HF and reduced systolic left ventricular function in this study population. A study in AF patients with normal left ventricular systolic function reported prevalence rates of 31% for CSA/CSR and 43% for OSA.190
Among participants in the Sleep Heart Health Study, moderate-to-severe SDB, as compared with minimal SDB, was associated with a four-fold increased adjusted odds of AF on overnight PSG. Among elderly individuals, stronger associations have been reported between AF and CSA compared with OSA.191
Patients with AF with untreated SDB have a higher recurrence of AF after cardioversion than patients without a known SDB diagnosis or patients with treated SDB.192 Data from a meta-analysis reported that the risk ratio for recurrent AF after pulmonary vein isolation was 1.25 in patients with, versus without, OSA.193 Prevention of obstructive respiratory events in OSA using CPAP reduces the risk of AF recurrence after ablation therapy.194,195 In a study of 426 patients,195 CPAP therapy in patients with OSA and AF undergoing pulmonary vein isolation was associated with a higher AF-free survival rate at 12 months (71.9% vs 36.7% in OSA patients not treated with CPAP), a rate only slightly higher than found in the group of patients without OSA. In AF management guidelines, OSA is mentioned as being associated with AF and as a factor contributing to a reduction in the success of ablation procedures.196 Consideration of screening for sleep apnea in such patients is reasonable, and if OSA is diagnosed, treatment with CPAP may maximize the effectiveness of other rhythm control strategies.
An increased occurrence of AF after coronary artery bypass graft surgery also has been reported to occur in patients with SDB compared with those without SDB, suggesting the importance of untreated SDB in modifying post-cardiac surgery cardiovascular outcomes.197
Several mechanisms may contribute to the development of arrhythmia (such as AF) in sleep apnea.198 In animal studies and in clinical observation, the negative thoracic pressure during obstructive respiratory events in particular was identified as the most relevant factor for the perpetuation and initiation of AF. Negative thoracic pressure changes result in increased occurrence of atrial premature contractions, potentially triggering AF episodes.199,200 In a pig model of OSA, application of negative tracheal pressure during tracheal occlusion, but not tracheal occlusion without applied negative tracheal pressure, reproducibly and reversibly shortened the atrial refractory period and strongly enhanced the inducibility of AF. These arrhythmogenic electrophysiologic changes were largely driven by combined sympathovagal activation, as it could be modulated by sympathetic as well as vagal inhibition.199,200,201 Additionally, repetitive obstructive respiratory events resulted in an arrhythmogenic structural substrate for AF characterized by local conduction disturbances as a result of increased atrial fibrosis and distribution of connexins in a rat model of sleep apnea.202
An increase in ventricular arrhythmias in association with SDB was demonstrated in the Sleep Heart Health Study, which reported that after adjusting for age, sex, BMI, and prevalent coronary heart disease, individuals with SDB had a three-fold increased odds of nonsustained ventricular tachycardia and almost twice the odds of complex ventricular ectopy based on electrocardiographic data from overnight PSG.203 An attenuated association of SDB and ventricular cardiac arrhythmias was observed with increasing age, with potential reasons including survivorship bias, competing risk factors, and/or age-related alterations in the cardiac conduction system altering risk profiles in older adults.203 A large community-based cohort of older men, the Outcomes of Sleep Disorders in Older Men Study, identified stronger associations of OSA and hypoxia with nocturnal ventricular arrhythmias compared with CSA.191 Several clinic-based studies also have examined the association between arrhythmias and SDB. In a study of 400 patients with severe SDB, almost half demonstrated cardiac arrhythmias after evaluation by PSG and 24-hour Holter monitoring.204 Two other studies, however, yielded conflicting results as a result of attenuation of associations after adjustment for confounders.205,206 Improvement in ventricular ectopy with CPAP treatment has been shown in HF patients207 and in general SDB patients,208 with one study showing concomitant improvement in sympathetic activity.207
An AHI of > 20/h was a significant and independent risk factor for incident sudden cardiac death in a study of more than 10,000 patients with HF referred for PSG.209 Coexisting HF and SDB (both OSA and CSA) increase the risk of developing malignant ventricular arrhythmia in patients with implanted cardioverter-defibrillators210 (Fig 77–6). Severe OSA also increases the risk of ventricular premature beats, nonsustained ventricular tachycardias, and nocturnal sudden cardiac death.203,211 It has been shown that an episode of AF or nonsustained ventricular tachycardias was almost 18 times more likely to occur within 90 seconds of an apnea or hypopnea compared with normal breathing.212
Kaplan-Meier plot on appropriate cardioverter-defibrillator therapies, arranged according to no sleep-disordered breathing (no SDB), obstructive sleep apnea (OSA), and central sleep apnea (CSA) with a cut off apnea-hypopnea index ≥ 5. Reproduced with permission from Bitter T, Westerheide N, Prinz C, et al. Cheyne-Stokes respiration and obstructive sleep apnoea are independent risk factors for malignant ventricular arrhythmias requiring appropriate cardioverter-defibrillator therapies in patients with congestive heart failure. Eur Heart J. 2011 Jan;32(1):61-74.210
Registry data show that treatment of SDB with servo-assisted positive airway pressure (adaptive servo-ventilation [ASV]) in HF patients with implantable cardioverter-defibrillator devices is associated with less use of defibrillatory therapies and improvements in cardiac function and respiratory stability.213 However, in light of the increased mortality in a large randomized trial of ASV in patients with HF and reduced ejection fraction and predominantly CSA (SERVE-HF study), discussed further below, mask-based therapy for CSA should be avoided at the present time.
