Impaired Vasodilator Responses in Obstructive Sleep Apnea Are Improved with Continuous Positive Airway Pressure Therapy VIRGINIA A. IMADOJEMU, KEVIN GLEESON, SADEQ A. QURAISHI, ALLEN R. KUNSELMAN, LAWRENCE I. SINOWAY, and URS A. LEUENBERGER Divisions of Pulmonary, Allergy and Critical Care and Cardiology, and Department of Health Evaluation Sciences, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Lebanon Veterans Affairs Medical Center, Lebanon, Pennsylvania
Obstructive sleep apnea causes cardiovascular morbidity and premature death. Potential links between sleep apnea and cardiovascular complications are chronically elevated activity of the sympathetic nervous system and abnormal vascular function. To explore vascular function, we determined the reactive hyperemic blood flow (RHBF) responses to 10 minutes of forearm arterial occlusion (plethysmography), blood pressure, and muscle sympathetic nerve activity (MSNA, microneurography) in eight patients with sleep apnea and in nine nonapneic control subjects. Peak RHBF and vascular conductance were markedly attenuated in sleep apnea compared with control subjects (p 0.05). Seven sleep apnea patients were retested after at least two weeks of continuous positive airway pressure (CPAP) therapy. MSNA decreased after CPAP therapy (p 0.05, n 6), whereas blood pressure did not change. After CPAP therapy, peak RHBF and vascular conductance were increased compared with before treatment (p 0.05; n 7). Thus, vascular function is abnormal in sleep apnea and is improved by CPAP therapy. Furthermore, effective CPAP therapy decreases sympathetic activity in sleep apnea. Thus, sympathoexcitation and abnormal vascular function in patients with sleep apnea appear to be linked to the repetitive nocturnal apneic events. Keywords: obstructive sleep apnea; CPAP therapy; reactive hyperemia; vasodilation
Obstructive sleep apnea (OSA) is highly prevalent and is associated with hypertension, coronary artery disease, stroke, and premature death (1–3). The link between OSA and these cardiovascular complications remains unclear. It has been recognized that OSA is associated with chronically elevated activity of the sympathetic nervous system (4–7). In addition, recent findings also suggest that vascular function is impaired in OSA. For example, Carlson and coworkers found evidence for attenuated endothelium-dependent vascular relaxation in patients with OSA (8). Furthermore, Remsburg and associates reported that in some patients with OSA, the vasodilation that normally occurs during acute exposure to a hypoxic gas is absent (9). Abnormal vascular relaxation could thus explain the pressor effect of hypoxia that has been reported in OSA (10).
(Received in original form February 5, 2001; accepted in final form January 13, 2002) Supported by a National Institutes of Health (NIH) grant R01 AG12227 (L.I.S.), a Veterans Administration Merit Review Award (L.I.S.), AHA grant 9950426N (U.A.L.), and a NIH-sponsored General Clinical Research Center with National Center for Research Resources Grant M01 RR10732. Dr. Sinoway is a recipient of an NIH K24 HL04011 Midcareer Investigator Award in Patient-Oriented Research. Dr. Imadojemu is a recipient of an NIH K23 HL04190 Mentored Patient Oriented Research Award. Correspondence and requests for reprints should be addressed to Urs A. Leuenberger, M.D., Division of Cardiology, Mail Code H047, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, P.O. Box 850, Hershey, PA 17033. E-mail:
[email protected] Am J Respir Crit Care Med Vol 165. pp 950–953, 2002 DOI: 10.1164/rccm.2102003 Internet address: www.atsjournals.org
In this report, we intended to further explore the nature of the vascular abnormality in OSA. To this end, we examined the forearm blood flow responses to ischemia, i.e., the reactive hyperemic blood flow (RHBF) response. The RHBF response is a reproducible index of vascular function (11). In addition, we made microneurographic recordings of sympathetic vasoconstrictor nerve traffic. We hypothesized that the peak RHBF response was impaired in OSA. Furthermore, we postulated that if the RHBF response were improved after OSA treatment with continuous positive airway pressure (CPAP), this would support the concept that abnormal vascular responses are causally linked to OSA.
