Continuous positive airway pressure therapy improves arterial elasticity in patients with obstructive sleep apnea

Open ArchivePublished:May 31, 2010DOI:https://doi.org/10.1016/j.rmed.2010.05.002

      Summary

      Background

      Reduced arterial elasticity is an important mediator of accelerated atherogenesis and consequent increased cardiovascular morbidity in obstructive sleep apnea (OSA). The aim of our study was to investigate whether continuous positive airway pressure (CPAP) therapy may improve arterial elasticity in subjects with OSA.

      Methods

      In 44 subjects with OSA, we measured arterial elasticity by applanation tonometry before and after 6 months of treatment with CPAP. Nine OSA+ subjects withdrew from the study.

      Results

      The 35 patients with OSA who completed the 6-month CPAP treatment showed a marked reduction in both the large artery (LAEI, P=0.001) and small artery (SAEI, P=0.009) elasticity indices, independent of potential confounders. In OSA+ subjects who withdrew from the study, SAEI and LAEI did not change significantly over time.

      Conclusions

      Six months of CPAP therapy improves arterial elasticity in subjects with OSA.

      Keywords

      Introduction

      Multiple studies have demonstrated that obstructive sleep apnea (OSA) is strongly associated with known vascular risk factors and increased cardiovascular morbidity.
      • Garvey J.F.
      • Taylor C.T.
      • McNicholas W.T.
      Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation.
      • Shamsuzzaman A.S.
      • Gersh B.J.
      • Somers V.K.
      Obstructive sleep apnea: implications for cardiac and vascular disease.
      Of note, OSA itself may act as an independent risk factor for hypertension, ischemic heart disease, stroke, and arrhythmia.
      • Peppard P.E.
      • Young T.
      • Palta M.
      • et al.
      Prospective study of the association between sleep-disordered breathing and hypertension.
      • Harbison J.
      • O’Reilly P.
      • McNicholas W.T.
      Cardiac rhythm disturbances in the obstructive sleep apnea syndrome: effects of nasal continuous positive airway pressure therapy.
      • Wolk R.
      • Kara T.
      • Somers V.K.
      Sleep-disordered breathing and cardiovascular disease.
      Although the exact mechanisms by which OSA may be linked to increased vascular risk are not entirely understood,
      • Ryan S.
      • Taylor C.T.
      • McNicholas W.T.
      Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome?.
      • Bonsignore M.R.
      • Zito A.
      Metabolic effects of the obstructive sleep apnea syndrome and cardiovascular risk.
      • Parati G.
      • Lombardi C.
      • Narkiewicz K.
      Sleep apnea: epidemiology, pathophysiology, and relation to cardiovascular risk.
      it has been recently suggested that endothelial dysfunction and arterial elasticity may represent a pivotal link.
      • Chung S.
      • Yoon I.Y.
      • Lee C.H.
      • Kim J.W.
      The association of nocturnal hypoxemia with arterial stiffness and endothelial dysfunction in male patients with obstructive sleep apnea syndrome.
      Arterial compliance is defined as the ability of an artery to expand and recoil with cardiac pulsation and relaxation.
      • Zoungas S.
      • Asmar R.P.
      Arterial stiffness and cardiovascular outcome.
      • Duprez D.A.
      • Cohn J.N.
      Arterial stiffness as a risk factor for coronary atherosclerosis.
      Measurements of arterial elasticity, using applanation tonometry,
      • Cameron J.D.
      • McGrath B.P.
      • Dart A.M.
      Use of radial artery applanation tonometry and a generalized transfer function to determine aortic pressure augmentation in subjects with treated hypertension.
      provide useful information regarding vascular health and a decrease in arterial compliance can be regarded as a valid marker of early vascular dysfunction. Of great interest, estimation of arterial elasticity may serve not only as cardiovascular risk assessment but also as a surrogate marker of treatment benefits.
      • Akgullu C.
      • Ozdemir B.
      • Yilmaz Y.
      • Kazazoglu A.R.
      • Aydinlar A.
      Effect of intensive statin therapy on arterial elasticity in patients with coronary artery disease.
      • Weber T.
      • Auer J.
      • O’Rourke M.F.
      • et al.
      Arterial stiffness, wave reflections, and the risk of coronary artery disease.
      Nasal continuous positive airway pressure (CPAP) has become the gold standard of treatment of sleep-disordered breathing.
      • Giles T.L.
      • Lasserson T.J.
      • Smith B.H.
      • et al.
      Continuous positive airways pressure for obstructive sleep apnoea in adults.
      When worn during sleep, CPAP effectively reduces or eliminates most sleep-disordered breathing events, resulting in a global improvement in sleep architecture.
      • Lam B.
      • Sam K.
      • Mok W.Y.
      • et al.
      Randomised study of three non-surgical treatments in mild to moderate obstructive sleep apnoea.
      Evidence also suggests that CPAP may results in positive cardiovascular and metabolic effects in patients with OSA, ultimately leading to an improvement in the cardiovascular risk profile.
      • Noda A.
      • Nakata S.
      • Koike Y.
      • et al.
      Continuous positive airway pressure improves daytime baroreflex sensitivity and nitric oxide production in patients with moderate to severe obstructive sleep apnea syndrome.
      • Bayram N.A.
      • Ciftci B.
      • Bayram H.
      • et al.
      Effects of continuous positive airway pressure therapy on right ventricular function assessment by tissue Doppler imaging in patients with obstructive sleep apnea syndrome.
      Previous studies have shown that CPAP therapy can improve microvascular endothelial function and decrease stiffness of the central to middle-sized arteries.
      • Bayram N.A.
      • Ciftci B.
      • Keles T.
      • et al.
      Endothelial function in normotensive men with obstructive sleep apnea before and 6 months after CPAP treatment.
      • Keles T.
      • Durmaz T.
      • Bayram N.A.
      • et al.
      Effect of continuous positive airway pressure therapy on aortic stiffness in patients with obstructive sleep apnea syndrome.
      However, data on the long-term impact of CPAP on measures of arterial elasticity in patients with OSA are lacking. The aim of our study was to fill this gap and to evaluate the changes induced by CPAP on large and small arterial elasticity indices (LAEI and SAEI, respectively). The analysis of LAEI and SAEI allows an evaluation of the elasticity of the large conduit arteries and the small microcirculatory arteries. Although LAEI and SAEI measure different aspects of arterial elasticity, a reduction of both indices has been linked to an increased vascular risk.
      • Akgullu C.
      • Ozdemir B.
      • Yilmaz Y.
      • Kazazoglu A.R.
      • Aydinlar A.
      Effect of intensive statin therapy on arterial elasticity in patients with coronary artery disease.

