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Plasma Vascular Endothelial Growth Factor in Sleep Apnea Syndrome

Effects of Nasal Continuous Positive Air Pressure Treatment

Unit of Anatomy and Cell Biology; Sleep Laboratory, Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel; and Department of Clinical Pharmacology and Sleep Laboratory, Pulmonary Medicine, Sahlgrenska Hospital, Gothenburg, Sweden

Correspondence and requests for reprints should be addressed to L. Lavie, Unit of Anatomy and Cell Biology, Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa 31096, Israel. Email: lenal{at}tx.technion.ac.il

	ABSTRACT

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Sleep apnea syndrome is associated with recurrent episodic hypoxia during sleep, which has been implicated in the development of cardiovascular morbidity. Hypoxia is the major stimulus of vascular endothelial growth factor (VEGF), which is a potent angiogenic cytokine. In the present article we describe the results of three experiments in which plasma concentrations of VEGF were measured in patients with sleep apnea. In Experiment 1, apnea–hypopnea index was found to be a significant independent predictor of morning VEGF concentrations in 85 male subjects investigated in the sleep laboratory, of whom 47 had an apnea–hypopnea index greater than 20. In Experiment 2, VEGF concentrations measured hourly during the sleep period were found to be significantly higher in a group of five sleep apnea patients compared with six age-similar snorers and six normal young adults (129.1 ± 43.4 versus 74.6 ± 11.5 and 32.5 ± 12.8 pg/ml, respectively [p < 0.007]). In Experiment 3, VEGF concentrations were compared in patients with sleep apnea before and 1 year after nasal continuous positive airway pressure treatment. A significant decrease in VEGF concentrations was found only in patients in whom nocturnal hypoxia improved after treatment (57.1 ± 62.5 versus 39.6 ± 46.9 pg/ml, p < 0.01). There was no comparable improvement in patients who did not accept treatment (53.9 ± 23.6 versus 54.0 ± 21.5 pg/ml, ns). These results raise the possibility that VEGF may contribute to the long-term adaptation of sleep apnea syndrome to recurrent nocturnal hypoxia.

Key Words: vascular endothelial growth factor • sleep apnea • nasal continuous positive air pressure

	INTRODUCTION

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Sleep apnea syndrome, which is a common public health problem affecting as much as 4% of the adult population, is associated with recurrent episodic hypoxia during sleep (1). In patients with severe sleep apnea syndrome, oxygen saturation may repeatedly decrease during the apneic events to concentrations as low as 50% saturation, or less than 30 mm Hg partial oxygen pressure. Arterial oxygen desaturation events have been implicated in the development of cardiovascular morbidity in the syndrome (2–4). A prominent physiologic adaptive response of a tissue to hypoxia or ischemia is angiogenesis, the formation of new blood vessels (5). By increasing the blood supply, the ischemic tissue or organ compensates for the decreased oxygen concentrations. Moreover, chronic hypoxic exposure of animals was shown to induce vascular remodeling, particularly in precapillary pulmonary vessels (6). Vascular endothelial growth factor (VEGF) is a soluble 34–46 kD angiogenic heparin-binding glycoprotein. This cytokine regulates multiple endothelial cell functions including mitogenesis, vascular permeability, and vascular tone (7, 8). Hypoxia is the major stimulus that upregulates VEGF synthesis by controlling gene transcription and mRNA stabilization, although its synthesis is also stimulated when cells become deficient in glucose and in inflammatory reactions (9, 10). Recent results have shown increased VEGF concentrations also in patients with hyperlipidemia and hypertension (11, 12). A preliminary report from our laboratory on plasma VEGF (13) and recent papers by Imagawa and colleagues (14) and Schulz and colleagues (15) on serum showed that sleep apnea patients had elevated concentrations of VEGF, which were correlated with the severity of the syndrome as indexed by nocturnal hypoxia and apnea–hypopnea index (AHI). In the present study, we investigated the plasma concentrations of VEGF in sleep apnea patients and control subjects throughout the sleep period and compared the concentrations of VEGF in sleep apnea patients before and after treatment with nasal continuous positive air pressure (nCPAP).

	METHODS

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Three independent studies were conducted to investigate the plasma concentrations of VEGF in patients with sleep apnea. The purpose of the first study was to investigate the morning concentrations of plasma VEGF in sleep apnea patients as a function of severity of the syndrome, as indexed by their degree of nocturnal hypoxia and AHI. The second study investigated the overnight concentrations of VEGF in sleep apnea patients in comparison with two control groups: age-similar simple snorers and young adults. The third study investigated morning concentrations of VEGF before and after nCPAP treatment in acceptors and nonacceptors of treatment. All three studies were approved by the appropriate ethics committees, and patients signed an informed consent form before being enrolled.