METHODS Subjects Eight patients with polysomnographically proven OSA (six male, two female) and nine age- and weight-matched control subjects without OSA (seven male, two female) participated in our studies. OSA patients were recruited through the Sleep Disorders Clinic of the Hershey Medical Center. Polysomnography was performed in standard fashion and in accordance with recommendations by the American Thoracic Society as described previously (12). Airway obstruction during sleep was documented by the presence of inspiratory effort (chest/abdominal strain gauges) and the absence of airflow (nasal/oral thermocouples). For OSA patients, an apnea–hypopnea index (AHI) of 20 per hour or greater and daytime hypersomnolence were required for inclusion in the study. Patients with unstable coronary artery disease or intrinsic lung disease were excluded. Control subjects were recruited locally, and OSA was excluded (AHI 5 per hour) by full-night polysomnography. Subject characteristics are shown in Tables 1 and 2. Studies were conducted in a human research laboratory during the daytime hours. The experimental protocol was approved by the Institutional Review Board at Hershey Medical Center. Written informed consent was obtained.
Measurements Blood pressure and heart rate (three measurements per minute) were determined with an automatic sphygmomanometer (Dinamap, Critikon, Tampa, FL). Muscle sympathetic nerve activity (MSNA) was measured via peroneal microneurography as described previously (6, 13). MSNA was averaged over 5–10 minutes during quiet restfulness and was expressed as bursts per minute. We and others demonstrated previously that, for a given subject, basal MSNA expressed as bursts per minute is highly reproducible when measured serially over weeks to months (13, 14). Forearm blood flow (FBF) was measured via venous occlusion plethysmography as described previously (15, 16). At least six to eight flow curves (over three to four minutes) were obtained and were averaged. FBF was expressed as ml · minutes1 per 100 ml forearm tissue. Simultaneous blood pressure measurements were used to calculate forearm vascular conductance (FVC) as FBF divided by mean arterial pressure.
Reactive Hyperemic Blood Flow Protocol After measurements of basal FBF, a “primer RHBF” was performed as described previously (15). Patterson and Whelan demonstrated
Imadojemu, Gleeson, Quraishi, et al.: Vasodilator Responses in Sleep Apnea TABLE 1. CHARACTERISTICS OF SLEEP APNEA PATIENTS Subject
Age (yr)
Sex
1 2 3 4 5 6 7 8
34 49 54 53 62 70 50 46
M F M F M M M M
Mean SE
52 4
Weight (kg)
BMI (kg/m2)
AHI (events/h)
175 139 113 86 97 83 106 177
54 51 36 32 33 26 35 54
61 36 54 25 24 74 27 74
122 13
40 4
47 8
HTN Y Y N Y Y N Y N
Meds Lisinopril 10 mg/d
formed to compare RHBF and FVC between OSA and control subjects at each time point. The p values were adjusted to account for multiple comparisons using the Bonferroni method (19). All analyses were performed using SAS statistical software (SAS Institute Inc., Cary, NC). The data were expressed as mean SE, unless otherwise indicated. A p value less than 0.05 was considered statistically significant.
Atenolol 50 mg/d
RESULTS
Enalapril 5 mg/d
Baseline Characteristics
Definition of abbreviations: AHI apnea–hypopnea index; BMI body mass index; HTN hypertension.
that a “priming” maneuver augments RHBF and enhances its reproducibility (11). Therefore, the upper arm cuff was inflated to suprasystolic pressure (250 mm Hg) for one minute, upon which the arterial occlusion was released. After a rest period, the wrist cuff and the upper arm cuffs were inflated to suprasystolic pressure (250 mm Hg) for 10 minutes. Thereafter, the upper arm cuff, but not the wrist cuff, was deflated. Intermittent inflations to 50 mm Hg were then applied at 5 and 15 seconds upon release of the arterial occlusion, as well as every 15 seconds for a total of 3 minutes. For each flow measurement the single closest blood pressure measurement was used to calculate the corresponding FVC (ml · minutes1 per 100 ml forearm tissue · mm Hg1). In our laboratory, in healthy control subjects, measurements of forearm RHBF obtained at least one month apart did not differ significantly (p NS; n 11), and the coefficient of variation was 7.1 1.9% (17, 18).
