Vascular Reactivity in Obstructive Sleep Apnea Syndrome HANS W. DUCHNA, CHRISTIAN GUILLEMINAULT, RICCARDO A. STOOHS, JOHN L. FAUL, HEITOR MORENO, BRIAN B. HOFFMAN, and TERENCE F. BLASCHKE Stanford Sleep Disorders Center and Division of Clinical Pharmacology, Stanford University Medical Center, Stanford, California; and Geriatric Research, Education and Clinical Center, VA Medical Center, Palo Alto, California
The obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular disease and systemic hypertension. Because systemic arterial blood pressure is proportional to venodilation and venous return to the heart, we hypothesized that altered vascular responsiveness might exist in the veins of subjects with OSAS. We therefore investigated venodilator responses in awake, normotensive subjects with and without OSAS, using the dorsal hand vein compliance technique. Dose–response curves to bradykinin and nitroglycerin were obtained from 12 subjects with OSAS and 12 matched control subjects. Maximal dilation (Emax) to bradykinin was significantly lower in the OSAS group (62.1% 6 26.1%) than in the control group (94.3% 6 10.7%) (p , 0.005). Vasodilation to nitroglycerin tended to be lower in the OSAS group (78.6% 6 31.8%) than the control group (100.3% 6 12.9%), but this effect did not reach statistical significance. When six of the OSAS subjects were retested after 60 d of treatment with nasal continuous positive airway pressure (CPAP), Emax to bradykinin rose from 60.3% 6 20.3% to 121.4% 6 26.9% (p , 0.01). Vasodilation to nitroglycerin also increased, but this effect did not reach statistical significance. These results demonstrate that a blunted venodilatory responsiveness to bradykinin exists in OSAS. This effect appears to be reversible with nasal CPAP therapy. Duchna HW, Guilleminault C, Stoohs RA, Faul JL, Moreno H, Hoffman BB, Blaschke TF. Vascular reactivity in obstructive sleep apnea syndrome. AM J RESPIR CRIT CARE MED 2000;161:187–191.
Several pathophysiologic mechanisms have been proposed to explain the association between systemic arterial hypertension and the obstructive sleep apnea syndrome (OSAS) (1–5). No prior research has investigated venodilation in human subjects with OSAS. Because systemic arterial blood pressure is positively associated with venous return to the heart, we hypothesized that abnormal regulation of venodilation might exist in subjects with OSAS. Arterial blood pressure is a function of cardiac output, which in turn is partially determined by the venous return of blood to the heart. Several factors influence the venous return of blood to the heart. The (nonturbulent) flow of blood through veins is thought to obey Poisseuille’s equation of fluid mechanics: Q 5 pr4(P1 2 P2)/(8hL), where Q is the venous blood flow, r is the vein radius, L is the length of the vein, (P1) is the hydrostatic pressure within a vein, (P2) is the pressure in the right atrium (reflected by the intrathoracic pressure), and h is the coefficient of viscosity (the coefficient of viscosity for blood is approximately (4 3 1023 Pa s). Because L, P1, and h are relatively constant, the venous blood flow to the heart (Q) is largely influenced by changes in intrathoracic pressure during the respiratory cycle (reductions
(Received in original form October 20, 1998 and in revised form May 24, 1999) Dr. Duchna was supported in part by the Bochumer Arbeitskreis für Pneumologie und Allergologie, e.V. Correspondence and requests for reprints should be addressed to Christian Guilleminault, M.D., Stanford Sleep Disorders Center, 401 Quarry Rd., Suite 3301-A, Stanford, CA 94305. E-mail:
[email protected] Am J Respir Crit Care Med Vol 161. pp 187–191, 2000 Internet address: www.atsjournals.org
in P2), and by r. Because r enters into the equation at the fourth power, even small changes in r can be expected to significantly alter Q. The mechanics of breathing produce reductions in intrathoracic pressure that facilitate blood return to the heart (5–7). Hence, we hypothesized that subjects with sleepdisordered breathing might experience abnormal venous return during apneas. This is supported by experimental work in the rat (8). We further hypothesized that significant alterations in venodilatory responses might exist in awake subjects with OSAS. Regulation of venodilation is influenced by a variety of vasoactive mediators (9, 10). For example, acetylcholine, bradykinin, and substance P activate nitric oxide synthase (NOS) in endothelial cells leading to the generation of nitric oxide (NO) from L-arginine (9). NO diffuses into smooth muscle cells where it activates guanylyl cyclase, leading to the production of cyclic guanine monophosphate (cGMP) which leads to vascular smooth muscle relaxation and vasodilation (10, 11). Other compounds, such as nitroglycerin and nitroprusside, appear to activate vascular smooth muscle cell guanylyl cyclase independent of endothelial cell function. To study endothelium-dependent and endothelium-independent effects, we decided to investigate vascular reactivity (venodilation) to bradykinin and nitroglycerin in patients with and without OSAS. In this study, we employ the human dorsal hand vein technique to construct full dose–response curves for vasoactive substances in vivo (12, 13). This validated technique allows the direct measurement of changes in vein diameter during infusions of vasoactive substances, without eliciting clinically significant (or potentially confounding) changes in systemic hemodynamics (12, 13).
