Interleukin‐6 in ischemic stroke associated with obstructive sleep apnea

We thank Dr. Gao and co-workers for their interest in our article, which describes the increased levels of Interleukin-6 (IL-6), an inflammatory marker, in stroke patients commensurate with severity of obstructive sleep apnea (OSA). According to our data, IL-6 is also correlated with oxyhemoglobin desaturation and with desaturation index (1). In their letter, Dr. Gao and co-workers raise concerns about the possibility of a confounding effect of obesity and metabolic syndrome on the relationship between OSA and inflammation described in our patients. Although we partially agree with their observations, there are some aspects that need to be addressed. Dr. Gao and co-workers are correct to point out that OSA, obesity, and metabolic syndrome are considered risk factors for cardiovascular mortality including coronary artery disease and stroke. While this may be true, it has also been demonstrated that OSA has an independent role in the development of metabolic dysfunction (2). Furthermore, oxygen desaturation is an independent risk factor for insulin resistance (3), and sleep loss is associated with increased IL-6 and TNF-alpha (4). Of interest, intermittent hypoxia without high-cholesterol diet showed proatherogenic effects; unfortunately, inflammatory markers were not evaluated in the previous study (5). Crucial to this discussion, an independent correlation between oxygen desaturation and inflammation has been recently described (6). Finally, it has been argued that underlying chronic intermittent hypoxia caused by OSA could explain the paradoxical protective effect of obesity on morbidity/ mortality (7). In our study, we found that obesity is rare in acute ischemic stroke patients, confirming a previous report (8). Additionally, neck circumference and body mass index were not determinants for increased IL-6. It has been previously shown that neck circumference is associated with the severity of OSA independently of visceral obesity, particularly in non-obese patient (9). This is in agreement with a recent report associating neck circumference with mortality in acute ischemic stroke patients (10). Based on these findings, neck circumference may be a better measure than hipwaist or the body mass index in the detection of OSA and increased morbidity and mortality. The atherosclerotic process is definitely linked to inflammation and it has been shown that OSA-related hypoxia and systemic inflammation might be associated with the progression of atherosclerosis and thus increase the risks of cardiovascular and cerebrovascular complications in patients with OSA (11). Presently, it may be difficult to discriminate between the effects of atherosclerosis and OSA. However, future studies designed to compare the effects of endothelial dysfunction and oxygen desaturation on inflammatory markers may clarify the differential role of atherosclerosis and OSA on inflammation. It should also be mentioned that prospective epidemiological studies demonstrating an association between increased circulating inflammatory markers and mortality rates (12) and the lack of association with recurrent vascular events (13) have not taken into consideration the presence of OSA. Interestingly, a metanalysis showing the association between C-reactive protein (CRP) and risk of coronary heart disease, ischemic stroke, vascular mortality, and death from several cancers and lung disease has suggested that the relevance of CRP to such a range of disorders is unclear: consequently, the association of CRP with ischemic vascular disease probably depends considerably on other conventional risk factors and other markers of inflammation (14). In summary, there is enough evidence to support a key role for IL-6 as an inflammatory marker in ischemic stroke associated with OSA, as described in our study.