CPAP Therapy After the pretreatment studies, patients returned to the sleep laboratory for a CPAP trial. A CPAP device was fitted and applied at a pressure that would eliminate obstructive apneas. Seven patients returned for retesting after 2 weeks through 24 months of CPAP therapy. One patient who did not tolerate CPAP was not restudied. Two of the subjects had compliance monitors in their CPAP device, the others kept a diary of CPAP use. During retesting, post-CPAP, MSNA, blood pressure, FBF, and RHBF were determined in an identical fashion.
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Baseline characteristics of the OSA patients (n 8) and the control subjects (n 9) are shown in Tables 1 and 2. There were no significant between-group differences in age (p 0.93), weight (p 0.48), or body mass index (BMI; p 0.29). Although systemic hypertension was more prevalent in the OSA group, mean arterial pressure was not significantly different (OSA versus controls: 100 5 mm Hg versus 97 5 mm Hg, p 0.69). Resting MSNA was higher in OSA patients (n 7) compared with nonapneic controls (n 5) (OSA versus controls: 50.7 4.8 bursts/minute versus 30.0 6.0 bursts/minute; p 0.02). Comparison of RHBF Responses in OSA (n 8) and Control Subjects (n 9)
Baseline FBF was similar in OSA and controls (OSA versus controls: 4.0 0.5 versus 3.5 0.3 ml · minutes1 per 100 ml forearm tissue; p NS). However, the RHBF response was markedly attenuated in OSA compared with controls (p 0.01; Figure 1). Baseline FVC was similar in the two groups (OSA versus controls: 0.041 0.005 versus 0.034 0.003 ml · minutes1 per 100 ml forearm tissue · mm Hg1; p NS). However, the FVC response to 10 minutes of arterial forearm occlusion was markedly attenuated in the OSA patients (p 0.03; Figure 1). The responses of peak RHBF and peak FVC are shown in Figure 2. By linear regression analysis, there were no significant correlations between weight, BMI, or blood pressure and peak RHBF (p NS for all). Effects of CPAP Therapy (n 7)
Statistical Analysis Comparisons of baseline characteristics, MSNA, and FBF, as well as of peak RHBF and peak FVC between OSA and control subjects were made with a two-tailed nonpaired t test (19). Comparisons of pre- and post-CPAP data were made with a two-tailed paired t test. Repeated measures analysis of variance models were fit to examine differences of RHBF and FVC over time (in seconds) between OSA and control subjects (20). Post hoc tests of simple effects were per-
TABLE 2. CHARACTERISTICS OF NONAPNEIC CONTROL SUBJECTS Subject
Age (yr)
Sex
Weight (kg)
BMI (kg/m2)
AHI (events/h)
HTN
Meds
1 2 3 4 5 6 7 8 9
31 46 51 64 72 74 44 41 42
M F F M M M M M M
120 134 86 100 77 88 137 153 97
31 51 30 27 24 29 42 47 30
0 1.4 0.6 0 0.6 0.1 0.7 0 0.2
Y N N N Y N N N N
Atenolol 50 mg/d Nadolol 20 mg/d
Mean SE
52 5
110 9
35 3
0.4 0.2
Definition of abbreviations: AHI apnea–hypopnea index; BMI body mass index; HTN hypertension.
Seven of eight OSA patients returned for retesting after 2 weeks through 24 months of CPAP therapy. Their data are shown in Table 3. All patients were compliant with CPAP therapy, were subjectively improved, and applied the device every night for at least two weeks before the study. CPAP therapy had no effect on baseline blood pressure (pre-CPAP 100 5 mm Hg versus post-CPAP 98 6 mm Hg; p NS), and weight (pre-CPAP 114 13 kg versus post-CPAP 113 10 kg; p NS). In each OSA patient in whom it was measured, MSNA decreased after CPAP therapy (p 0.05; n 6). Pre- and post-CPAP therapy data on RHBF were obtained in seven patients. CPAP led to a statistically significant increase in peak RHBF (21.1 6.6%) and peak FVC (23.6 8.5%) (Table 3).