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METHODS Subjects Twelve male subjects with OSAS were recruited from the Stanford Sleep Disorders Clinic. In each case, OSAS was diagnosed by polysomnography (overnight recording of sleep/wake cycles, electrocardiogram [ECG], electroencephalogram [EEG], electromyogram [EMG], anterior tibialis EMG, oronasal airflow, chest wall and abdominal wall effort, esophageal pressure, and pulse oximetry). All subjects with OSAS had an apnea/hypopnea index (AHI) of greater than 10. Twelve healthy control subjects (matched for age, sex, height, and weight) were also recruited. Each control subject underwent nocturnal monitoring (Edentrace) that confirmed normal nocturnal respiration. Control subjects were excluded if they had a history of snoring or witnessed apnea. All subjects with a past history of arterial hypertension (World Health Organization [WHO] criteria), abnormal circadian sleep–wake schedule, drug addiction, dyslipidemia, alcoholism, and current smokers were excluded from the study. The study was conducted according to the Declaration of Helsinki and was approved by the review board for human studies at Stanford University. Each subject provided written informed consent and underwent a complete physical examination, blood pressure monitoring (WHO protocol), ECG, urinanalysis, and blood tests (including chemistry panel, hemoglobin, and white cell count). Subjects were not allowed caffeine for at least 12 h before polysomnography or hand vein study.
Study Design Subjects were admitted to the Palo Alto Veterans Administration Health Care System on the morning of the study. The dorsal hand vein technique was used for in vivo measurements of drug-related vein diameter. This technique has been described in detail by Aellig (12, 13). Subjects were admitted to a quiet room which was kept at 74 6 28 F. The subjects were kept supine with one arm resting on a padded support at an angle of 30 degrees from the horizontal. In order to avoid bruising, a 23-gauge butterfly needle was inserted into an appropriate dorsal hand vein. Normal saline (0.9%) was infused over 30 min at a rate of 0.3 ml/min. This allowed the vein to equilibrate after the vasoconstriction caused by insertion of the needle. A tripod holding a linear variable differential transducer (LVDT; Shaevitz Engineering, Pennsuaken, NJ) was placed on the dorsal surface of the hand and secured over the vein in a stable position. The central aperture of the LVDT contains a movable metallic core which was placed at the apex of the chosen dorsal hand vein less than 1 cm from the end of the infusion needle. The signal output of the LVDT, which is linearly proportional to vertical movement of the core, was amplified (Shaevitz Signal-conditioner ATA 101) and recorded on a strip-chart recorder. Recordings of the position of the core were made both before and after inflation of a sphygmometer cuff to 40 mm Hg. The difference in position of the core before and after inflation gives a measure of the diameter of the vein under a given congestive pressure. This baseline vasodilation during saline infusion with the cuff inflated was defined as 100% relaxation. The vein was then constricted to 20% of the baseline size (cuff deflated, vein emptied) by infusing increasing doses of phenylephrine (99 to 1,583 ng/min), an a1-adrenergic selective agonist. The dose of phenylephrine that produced 80% constriction (ED80) was then infused at a constant rate during the subsequent performance of all other dose–response curves. This degree of preconstriction was defined as 0% dilation. After preconstriction with phenylephrine (ED80), dose–response curves to bradykinin were constructed by infusing bradykinin (at increasing doses ranging from 1 to 278 ng/min) into the dorsal hand vein. After a washout period of 35 min, a single high dose of nitroglycerin (1,583 ng/min) was infused into the phenylephrine-preconstricted vein. Response to each concentration of the drug was recorded after infusing for at least 5 min, which allowed sufficient time to reach the maximal effect at each infusion rate. Drugs were infused using a Harvard infusion pump (Harvard Apparatus Inc., South Natick, MA) at a constant flow rate of 0.3 ml/ min. Blood pressure and heart rate were monitored in the opposite arm with a Dinamap Blood Pressure Monitor Model 845 (Critikon, Tampa, FL). Subjects with OSAS were asked to undergo the same
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protocol after at least 60 d of nasal continuous positive airway pressure (CPAP) therapy. Nasal CPAP therapy compliance was assessed by analyzing pressure-dependent nasal CPAP time odometers without the subject’s knowledge.