Experiment 1
Eighty-five consecutive adult male patients, who were referred to the Technion Sleep Disorders Center for whole-night polysomnographic (PSG) recording because of suspected sleep apnea syndrome, were recruited for this study. Diagnosis of obstructive sleep apnea was based on at least one night of PSG. This included monitoring of respiration using chest and abdomen respiratory belts and oro-nasal temperature sensors, as substitute measurements of respiratory effort and flow, and oxygen saturation. From these measures we obtained AHI (the total number of apneas plus hypopneas divided by the hours of sleep) and lowest nocturnal oxygen saturation (MinSAT). Apnea was defined as a cessation in airflow of at least 10 seconds, and hypopnea was defined as a decrease in the amplitude of the respiratory signal of at least 50% for a minimum of 10 seconds followed by either a decrease in oxygen saturation of 4% or signs of electroencephalographic arousal. Height and weight were recorded, and body mass index (BMI) was calculated. Each patient was also interviewed by one of the sleep laboratory physicians regarding their sleep-related complaints and medical history. Hypertension was defined as either current treatment with antihypertension medications or a blood pressure greater than 140/90 mm Hg. All patients were included in the analysis regardless of their AHI.

Blood collection.
A 5 ml venous blood sample was obtained from each patient after overnight fasting. Blood samples were collected in precooled tubes (vacutainers; Becton-Dickinson, Plymouth, UK) containing ethylenediaminetetraacetate and kept on ice. Plasma was separated within 2 hours in a refrigerated centrifuge, aliquoted, and stored at -70°C until assayed. Serum was obtained for the determination of cholesterol, triglycerides, low density lipoproteins (LDL), high density lipoproteins (HDL), and creatinine.

Experiment 2
Three groups participated in this study: five patients with severe sleep apnea, six men who were referred to the Technion Sleep Disorder Center because of suspected sleep apnea primarily because of loud snoring but were found to have an AHI less than 10, and six healthy young adults. The latter group was examined to ensure a satisfactory state of health by physical examination, medical history, whole-night PSG recordings, and blood testing. Polysomnographic recordings in this group revealed scattered hypopneas that were not associated with oxygen desaturation. Subjects were instructed to avoid alcohol and caffeine containing beverages during the 24 hours that preceded each of the experimental periods. All subjects were admitted to the laboratory at 18:00 for whole-night PSG monitoring and blood sampling. At 7:00 P.M. a catheter was inserted into an antecubital vein and was kept patent by a slow infusion of saline. Electrodes were attached for PSG monitoring. Lights were turned off strictly during the sleep period (from 11:00 P.M. to 6:00 A.M.). Five milliliter blood samples were collected every hour starting at 7:00 P.M. until 6:00 A.M., in tubes containing ethylenediaminetetraacetate, immediately centrifuged at 4°C, and plasma was stored at -70°C until assay.

Experiment 3
Data of the third experiment were part of a study on nCPAP acceptance and compliance conducted at the sleep laboratory of the Sahlgrenska University Hospital in Gothenburg, Sweden. Details of the study can be found elsewhere (16). A subsample of 22 patients out of the 149 consecutive patients from the original parent study cohort participated in this experiment. Inclusion criteria were based on PSG findings of at least 10 events of arterial oxygen saturation of less than 90% (D90) per hour of sleep at inclusion (I-D90 > 10) or at follow-up (F-D90 > 10) approximately 1 year later. The reason for using D90 rather than AHI as in the first two experiments is that this variable was reasoned to represent a better surrogate of the extent of nocturnal hypoxic exposure. Unfortunately, D90 was not available in the first two experiments. We should note however, that AHI and D90 were highly correlated in this group (r = 0.75, p < 0.001) and that repeating this experiment using AHI instead of D90 resulted in similar findings. Based on the results of the PSGs on the two occasions, two subgroups were classified: "nCPAP acceptors" included patients who accepted nCPAP treatment and had I-D90 less than 2 (n = 10) at the follow-up recording; and "nCPAP nonacceptors" included patients who refused to use nCPAP or had I-D90 greater than 10 (n = 7) at the follow-up recording. Six of the 7 nonacceptors did not use nCPAP at follow-up and one used it ineffectively. All 10 acceptors used nCPAP at follow-up. One patient showed a marked improvement after a weight reduction (BMI decreased from 31.4 to 27.1 kg/m²) and his results were added to the acceptors. Data of four patients were not available for analysis either because they did not return for a follow-up recording (n = 3) or because they showed an intermediate decrease in D90 (n = 1). Mean nCPAP at follow-up for the acceptors was 9.6 ± 4.6 cm H₂O, and mean daily use was 4.2 ± 2.4 hours per day. All blood samples were obtained in pre-cooled tubes upon awakening in the laboratory at 6:20 A.M. Blood was immediately centrifuged. Plasma was kept frozen at -70°C until air transported from Gothenburg to Haifa on dry ice for the VEGF analysis. Samples obtained for determination of cholesterol, triglycerides, LDL, and HDL were analyzed in the accredited hospital laboratory, Gothenburg, Sweden.