Figure 1. RHBF and FVC responses in patients with OSA and in matched control subjects. *p 0.05, OSA versus control subjects.
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Figure 2. Peak RHBF and peak FVC responses in patients with OSA and in matched control subjects. *p 0.05, OSA versus control subjects.
By linear regression analysis, there were no significant correlations between basal MSNA and RHBF or between the decrease in MSNA and the improvement of RHBF found postCPAP therapy (p NS for both).
DISCUSSION There are two new findings in this report. First, the reactive hyperemic blood flow response to 10 minutes of forearm arterial occlusion is attenuated in patients with OSA compared with a matched control group. Second, CPAP therapy improves the RHBF response in OSA. This suggests that OSA is accompanied by impaired vascular function that is in part reversible with effective CPAP therapy. Peak RHBF is an index of maximal limb vasodilator capacity (11, 21) that has been found to be reproducible on serial testing (17, 18, 22). It is generally thought that the largest component of the peak RHBF results from changes in vascular myogenic tone (21, 23). That is, during regional circulatory arrest, the intravascular distending pressure distal to the obstruction decreases precipitously, resulting in a marked decrease in myogenic tone (21) and an increase in flow capacity. The return of myogenic tone after the release of the arterial occlusion then leads to the return of blood flow to basal levels. A smaller proportion of the RHBF response is thought to be related to the release of vasodilator metabolites such as prostaglandins (21, 22), adenosine (21), and/or nitric oxide (22). In addition, sympathetic vasoconstrictor nerve activity may also affect peak RHBF. However, such an effect is only apparent when the sympathetic nervous system is excited by an intense sympathoexcitatory stimulus (24, 25). Lastly, it is possible that structural vascular changes have an influence on RHBF (26). It should be emphasized that reduced levels of RHBF responses have been described in a variety of conditions, including congestive heart failure (26, 27), hypertension (28, 29), and microvascular angina (30). Our finding of attenuated RHBF responses in OSA appears to differ from that of Remsburg and
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associates, who reported similar relative decreases of forearm vascular resistance in OSA and controls after forearm ischemia (9). However, these authors employed a 5-minute (rather than 10-minute) arterial occlusion protocol without a “priming” maneuver, thus providing a substantially smaller vasodilator stimulus (11). Similar to prior reports, we found resting sympathetic nerve activity to be increased in OSA (4–7). In addition, the present data confirm our prior finding of a decrease in sympathetic nerve activity following treatment with CPAP (13). Because CPAP therapy markedly diminished or eliminated obstructive apnea events, this finding strongly suggests that physiologic events associated with obstructive apnea, such as repetitive hypoxia and/or arousal, may be responsible for the state of sympathoexcitation in OSA. This concept has received important support from several animal models where repetitive hypoxia in rodents (31) and hypoxia coupled with intermittent airway obstruction in dogs (32) lead to daytime hypertension. Our data do not allow us to draw conclusions regarding the mechanism of the impaired vascular function in OSA. Because maximal vasodilator capacity is improved after CPAP therapy even though weight does not change, obesity and/or a change of body weight alone is an unlikely explanation for this finding. Furthermore, because blood pressure did not change significantly with CPAP therapy, hypertension per se does not appear to be the cause. In addition, none of our patients was edematous. This speaks against right heart failure and vascular edema as the cause. In this context, it should be noted that in patients with congestive heart failure, only a substantial acute weight reduction was associated with an improvement in RHBF (27). The fact that RHBF improved after relatively shortterm CPAP therapy also argues against advanced OSA-related structural vascular changes as a cause of the impaired vasodilator capacity. Thus, it appears likely that the impaired vascular responses in OSA are related to