      Methods

       Study participants and diagnostic polysomnography

      We initially considered for our study 97 consecutive subjects referred to our laboratory because of symptoms of OSA for diagnostic polysomnography. Exclusion criteria were as follows: use of immunomodulatory drugs; history of coronary artery disease, peripheral artery disease, or cerebrovascular disease according to medical history and clinical examination; transplantation; alcohol and drug abuse; HIV infection; significant medical illnesses (active infections, autoimmune disorders, malignancy, liver disease, chronic obstructive pulmonary disease, asthma, neuromuscular disorders).
      In all participants, overnight polysomnography was performed with a Compumedics Sleepwatch System (Compumedics p-series: Compumedics, Melbourne, Australia). The study subjects reported to the sleep laboratory at approximately 8:30 p.m., and polysomnography was started at approximately 10:30 p.m. Polysomnographic recordings included two electroencephalography channels (C3/A2 and O2/A1), two electrooculogram channels, one submental electromyogram channel, and one electrocardiography channel. Ventilatory monitoring included recording of oronasal airflow (with an oronasal thermistor), hemoglobin oxygen saturation by pulse oximetry (SaO2 was measured via a finger oximeter), respiratory movement of the chest (with inductive plethysmography), and abdomen and body posture. Sleep staging was performed according to the standard criteria of Rechtschaffen and Kales.
      Nasal airflow was carefully analyzed in order to assess ventilation during sleep. Apnea was defined as an episode of airflow cessation lasting at least 10 s. Hypopnea was defined as an episode of reduced thermistor signal amplitude of at least 50% and an associated drop in oxygen saturation of at least 3% or an arousal lasting 10 s or longer. The sum of the time elapsed in periods of apnea and hypopnea was divided by the total sleep time to obtain the Apnea-Hypopnea Index (AHI). OSA was diagnosed when the patient’s AHI was more than or equal to 5. The Epworth Sleepiness Scale (ESS) was used to measure excessive sleepiness.
      • Izci B.
      • Ardic S.
      • Firat H.
      • Sahin A.
      • Altinors M.
      • Karacan I.
      Reliability and validity studies of the Turkish version of the Epworth Sleepiness Scale.
      The study protocol was approved by the Ethics Committee of the Uludag University Medical School. A written informed consent was obtained from all participants.