VEGF Determinations
VEGF was measured in duplicate determinations by a quantitative enzyme-linked immunoassay technique using a commercially available kit (R&D Systems, Abingdon, UK). The VEGF assay had a minimum sensitivity of 9 pg/ml, with intra-assay coefficients of variation of 6.7% and 4.5% for concentrations of 54 and 235 pg/ml, respectively, and inter-assay coefficient of variation of 8.8% and 7% for concentrations of 64 and 250 pg/ml, respectively. The technician performing the assay was unaware of the origin of the samples. In Experiment 1, cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol, and creatinine were analyzed from serum with a Vitros 250 Chemistry system (Johnson and Johnson Clinical Diagnostics; Rochester, NY) by the American Medical Laboratories, Haifa, Israel. In Experiment 3, lipids were determined in the hospital laboratory in Gothenburg, Sweden.

Statistical Analysis
Univariate and multivariate analyses were used to investigate the relationship between plasma VEGF concentrations and sleep apnea. In the first experiment, stepwise multiple regression analysis was applied to predict VEGF concentrations using BMI, age, AHI, MinSAT, hypertension, ischemic heart disease, smoking, medications usage, LDL, HDL, cholesterol, creatinine, and triglycerides as potential predictors. Since the distribution of VEGF concentrations deviated from a normal distribution, a natural log transformation (Ln) was performed before the analysis. In the second experiment, analysis of covariance was used to compare VEGF concentrations between groups using age and BMI as covariates. This was followed by a post hoc Duncan's multiple range test to determine differences between pairs of groups. In the third experiment, independent and paired t tests were used to compare plasma VEGF concentrations between groups at baseline and at follow-up and within groups before and after treatment (significance was determined to be p < 0.05).

	RESULTS

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Experiment 1
Patients mean age and BMI were 52.8 ± 12.3 years and 29.9 ± 4.4 kg/m², and mean AHI and MinSAT were 31.1 ± 21.9 events/hour and 83.0 ± 11.6%, respectively. A total of 38 participants (44.7%) had an AHI less than 20, 21 participants (24.7%) had an AHI between 21 and 40, 14 participants (16.4%) had an AHI between 41 and 60, and 12 participants (14.1%) had an AHI greater than 60. There was a large between-patients' variability in morning VEGF concentrations, with an overall mean of 73.0 ± 49.6 pg/ml, range: 7.9–221.8 pg/ml (see Table E1 in the online data supplement). Figure 1 demonstrates that the concentrations of VEGF (natural Log transformed) increased linearly as a function of AHI category. Stepwise regression analysis identified the following variables as significant predictors of VEGF: BMI (p < 0.001), AHI (p < 0.04), age (p < 0.08) and LDL (p < 0.07). Age entered with a negative sign so increasing age was associated with decreasing VEGF concentration (Table 1). Together these variables explained 24.8% of the total variability in VEGF.

View larger version (10K): [in this window] [in a new window]   Figure 1. Mean morning Ln transformed VEGF concentrations as a function of AHI category in 85 men investigated by whole night polysomnographic monitoring and fitted linear regression.

View larger version (15K): [in this window] [in a new window]   Figure 2. Mean (± SD) hourly VEGF concentrations measured throughout the night in apnea patients (n = 5), in normal young adults (Control 1, n = 6), and in age-similar snorers (Control 2, n = 6). Statistical analysis revealed significantly higher VEGF concentrations in the sleep apnea group than in the two control groups.

View larger version (17K): [in this window] [in a new window]   Figure 3. VEGF concentrations at baseline and after approximately 1 year follow-up in acceptors and nonacceptors of nCPAP treatment. (A) Acceptors of treatment (n = 9). Data of one patient with exceptionally high VEGF concentrations (232 pg/ml before nCPAP and 175 pg/ml after nCPAP) are not presented for clarity of the figure. (B) Nonacceptors of treatment (n = 7). Dashed lines indicate mean concentrations. Statistical analysis revealed a significant reduction in VEGF concentrations only in acceptors.

