© 2003 American Thoracic Society
Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe night time hypoxiaTo the Editor:Schulz and colleagues (1) reported on elevated serum levels of vascular endothelial growth factor (VEGF-SL) in patients with obstructive sleep apnea (OSA) and severe night time hypoxia, and that VEGF-SL correlates with the degree of nocturnal oxygen desaturations in those patients. Several aspects should be taken into account to interpret these data more accurately. As stated in the article, a methodological limitation of the presented study is that VEGF-SL, and not plasma levels of VEGF were measured. Under physiological conditions, virtually no soluble VEGF is present in the blood. The main transporter of VEGF in the blood stream are thrombocytes (2). Platelets contain large amounts of VEGF and a tight correlation between blood platelet counts and VEGF-SL exists, influenced further by the platelet size (3). In serum samples, VEGF released from activated platelets during the in vitro clotting process is measured. When citrated plasma samples are analyzed instead (where platelets remain intact), negligible levels of VEGF are found (4). Thus, the elevated VEGF-SL in patients with OSA and severe night time hypoxia might reflect merely platelet activation and destruction in vitro. Patients with OSA syndrome are subject to increased cardiovascular morbidity, including myocardial infarction and stroke. Platelets play an important role in the pathogenesis and triggering of acute cardiovascular syndromes. In patients with OSA syndrome, platelet activation and increased aggregability are frequently present (5, 6). Therefore, increased VEGF-SL might reflect platelet activation and subsequent release of VEGF in vivo and/or in vitro under these circumstances. Schulz and colleagues state in their article that enhanced VEGF production in OSA syndrome constitutes an adaptive mechanism to counterbalance the emergence of OSA-related cardiovascular disease (1). The measured levels do not necessarily represent an adaptive mechanism to induce new vessel formation in ischemic vascular and atherosclerotic regions. Instead they may simply constitute a marker for platelet activation in patients with severe OSA syndrome. Thus, elevated VEGF-SL in patients with OSA and severe night time hypoxia are likely to be caused by platelet activation. To further illuminate the findings of Schulz and colleagues, a more suitable control group should be considered, i.e., patients with chronic obstructive pulmonary disease or emphysema without current infection, and additionally, plasma VEGF levels should be determined. Nevertheless, the findings of Schulz and colleagues might help to elucidate the role of platelet activation in patients with OSA and severe night time hypoxia, and the potential role of VEGF blood levels in those patients, as VEGF-SL may correlate with patients at risk for stroke and myocardial infarction even under nasal continuous positive airway pressure or biphasic positive airway pressure therapy.
University of Innsbruck Innsbruck, Austria REFERENCES
From the Authors:We thank Dr. Kähler and colleagues for their comments concerning our article on vascular endothelial growth factor (VEGF) levels in obstructive sleep apnea (OSA) (1). The major point of criticism is that the measurements of VEGF were carried out from serum samples and that this might merely reflect platelet activation in OSA.However, we think that it is not justified to speculate that platelets are the only possible site of VEGF release in OSA. First of all, there were no differences in platelet counts between the healthy control subjects and the OSA patients with moderate and severe night time hypoxia (means ± SEM: 23.0 ± 1.8 versus 22.7 ± 1.3 versus 21.3 ± 1.7 x 104/µl). Furthermore, even if one would assume platelet activation to have occurred in the OSA patients, this phenomenon has not yet been shown to be directly related to parameters of apnea severity. In contrast, VEGF serum levels in OSA were correlated with the degree of nocturnal oxygen desaturation in our patients and with the apnea–hypopnea index in two other studies reporting similar findings (2, 3). Finally, in vitro experiments have found that the release of VEGF from platelets is not stimulated by hypoxia (4). Thus, the possibility that the VEGF induction in OSA is due to enhanced endothelial gene transcription under the influence of apnea-related intermittent hypoxia can not be excluded. We concur with Kähler and colleagues that in order to resolve these issues VEGF measurements should be performed from plasma samples. Furthermore, in addition to free circulating VEGF, determinations of the circulating fraction of VEGF bound to its soluble receptor Flt-1 and of the VEGF content of platelets would be helpful to better characterize the alterations of the VEGF system in OSA. Regardless of these methodological considerations, we disagree with Dr. Kähler that the VEGF levels are simply a marker of the individual cardiovascular risk in OSA. This assumption neglects the biological properties of endothelial-derived VEGF as a promoter of neoangiogenesis and of platelet-derived VEGF as an inducer of wound healing at sites of vascular injury (5). Therefore, we still favor the view that the elevated VEGF levels in OSA constitute an adaptive mechanism irrespective of the exact source of VEGF release. On the other hand, it has recently been documented that VEGF might lead to atherosclerotic plaque progression (6). Thus, the pathophysiological significance of VEGF activation in OSA awaits further clarification. In a recent study by Lavie and colleagues, plasma levels of VEGF were measured in a sample of OSA patients (7). These authors showed that plasma VEGF is elevated in untreated OSA and is reduced after improvement of nocturnal hypoxia by CPAP therapy.
Justus-Liebig-University Gießen, Germany REFERENCES
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