       Definition of cardiovascular risk factors

      Age was analyzed as a continuous variable. Body mass index (BMI) was calculated by taking the weight (in kilograms) over the height (in meters-squared). The use of cardiac drugs (β-blockers, statins, calcium antagonists, angiotensin-converting enzyme inhibitors, aspirin) was recorded in all participants. In our study, smoking was defined as regular smoking of cigarettes. Diabetes mellitus was diagnosed on the basis of fasting blood glucose concentrations ≥126 mg/dL or current use of antidiabetic medications. Arterial hypertension was defined as active treatment with antihypertensive medications or documentation of systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure90 mm Hg on at least two separate occasions. Serum samples were measured for lipid variables using commercially available kits on a Hitachi 7350 Autoanalyzer (Hitachi Ltd., Tokyo, Japan).

       Measurements of arterial elasticity

      All measurements of arterial elasticity were performed on the radial artery using the noninvasive technique of arterial applanation tonometry. The PulseWave Sensor HDI (Hypertension Diagnostics, Eagan, MN, USA) was used to determine LAEI and SAEI. Applanation tonometry is based on the principle that when the curved surface of a rounded pressure-containing chamber (in this case, an artery) is partially flattened, pressures are normalized and a sensor placed on the flattened surface can record the pressure in the chamber.
      • Cameron J.D.
      • McGrath B.P.
      • Dart A.M.
      Use of radial artery applanation tonometry and a generalized transfer function to determine aortic pressure augmentation in subjects with treated hypertension.
      • O’Rourke M.F.
      • Gallagher D.E.
      Pulse wave analysis.
      This technique, which analyzes the signal-averaged radial artery waveform based on a modified Windkessel model, correlates well with other methods that measure hemodynamic parameters in humans.
      • Akgullu C.
      • Ozdemir B.
      • Yilmaz Y.
      • Kazazoglu A.R.
      • Aydinlar A.
      Effect of intensive statin therapy on arterial elasticity in patients with coronary artery disease.

       Data analysis

      Continuous variables are presented as means ± standard deviation. Categorical variables are reported as counts and compared using the χ2-test. Differences between subjects with and without OSA were evaluated by the unpaired t-test. Within-group comparisons were performed using the paired Student’s t-test. Correlations among the study variables were examined by Pearson’s correlation. Simple linear regression analysis was used to assess whether changes in SAEI and LAEI were independent of potential confounders, including age, gender, BMI, blood pressure values, heart rate, lipid parameters and the use of cardiac drugs. All statistical analyses were performed using the SPSS 13.0 software package (SPSS Inc., Chicago, IL, USA). A two-tailed P value < 0.05 was regarded as significant.