	DISCUSSION

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VEGF, a key mediator in angiogenesis, was shown to be upregulated under hypoxic conditions in cardiac myocytes, vascular smooth muscle cells, and endothelial cells (20–23), as well as in heart tissue following myocardial ischemia (24–26). The circulating serum concentrations of VEGF were also elevated shortly after acute myocardial infarction (27–29), after acute stroke (30), and in children with cyanotic congenital heart disease (31). Exogenous administration of VEGF in vivo was shown to augment collateral blood flow to the ischemic myocardium (24, 32).

The association between nocturnal hypoxia and plasma VEGF concentration in sleep apnea patients suggests that repeated intermittent nocturnal hypoxemic insults may result in increased hypoxia-sensitive gene expression and consequently in upregulation of the protein production. The fact that patients with sleep apnea were found to have a persistent elevation of VEGF concentrations in comparison with control subjects throughout the night indicates that these differences may not be confined to the nocturnal period alone but may persist throughout a 24 hour period. Previously it was shown that the augmented serum VEGF concentration associated with physical exercise at high altitude only gradually normalized after returning to low altitude, suggesting that elevated VEGF production was sustained for some time after the disappearance of the hypoxic state (33). Others however, when investigating a small number of patients, could not demonstrate an elevated plasma VEGF concentration in association with hypoxia in mountaineers at high altitude (34).

Aside from a role in angiogenesis, recent studies have shown that VEGF may also contribute to the atherogenic process itself. VEGF induced monocyte activation and migration (35), modulated the growth of smooth muscle cells (36), and was closely related to the progression of coronary atherosclerosis in humans (37, 38) and the extent of carotid stenosis (39). VEGF was also higher in patients with uncomplicated hyperlipidemia, with and without atherosclerosis, which could be lowered by lipid's lowering therapy (11). Likewise, patients with uncomplicated and untreated essential hypertension exhibited higher plasma VEGF concentrations than control subjects, and these elevated values could be decreased by blood pressure reduction (12).

Based on the above observations, it could be argued that the increased VEGF concentration in sleep apnea patients resulted from comorbid cardiovascular conditions, or an existing subclinical condition of atherosclerosis, rather than from breathing disorders and hypoxia per se. This possibility, however, appears unlikely in view of the results of the independent predictive value of AHI in the multivariate analysis on VEGF concentration and the decrease in VEGF concentration after a successful nCPAP treatment. We should note, however, that the percent of variability in morning VEGF concentration explained by AHI was moderate. This is not surprising considering the large interindividual differences in the magnitude of VEGF in response to hypoxia (40). This study demonstrated that whereas some individuals responded vigorously to hypoxia in vitro by elevated VEGF mRNA synthesis, others responded only minimally or not at all. Moreover, this individual response correlated with the size of the coronary collaterals tree as visualized by angiography.

The clinical significance of elevated VEGF concentrations in patients with sleep apnea is a matter of speculation at this stage. On the one hand it is tempting to speculate that VEGF upregulation plays a role in the long-term adaptation to the hypoxic state in some patients with sleep apnea. There is clinical evidence that in at least some patients with sleep apnea there is a cardiovascular adaptation to some components of the breathing disorder. For instance, the risk for hypertension in sleep apnea patients appeared to be age-dependent and reaches a peak at the younger age groups of 30–50 years (41, 42). Likewise, excess mortality in sleep apnea patients appears to be restricted to patients younger than 50 years (43, 44). So far there is no explanation for these apparent interindividual differences in adaptation to the syndrome. Findings that demonstrate vast interindividual heterogeneity in the VEGF response to hypoxia may provide potential explanations for such differential adaptation (40). On the other hand, it should be noted that VEGF has been associated with abnormal angiogenesis, as seen in proliferative retinopathy, rheumatoid arthritis, psoriasis, and malignancy (45, 46). Consequently, the augmented VEGF concentration in sleep apnea patients having comorbidities may reflect a contributory mechanism for development of cardiovascular disease. Therefore, a reduction of VEGF concentration following treatment of sleep apnea and potentially reduced angiogenesis may be a mechanism of clinical significance. No doubt, further studies addressing VEGF expression in sleep apnea and outcome in terms of cardiovascular function and disease are needed to answer these questions.

	Acknowledgments

 
The authors greatly appreciate the help of the Technion Sleep Disorders Center Staff.

Supported by a grant from the Israeli Academy of Sciences (L. L., P. L.).

	FOOTNOTES

 
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Received in original form October 20, 2001; accepted in final form February 21, 2002

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