Animal studies support the occurrence of myocardial ischemia in settings of limited coronary artery flow and SDB, with SDB-associated physiologic stressors causing reductions in myocardial oxygen delivery and increased myocardial oxygen consumption in regions of vulnerable myocardium.214,215 Similar mechanisms for myocardial ischemia have been identified in studies of SDB patients; increased myocardial oxygen consumption associated with increased diastolic pressure and decreased oxygen supply have been observed to occur during peak changes in hemodynamics during the rebreathing phase of the OSA.216 CAD patients with OSA have been also shown to have a higher frequency of noncalcified/mixed atherosclerotic plaques, along with more serious stenosis and a higher number of affected vessels than CAD patients without OSA.217
The prevalence of OSA in patients with CAD is high (up to 87% in CAD patients referred for coronary artery bypass graft surgery) and is significantly increased compared with healthy controls.218,219,220,221,222,223 In a cohort of patients who had undergone revascularization for CAD, the prevalence of OSA was higher than that of obesity, hypertension, diabetes, and AF.224
Case-control studies have shown associations between CAD and SDB, with one study showing the persistence of this association even after taking into account potential confounding factors.221,222,225 In a cross-sectional analysis of the Sleep Heart Health Study data, SDB was marginally associated with self-reported coronary heart disease (upper vs lower AHI quartile: OR = 1.27; 95% confidence interval [CI], 0.99-1.62).226 Prospective analyses showed a 70% increased 8-year incidence of CAD in men younger than 70 years of age in the Sleep Heart Health Study cohort.227 Over a 7-year study of the Gothenburg Sleep Cohort, CAD was observed in 16% of patients with SDB (defined as ≥ 30 oxygen desaturation events) compared with 5.4% of patients without SDB, with reduced rates of CAD among those with SDB who used CPAP.228 A Spanish observational study involving solely male patients assessed incidence of fatal and nonfatal cardiovascular events over a 10-year period and reported that patients with untreated severe SDB had a 2.9-fold increased risk of fatal and 3.2-fold increased risk of nonfatal cardiovascular events compared with healthy participants, even after taking into account potential confounders. The authors concluded that, in men, severe SDB significantly increases the risk of fatal and nonfatal cardiovascular events.139
In a study in which cardiovascular mortality was prospectively investigated in consecutive patients with known CAD during a follow-up period of 5 years, cardiovascular death occurred in 38% of those with SDB compared with 9% of the non-SDB group (P = .02).140 In another prospective cohort study involving 408 patients ≤ 70 years old with verified coronary disease who were followed for a median of 5.1 years, there was a significant 70% relative increase and a 10.7% absolute increase in the primary composite end point of death, cerebrovascular event, and MI in patients with SDB defined as an oxygen desaturation index of ≥ 5 (risk ratio = 1.70). Patients with an AHI ≥ 10 had a significant 62% relative increase and a 10% absolute increase in the composite end point (risk ratio = 1.62).229 These results suggest that individuals with CAD and SDB have a worse cardiovascular prognosis than individuals with CAD without SDB, and may benefit from SDB treatment in addition to more aggressive treatment of their vascular risk factors. The Sleep Apnea Cardiovascular Endpoints Trial is due to report in 2016230; this international, multicenter, open, blinded end point randomized trial recruited more than 2700 patients with CVD and OSA and is designed to determine the effect of CPAP therapy on cardiovascular end points (ClinicalTrials.gov identifier: NCT00738179). The average duration of follow-up by the time the trial reports results is likely to be more than 4 years.