Study Drugs All study drugs were diluted in (0.9%) normal saline. Phenylephrine hydrochloride (1%) (American Regent Laboratories, Shirley, NY) was infused over a range of 99 to 1,583 ng/min. Bradykinin acetate salt (Sigma F&D division, St. Louis, MO) was infused at rates of 1 to 278 ng/min. Nitroglycerin (American Regent Laboratories, Shirley, NY) was infused at a constant rate of 1,583 ng/min.
Statistical Analysis Individual dose–response curves were analyzed using the Allfit computer program, version 2.7, obtained from P. Munson at the National Institutes of Health (Bethesda, MD). Allfit is a program that can provide simultaneous fitting of sigmoidal dose–response curves using a four-parameter logistic equation; it was used to compare the maximal response (Emax) and the infusion rate producing half-maximal response (ED50) values derived from cumulative dose–response curves. A log transformation was performed on individual ED50 values to obtain geometric means. Student’s t test for paired and unpaired observations was used, with a two-tailed p value less than 0.05 considered statistically significant. Results were expressed as mean 6 standard deviation. Linear regression analysis was used to determine the independent effects of variables on dependent variables.
RESULTS Subjects in the OSAS group (n 5 12) and the control group (n 5 12) were similar in age (49.3 6 8.7 yr and 45.5 6 8.3, respectively, p 5 not significant [NS]) and body mass index (BMI) (29.8 6 4.8 kg/m2 and 27.8 6 1.7 kg/m2, respectively, p 5 NS). Blood pressure recordings were similar in the two groups. No significant difference was seen in systolic blood pressure between the two groups: (126 6 2.8 mm Hg in the OSAS group and 127 6 2.3 mm Hg in the control group, p 5 NS). Diastolic blood pressure was 79 6 2.9 mm Hg in subjects with OSAS versus 78 6 2.1 mm Hg in control subjects (p 5 NS). All subjects with OSAS were diagnosed with moderate to severe OSAS based on polygraphic recording during sleep. Seven subjects with OSAS presented with daytime sleepiness (Epworth Sleepiness Scale Scores in excess of 9) (14). Polysomnographic measures for the OSAS group are presented in Table 1. Responses to Bradykinin
Individual dose–response curves to bradykinin are presented in Figure 1. The maximal response (Emax) to bradykinin was significantly lower in the OSAS group (62.1 6 26.1%) than in the control group (94.3 6 10.7%) (p , 0.005). In subjects with
TABLE 1 POLYGRAPHIC MEASURES AT BASELINE Time in bed Total sleep time (TST) Sleep efficiency, % Sleep latency, min REM sleep, % of TST NREM, % of TST AHI Average nightly SaO2, % Minimal SaO2, % SaO2 time below 90%, min
401.6 6 78.3 311.9 6 77.4 77.9 6 11.2 33.2 6 29.9 11.9 6 6.2 88.1 6 6.2 39.3 6 31.4 93.3 6 3.1 78.8 6 12.4 58.6 6 66.9
Values are expressed as mean 6 SD. Polygraphic measures of study subjects with OSAS. Respiratory data indicate severe sleep-related respiratory abnormality with frequent apnea, hypopnea, and associated hypoxemia.
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Figure 1. Dose–response curves to bradykinin at baseline in the OSAS group (left panel) and control group (right panel).
OSAS, mean log ED50 was 0.87 6 0.48 (ED50: 7.4 ng/min) versus 1.15 6 0.37 in control subjects (14.1 ng/min) (p 5 0.101). Responses to Nitroglycerin
The mean venodilation to nitroglycerin, tested as a single high-dose infusion, was also reduced in the OSAS group (78.6 6 31.8%) compared with the control group (100.3 6 12.9%), although this difference did not reach statistical significance (Figure 2, left panel ). Three of the OSAS subjects had maximal responses to bradykinin similar to control subjects (see Figure 1). There was no significant difference in severity of OSAS between these subjects and those with abnormal responses to bradykinin (i.e., no significant differences in AHI, average SaO2, and lowest SaO2 during polysomnography). Subset post hoc analysis demonstrated that subjects with blunted venodilation responses reported OSAS symptoms for 15.5 6 5.7 yr compared with 4.7 6 0.58 yr (p 5 0.035) in OSAS subjects with normal responses. Concentrations of bradykinin causing a half-maximum response were significantly correlated with measures of oxygenation during sleep. Regression analysis of the minimal SaO2 value during the recording time on log ED50 revealed a statis-
Figure 2. Response to a single high dose of nitroglycerin. The left panel compares the OSAS group (n 5 12) and control group (n 5 12) at baseline values. The right panel presents the response of the six patients submitted to treatment before and after 2 mo of treatment with nasal CPAP. Note: some data points overlap. The mean obtained for each group is represented by a horizontal line.