      Results

       General characteristics of the study participants

      OSA was diagnosed in a total of 66 subjects. Twenty-two individuals with OSA did not receive CPAP treatment and were excluded from the analysis. A total of 44 subjects with OSA (OSA+) and 31 subjects without OSA (OSA−) were finally included. The baseline characteristics of subjects with and without OSA are depicted in Table 1. There were no significant differences between the two groups in terms of age, BMI, blood pressure parameters, diabetes, and lipid profile. In addition, the use of cardiovascular drugs (statins, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers) did not differ in the two groups (data not shown). Compared with the OSA− group, OSA+ subjects showed higher ESS scores, systolic blood pressure, diastolic blood pressure, and mean arterial pressure. LAEI and SAEI values at baseline showed a trend toward lower values in OSA+ subjects compared with OSA− individuals; this difference, however, failed to reach statistical significance probably due to the small sample size.
      Table 1General characteristics of subjects with and without OSA.
      OSA+ (n=66)OSA− (n=31)P
      Age, years52±1050±9ns
      Sex, males/females54/1220/11ns
      Smoking, yes/no12/545/26ns
      Hypertension, yes/no25/4110/21ns
      Diabetes mellitus, yes/no10/562/29ns
      Epworth scale13±410.3±40.04
      BMI, kg/m232±531±5ns
      SBP, mmHg142±16.7132±160.04
      DBP, mmHg84±1077±90.05
      MBP, mmHg106±1697±110.05
      Total cholesterol, mmol/L5.2±0.94.9±0.6ns
      HDL cholesterol, mmol/L1.1±0.31.1±0.2ns
      Triglycerides, mmol/L1.8±0.71.7±0.7ns
      LAEI, mL/mmHg×1013±414±5ns
      SAEI, mL/mmHg×1005±36±3ns
      BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure, MBP: mean blood pressure, HDL: high-density lipoprotein; LAEI: large artery elasticity index, SAEI: small artery elasticity index, ns: not significant.

       Polysomnographic measures

      The polysomnographic measures of nocturnal sleep in the two study groups are shown in Table 2. As expected, the two groups differed for a number of polysomnographic parameters, the only exceptions being the time of REM sleep and the average oxygen saturation while awake.
      Table 2Polysomnographic data of subjects with and without OSA.
      OSA+ (n=66)OSA− (n=31)P
      Time of REM sleep, min58±3058 ± 36NS
      Time of sleep stage 3–4, min28±2558±34<0.001
      Sleep efficiency, %84±976±140.01
      Average O2 saturation while awake, %94±394±4NS
      Average O2 saturation during sleep, %89±695±2<0.001
      Average desaturation, %9±54±2<0.001
      Time with oxygen saturation of less than 90%, min64±943±11<0.001
      Time with oxygen saturation of less than 80%, min17±431±1<0.001
      Time of apnea-hypopnea, min145±863±3<0.001, by design
      Apnea-hypopnea index50±242±1<0.001, by design
      Arousal index/h33±2018±8<0.001
      ns: not significant.

       Baseline determinants of arterial elasticity in the OSA+ group

      Pearson’s correlation coefficients were determined to assess whether baseline measures of arterial elasticity were associated with the general or the polysomnographic characteristics of the OSA+ group. Both SAEI and LAEI were negatively correlated with systolic blood pressure (r=−0.463, P=0.05 and r=−0.483, P=0.03, respectively). In addition, SAEI showed an inverse correlation with diastolic blood pressure (r=−0.422, P=0.01). No other significant correlation was found.