altered activity of the myogenic reflex and/or some impairment of local vasodilator mechanisms. In this regard, impaired vasodilator responses to intra-arterial infusion of acetylcholine have been reported in OSA (8, 33). Not surprisingly, we found no significant relationships between basal MSNA and peak RHBF or between the magnitude of the decrease in resting sympathetic activity and the improvement of RHBF. These observations are consistent with the concept that peak reactive flow is largely independent of changes in resting levels of sympathetic discharge (25). Several limitations of our study should be noted. Despite our efforts to match our subjects with regards to body weight
TABLE 3. EFFECTS OF CPAP THERAPY ON MSNA, PEAK FOREARM RHBF, AND VASCULAR CONDUCTANCE
Subject 1 2 3 4 5 6 7 Mean SE
MSNA (bursts/min)
RHBF
Conductance
(ml/[min 100 ml])
(ml/[min 100 ml mm Hg])
AHI on CPAP (events/h)
Duration of CPAP Therapy (mo)
Compliance (h/night)
Pre
Post
Pre
Post
Pre
Post
1.0 — 0 0 3.0 0 2.9
1 3 2 0.5 1 24 1
5.1* 6.5 6.5 5.3 5.3 6.5* 6.8
— 61.6 46.4 35.2 56.2 42.6 66.0
— 29.5 30.6 23.6 33.3 23.0 56.8
50.7 45.0 42.0 43.9 25.3 45.2 33.5
52.6 45.8 57.1 65.8 28.4 54.2 41.6
0.695 0.495 0.359 0.414 0.210 0.486 0.316
0.702 0.495 0.429 0.693 0.266 0.616 0.392
1.2 0.6
4.6 3.2
6.0 0.3
51.3 4.8
32.8 5.1†
40.8 3.2
49.4 4.6†
0.425 0.059†
0.53 0.062†
Definition of abbreviations: AHI apnea–hypopnea index; CPAP continuous positive airway pressure; MSNA muscle sympathetic nerve activity; Post post-CPAP therapy; Pre pre-CPAP therapy; RHBF reactive hyperemic blood flow. * Computer chip–derived compliance. † p 0.05 post- versus pre-CPAP.
Imadojemu, Gleeson, Quraishi, et al.: Vasodilator Responses in Sleep Apnea
and blood pressure, obesity and systemic hypertension were more prevalent in the OSA group. However, the betweengroup differences of weight, body mass index, and blood pressure were not statistically significant. Furthermore, peak RHBF was not correlated with any of these parameters. In addition, if a difference in body mass index were the cause of the difference in RHBF in the two groups, one would not expect the improvement of RHBF that we observed after CPAP therapy. Because we did not precisely quantify CPAP compliance in all subjects, our CPAP data should be interpreted with caution. However, that CPAP therapy was effective in our patients is supported by the marked attenuation of obstructive apneas by CPAP in the sleep laboratory, by the subjective improvement of daytime sleepiness, by self-reported or computer chip–derived compliance with CPAP, and by the decrease of MSNA, a surrogate marker of effective CPAP therapy in OSA (13). We did not study an untreated control group because CPAP therapy is strongly recommended in all patients with symptomatic OSA (34). It should also be mentioned that three of our patients and two control subjects were on vasoactive medications, which we did not discontinue before testing. Although we cannot rule out a drug effect on basal sympathetic nerve activity or hyperemic blood flow responses, we doubt that such an effect would alter the interpretation of our data because the medications remained unchanged from preto post-CPAP. We believe our findings are clinically relevant. Our data not only confirm that effective CPAP therapy reduces sympathetic nerve activity but also suggest that abnormal vascular function may improve with this treatment. Both the state of sympathoexcitation as well as abnormal vascular function may contribute to hypertension commonly noted in OSA. In addition, the improvement in the state of sympathoexcitation as well as of the vascular impairment in OSA after CPAP therapy strongly suggests that both abnormalities are causally linked to the repetitive nocturnal apneic events. In summary, our data demonstrate that the maximal vasodilator capacity in response to an ischemic flow stimulus is impaired in OSA and improves with effective CPAP therapy. Our findings emphasize the complexity of the neurocirculatory abnormalities in OSA and provide a pathophysiologic rationale for the use of CPAP therapy. Acknowledgment : The authors would like to thank Jennie Stoner for her excellent secretarial assistance. They would also like to thank Kristen Gray and Michael Herr for their technical help.
9.
10.
11. 12.
13.
14. 15.
16.
17. 18. 19. 20. 21.
22.
23. 24.
25.
26.
27.
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