Figure 3. Linear regression analysis of log ED 50 and minimal oxygen saturation during the recording night obtained from the 12 OSAS patients at baseline values.
tically significant model with proportion of variance explained by the model (R2) of 0.63 (p 5 0.0003). Subjects with more significant hypoxemia needed a significantly higher dose of bradykinin to produce a half-maximum response (Figure 3). Similar results were obtained for the total time spent with SaO2 values below 90%. CPAP Intervention in Cases of OSAS
Six of 12 subjects with OSAS agreed to be restudied after treatment with nasal CPAP for a mean of 63 d. Repeat polygraphic recordings demonstrated normal AHI with the use of nasal CPAP. The mean CPAP pressure needed for normalization of sleep-related breathing pattern in these subjects was 8.2 6 1.8 cm H2O. Their mean nightly usage of nasal CPAP was 5.4 6 0.5 h/night (objectively verified through time odometers). Maximal venodilation to bradykinin was significantly greater after treatment with nasal CPAP (121.4 6 26.9%) than at baseline values (60.3 6 20.3%) (p , 0.01). Mean log ED50 to bradykinin was 0.94 6 0.52 (ED50: 8.5 ng/min) at baseline versus 1.15 6 0.48 (14.1 ng/min; p 5 0.852) (see Figure 4). Venodilation in response to nitroglycerin after nasal CPAP treatment was 92.8 6 19.5% compared with 74.5 6 35.2% at baseline (p 5 0.302). This difference did not reach statistical significance (see Figure 2). Individual dose–response curves to bradykinin and nitroglycerin before and after nasal CPAP treatment are shown in Figure 2 (right panel ) and Figure 4.
Figure 4. Dose–response curves to bradykinin in six patients treated with nasal CPAP at baseline values (left panel) and after a mean of 2 mo treatment with nasal CPAP (right panel).
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DISCUSSION This study demonstrates that bradykinin-stimulated vasodilation of peripheral veins, as measured by the dorsal hand vein technique, is impaired in normotensive, nonsmoking subjects with OSAS. We also demonstrate that blunted vascular responsiveness to bradykinin is significantly correlated with both the length of nocturnal hypoxemia (the duration spent with an oxygen saturation less than 90%) and the severity of desaturation (lowest SaO2 during the recording night). This effect was reversed after 2 mo of nasal CPAP therapy. Endothelial dysfunction has been implicated in the pathogenesis of diabetic vascular disease, pulmonary hypertension, and systemic hypertension (15–17). We demonstrate that blunted endothelium-dependent venodilation exists in awake normotensive subjects with OSAS. We also demonstrate preservation of endothelium-independent vasodilation by nitroglycerin in the majority of our cases of OSAS. The impaired responsiveness to bradykinin in our OSAS population, therefore, most likely results from impaired release of NO from vascular endothelium rather than a failure of NO to induce vascular smooth muscle relaxation (18–21). Previous work has demonstrated increased pulmonary artery pressor responses to increased blood flow and hypoxia in subjects with OSAS and pulmonary hypertension, consistent with pulmonary artery endothelial cell dysfunction (22). In addition, blunted endothelium-dependent vascular relaxation has been demonstrated in arteries of subjects with OSAS (23). Our study documents the existence of endothelial dysfunction in veins of subjects with OSAS. This finding suggests that further study of the role of vascular reactivity in the development of significant pulmonary and systemic vascular disease in subjects with OSAS is warranted. Hypoxemia and reoxygenation are thought to play an important role in the development of endothelial dysfunction and atherosclerosis in patients with OSAS (24–27). In the current study, the blunting of vascular responsiveness was correlated with the severity of hypoxemia. Subjects with upper airway resistance syndrome (i.e., those who do not suffer repetitive episodes of hypoxemia) may develop hypertension (28). This suggests that factors other than hypoxemia may also play an important role in the development of abnormal hemodynamics in subjects with sleep-disordered breathing. Abnormalities in catecholamine release, cardiac output, baroreflex activity, and changes in intrathoracic pressure have also been implicated in the development of hypertension in OSAS (29–31). Treatment with nasal CPAP leads to improved blood pressure control, reduction of sympathetic nerve activity (29), and a reduction in catecholamine excretion (30) in OSAS subjects. The current study demonstrates improved venodilatory reactivity (perhaps secondary to altered endothelial function) after nasal CPAP therapy in awake, normotensive subjects with OSAS. While it remains to be determined whether vascular reactivity is restored by CPAP treatment in OSAS patients who have systemic arterial hypertension (as might be demonstrable in a placebo-controlled study), the current findings suggest that important venodilatory effects of OSAS occur independent of, and possibly prior to, the development of systemic hypertension. The increased incidence of systemic hypertension and cerebrovascular and cardiovascular disease in OSAS is of considerable interest to both clinicians and researchers, because these effects can lead to significant morbidity and mortality. The cause of these increased incidences has not yet been fully determined. By employing the hand vein technique, which provides direct measurements of vessel diameter without changes
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