       Effect of CPAP therapy on arterial elasticity in the OSA+ group

      In the 44 subjects in the OSA+ group, we measured arterial elasticity before and after 6 months of treatment with CPAP. Nine OSA+ subjects withdrew from the study. Table 3 shows the changes in LAEI and SAEI in completers and noncompleters. After 6 months of CPAP treatment, the completer group (n=35) showed a marked reduction in both the LAEI (P=0.001, Fig. 1) and SAEI (P=0.009, Fig. 2) indices. In OSA+ subjects who withdrew from the study (n=9), SAEI and LAEI did not change over time.
      Table 3Changes in arterial elasticity and other clinical parameters after 6 months in completers and noncompleters.
      Completing CPAP therapy (n=35)PWithdrawn from CPAP therapy (n=9)P
      Baseline6 monthsBaseline6 months
      Total cholesterol, mmol/L5.1±0.95.1±0.7ns5.8±1.16.1±1.0ns
      HDL cholesterol, mmol/L1.1±0.21.1±0.3ns1.3±0.41.2±0.3ns
      Triglycerides, mmol/L1.8±0.71.7±0.6ns2.0±0.71.8±0.8ns
      BMI, kg/m233±633±6ns30±330±3ns
      SBP, mmHg141±18141±18ns137±12137±9ns
      DBP, mmHg82±1482±10ns82±983±9ns
      MBP, mmHg106±22102±13ns100±11105±11ns
      HR, beats/min76±1271±110.0174±1078±8ns
      LAEI, mL/mmHg×1013±417±40.00113±412±2ns
      SAEI, mL/mmHg×1006±47±30.0095±25±1ns
      BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure, MBP: mean blood pressure; HR: heart rate, LAEI: large artery elasticity index, SAEI: small artery elasticity index, ns: not significant.
      Figure thumbnail gr1
      Figure 1Changes in LAEI observed in OSA+ subjects treated by CPAP for 6 months (n=35) and in subjects who withdrew from treatment (n=9). LAEI: large artery elasticity index, CPAP: continuous positive airway pressure.
      Figure thumbnail gr2
      Figure 2Changes in SAEI observed in OSA+ subjects treated by CPAP for 6 months (n=35) and in subjects who withdrew from treatment (n=9). SAEI: small artery elasticity index, CPAP: continuous positive airway pressure.

       Multivariable analysis

      We used simple linear regression analysis to determine whether the magnitude of changes in SAEI and LAEI (∆SAEI and ∆LAEI) in the completers were independent of potential confounders. Results showed that both ∆SAEI (β=−0.41, t=−2.9, P=0.009) and ∆LAEI (β=−0.38, t=−2.7, P=0.01) were not influenced by the confounding effect of other clinical and demographic variables.