Few reports have documented the association between SDB events and symptomatic ischemia.231 One study reported a high prevalence of ST-segment depression in patients with SDB during sleep, even in the absence of documented CAD, with a reduction in periods of ST-segment depression occurring with initiation of CPAP therapy.232 Another study noted that patients with SDB have a higher frequency of cardiac rhythm disturbances and ST-segment depression episodes than controls, and that the ST-segment changes were related to heightened sympathetic tone and sleep fragmentation.233 Cardiac ischemia may also disrupt sleep. In one study, more frequent and more severe arousals were observed during periods with myocardial ischemia than during control episodes, suggesting a vicious cycle where apneas may induce ischemia, which then further disrupts sleep.234
In patients with CAD, SDB treatment with CPAP has been reported to reduce rates of nocturnal ischemia in one nonrandomized study216 and reduce rates of cardiovascular death, acute coronary syndrome, hospitalization for HF, and need for coronary revascularization in another observational study.235
The prevalence of SDB in the setting of acute coronary syndrome has been reported to be high. Specifically, of 104 patients admitted with acute coronary syndrome to one center in the United States, 66% had mild-to-moderate SDB (AHI ≥ 10), and 26% had moderate-to-severe SDB (AHI ≥ 30), with the predominant apnea pattern being obstructive (72%).236 In the first few days after an acute MI, the prevalence of moderate-to-severe sleep apnea (AHI > 15) was as high as 55% in one German center.237 AHI has been shown to be independently associated with less myocardial salvage and a larger infarct size at 3 months,238 and the presence of OSA appears to inhibit the recovery of left ventricular function after MI.223 In the acute setting, the presence of OSA has been shown to be an independent predictor of cardiovascular events in patients with non-ST-segment elevation coronary syndromes in a study from a Brazilian center (OR = 3.4; 95% CI, 1.3-9.0; P = .0002).239 Cardiovascular event rates over a 5-year follow-up were 37.5% and 9.3% in CAD patients with and without OSA, respectively (P = .018).239 A randomized trial of CPAP in patients with acute coronary syndrome and nonsleep OSA is being conducted in 15 teaching hospitals in Spain, with plans to recruit more than 1250 patients (ClinicalTrials.gov identifier: NCT01355087).240 Until the results are available (likely in 2017), patients should be managed on an individual basis.
The Sleep Heart Health Study identified OSA as an independent risk factor for the development of HF,226 with more impact in men than in women.227 Prospective data from the Wisconsin Sleep Cohort Study in a cohort of 1131 adults (men and women) aged 30 to 60 years and followed for 24 years show a 2.6-fold increase in the incidence of coronary heart disease and (self-reported) HF, after adjustment for age, sex, BMI, and smoking.241
SDB is common in patients with HF, with prevalence rates of 50% to 75%.242,243 SDB has been documented in patients with both HF with reduced ejection fraction244,245 or HF with preserved ejection fraction (HFpEF),246,247 with no difference in prevalence between the two groups,248 and in patients with acute decompensated HF, where the prevalence can be even higher (44%-97%).249,250,251
The prevalence of CSA/CSR appears to increase as the symptomatic severity of the HF syndrome increases242,246 (Fig. 77–7), and the severity of CSA/CSR seems to mirror underlying cardiac dysfunction.252,253,254 Furthermore, CSA is independently associated with a worse prognosis in patients with HF, including increased mortality.210,255,256,257,258,259 Approximately 20% to 45% of patients with chronic HF have OSA,242,243 and the predominant type of SDB in HFpEF appears to be OSA (70%-80%).246,260 OSA is independently associated with a worse prognosis in HF patients,255 even in those who are receiving maximal and optimal HF therapy, including cardiac resynchronization.261
Prevalence of sleep-disordered breathing (SDB) by symptomatic severity of heart failure. CSA, central sleep apnea; NYHA, New York Heart Association functional class; OSA, obstructive sleep apnea. Modified with permission from Jing J, Huang T, Cui W, et al: Effect on quality of life of continuous positive airway pressure in patients with obstructive sleep apnea syndrome: a meta-analysis. Lung. 2008 May-Jun;186(3):131-144.
