Rebuttal from Malcolm Kohler and John R. Stradling
Article first published online: 14 JUN 2012
© 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society
The Journal of Physiology
Volume 590, Issue 12, page 2821, June 2012
How to Cite
Kohler, M. and Stradling, J. R. (2012), Rebuttal from Malcolm Kohler and John R. Stradling. The Journal of Physiology, 590: 2821. doi: 10.1113/jphysiol.2012.235234
- Issue published online: 14 JUN 2012
- Article first published online: 14 JUN 2012
hypoxia inducible factor
obstructive sleep apnoea
reactive oxygen species
It is clear that the article by Lavie & Lavie (2012) is largely in agreement with ours (Kohler & Stradling, 2012). We all agree that most of the cardiovascular consequences of OSA are due to sympathetic over-activity that requires the carotid body (Lesske et al. 1997), and that the hypoxia sensing mechanism in the carotid body involves ROS pathways (Prabhakar, 2011). The main function of the carotid body is to detect hypoxia and as such is appropriately capable of detecting small drops in oxygen tension. This mechanism involves HIF production, and the very high metabolic activity of the carotid body will make it peculiarly sensitive to hypoxia.
Where we disagree is whether the intermittent hypoxia of OSA in humans could also activate ROS systemically, to an extent that results in significant inflammation, which then in turn could lead to endothelial dysfunction and atherosclerosis. The animal experiments that have shown systemic inflammation have required depths of intermittent hypoxia that are greater by far than those seen in the majority of patients with OSA (Li et al. 2007). It seems unlikely that the limited and transient hypoxia in humans with OSA will activate similar mechanisms systemically, and certainly there is no evidence for HIF activation by the night-time hypoxic dips of OSA, for example (Goldman et al. 1991). Given that the mechanism underlying endothelial dysfunction and early atherosclerosis is postulated to be via systemic inflammation, it is disappointing for their hypothesis that the vast majority of randomised controlled trials so far have failed to find evidence for systemic inflammation in humans with OSA (Kohler & Stradling, 2012).
Their apparently strongest evidence comes from interventional studies looking at the effects of antioxidants on endothelial function in patients with OSA. In the paper of Grebe et al. (2006), vitamin C improved the impaired endothelial function in patients with OSA, but not in the healthy control subjects who unfortunately had normal endothelial function at baseline, and were thus not an appropriate control group. In the study by El Solh et al. (2006), although allopurinol improved endothelial function, unfortunately there were no non-OSA control subjects. Thus any improvement may not have been relevant to OSA, particularly given that other co-morbidities frequently associated with OSA, such as the components of the metabolic syndrome, are also associated with increased oxidative stress (Rizvi, 2010). Evidence from appropriately designed randomised controlled trials in humans with OSA will be required to further this argument, as was the case in the vitamin C and cardiovascular disease debate some years ago (Lawlor et al. 2004).
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