      Discussion

      This study examined the effect of CPAP therapy on arterial elasticity in OSA+ subjects. We found that six months of 6 months of CPAP therapy significantly improved arterial elasticity of large and small arteries in patients with OSA, independent of potential confounders.
      Emerging evidence has suggested that arterial elasticity may serve as a surrogate endpoint for estimation of success in patients at high risk for adverse cardiovascular events.
      • Duprez D.A.
      • Cohn J.N.
      Arterial stiffness as a risk factor for coronary atherosclerosis.
      • Weber T.
      • Auer J.
      • O’Rourke M.F.
      • et al.
      Arterial stiffness, wave reflections, and the risk of coronary artery disease.
      The sustained improvement of large and small arterial elasticity observed in our study suggests that improved endothelial function may be the predominant mechanism of the changes in LAEI and SAEI.
      • Bayram N.A.
      • Ciftci B.
      • Keles T.
      • et al.
      Endothelial function in normotensive men with obstructive sleep apnea before and 6 months after CPAP treatment.
      Although the exact mechanisms by which arterial elasticity is improved by CPAP therapy remain to be determined, stimulation of endothelial nitric oxide synthase may play a role.
      • Ohike Y.
      • Kozaki K.
      • Iijima K.
      • et al.
      Amelioration of vascular endothelial dysfunction in obstructive sleep apnea syndrome by nasal continuous positive airway pressure–possible involvement of nitric oxide and asymmetric NG, NG-dimethylarginine.
      The results of the present study are of particular interest because all patients underwent polysomnographic measures. Kitahara et al.
      • Kitahara Y.
      • Hattori N.
      • Yokoyama A.
      • et al.
      Effect of CPAP on brachial-ankle pulse wave velocity in patients with OSAHS: an open-labelled study.
      showed that brachial-ankle pulse-wave velocity (PWV) – an index of arterial stiffness – decreased in patients with moderate-to-severe OSA after four months of CPAP treatment, without significant changes in total serum cholesterol levels, heart rate, systolic and diastolic blood pressures, mean blood pressure, and pulse pressure. These findings are consistent with our results, but the authors failed to include a matched OSA− group or a sham CPAP group. In this study, SAEI and LAEI did not improve significantly in the nine OSA+ subjects who withdrew from CPAP therapy. Nagahama and colleagues
      • Nagahama H.
      • Soejima M.
      • Uenomachi H.
      • et al.
      Pulse wave velocity as an indicator of atherosclerosis in obstructive sleep apnea syndrome patients.
      reported a significant increase in brachial-ankle PWV in patients with OSA compared with controls, though polysomnography was not performed. Philips et al.
      • Phillips C.L.
      • Yee B.
      • Yang Q.
      • et al.
      Effects of continuous positive airway pressure treatment and withdrawal in patients with obstructive sleep apnea on arterial stiffness and central BP.
      assessed arterial stiffness using the aortic augmentation index before and after two months of CPAP therapy, as well as in patients withdrawing from CPAP therapy. The authors found a significant reduction in the aortic augmentation index in the CPAP group, but not in the withdrawal group. Recently, Drager and colleagues
      • Drager L.F.
      • Bortolotto L.A.
      • Figueiredo A.C.
      • et al.
      Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea.
      demonstrated that four months of effective treatment with CPAP significantly improved carotid intima-media thickness, PWV, levels of C-reactive protein levels, and catecholamines in normotensive middle-aged men with severe OSA without significant comorbidities. On the other hand, our sample included older individuals with a higher frequency of vascular risk factors. Keles et al.
      • Keles T.
      • Durmaz T.
      • Bayram N.A.
      • et al.
      Effect of continuous positive airway pressure therapy on aortic stiffness in patients with obstructive sleep apnea syndrome.
      have recently shown that CPAP treatment provides improvement in aortic elastic parameters, but the authors failed to report on changes in small artery elasticity. To our knowledge, our study is the first to assess both the LAEI and SAEI compliance parameters in OSA+ patients undergoing CPAP.
      Several caveats of this study merit comment. First and foremost, we were unable to measure the changes in LAEI and SAEI at 6 months in subjects without OSA, mainly due to financial and logistic constraints. For similar reasons, we did not measure LAEI and SAEI in the 22 OSA+ subjects who did not receive CPAP treatment. Another limitation is that applanation tonometry is a noninvasive measure of large and small arterial elasticity, and an invasive measure would be more precise. We recognize that the most widespread noninvasive technique to assess endothelial function is flow-mediated dilation (FMD). However, FMD is time-consuming, the equipment is very expensive, and it requires an experienced examiner.
      • Akgullu C.
      • Ozdemir B.
      • Yilmaz Y.
      • Kazazoglu A.R.
      • Aydinlar A.
      Effect of intensive statin therapy on arterial elasticity in patients with coronary artery disease.
      Third, the generalizability of our results may be limited by the small sample size. It is noteworthy, however, that two thirds of subjects referred to our sleep laboratory for the evaluation of OSA revealed a pathologic result. This result highlights the need for increased awareness of this frequently neglected pathological condition. Finally, this study was designed as an exploratory pilot project. Although the improvement in large and small arterial elasticity was clear, our data need to be confirmed in randomized, placebo-controlled studies. The primary outcome measure in this study was arterial elasticity and thus the study was not powered to detect changes in the clinical outcome as a result of CPAP treatment in OSA+ subjects. Greater numbers and longer treatment duration are required to evaluate this possibility fully. However, our findings provide a strong rationale for such a study.
      In conclusion, we have shown an increase in arterial elasticity in OSA+ subjects after six months of CPAP treatment. These observations are likely to represent another beneficial vascular effect of CPAP therapy in this patient group.

       Conflict of interest

      All authors have no actual or potential conflict of interest.

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