One of the interesting features of SDB in patients with HF compared to general SDB patients is a relative lack of symptoms, especially of daytime somnolence,262,263 which could contribute to the lack of recognition and detection of SDB in HF patients.264 One possible explanation for a lack of daytime sleepiness in HF patients with SDB is the increased sympathetic nervous system activity in HF patients compared with healthy subjects,265,266 which is increased even further in the presence of OSA.7,267 Increased sympathetic stimulation could stimulate alertness to counteract the effects of sleep fragmentation and sleep deprivation.265 A significant inverse correlation between the degree of subjective daytime sleepiness and daytime muscle sympathetic nervous system activity has been documented in patients with HF and OSA.20 Furthermore, patients with HF are often taking a variety of medications that cross the blood-brain barrier, and these could also impact on sleep and SDB.268 One such group of agents is β-blockers, which have been shown to reduce daytime sleepiness and the prevalence of CSA.269
Although effective treatment of HF may improve CSA/CSR,253,270 its negative prognostic impact persists even in patients who are receiving maximal and optimal HF therapy, including cardiac resynchronization.210,261 In addition, when present, CSA in acute decompensated HF patients is usually severe (AHI > 30)250 and has been shown to be a predictor of hospital readmission and mortality.271 It is important to note that even with optimal medical management, resolution of acute decompensation, and return to baseline cardiopulmonary status, the severity of CSA may not change.13,250,272,273 The effect of the specific treatment of SDB in HF is discussed later in this chapter.
Pulmonary Arterial Hypertension
Pulmonary hypertension, defined as a mean pulmonary arterial pressure of > 25 mm Hg at rest or > 30 mm Hg during exercise, is characterized by a progressive and sustained increase in pulmonary vascular resistance that may lead to right ventricular failure. Acute changes in pulmonary arterial pressures have been observed to occur during apneas.274 The primary mechanism likely to be involved with pulmonary hypertension development in SDB is hypoxemia, which reflexively increases pulmonary arterial pressures.275
Several studies have shown pulmonary hypertension in 20% to 40% of patients with SDB in the absence of other known cardiopulmonary disorders.276,277,278 The pulmonary hypertension associated with SDB appears to be mild to moderate in severity and is thought to be a result of a combination of precapillary and postcapillary factors, including pulmonary arteriolar remodeling and hyperreactivity to hypoxia, left ventricular diastolic dysfunction, and left atrial enlargement.279 In a study involving 220 consecutive patients with moderate SDB, pulmonary arterial hypertension (mean arterial pressure > 20 mm Hg) was found in 17% of patients; however, the degree of pulmonary hypertension was relatively mild, and only 5% of patients had a pulmonary artery pressure > 35 mm Hg.280 Individuals with SDB and pulmonary hypertension tended to be more obese and to have hypoxemia and hypercapnia while awake, and some may have had underlying pulmonary disease.280 Severe SDB is independently associated with pulmonary hypertension in direct relationship with disease severity and presence of diastolic dysfunction.81 Although measurable changes in the structure and function of the right ventricle have been reported in association with SDB, the clinical significance of these changes is uncertain. Right ventricular failure in SDB appears to be uncommon and is more likely if there is coexisting left-sided heart disease or chronic hypoxic respiratory disease.279
In a study of patients with moderate SDB and mild pulmonary hypertension, CPAP treatment resulted in a significant decrease in pulmonary artery pressure, from an average of 16.8 mm Hg before CPAP to an average of 13.9 mm Hg after 4 months of CPAP, and a significant decrease in total pulmonary vascular resistance from 231.1 to 186.4 dyn/s/cm5.280 A randomized crossover trial demonstrated that effective CPAP induced a significant reduction in the values for pulmonary systolic pressure (from a mean of 28.9 to 24.0 mm Hg).281 The reduction was greatest in patients with either pulmonary hypertension or left ventricular diastolic dysfunction at baseline. Another study also reported that CPAP was associated with a reduction in pulmonary systolic pressure levels,282 including reduced hypoxic pulmonary vascular reactivity. The clinical relevance of these small changes in pulmonary artery pressure is not known.