O2 Placebo CPAP

Figure 15.6. Plasma NE clearance in patients with sleep apnea following 14 days of CPAP, oxygen (O2) or placebo CPAP. CPAP led to a significant increase in NE clearance (p < 0.01) whereas there was no change following O2 supplementation or placebo CPAP (Mills et al. 2006). 2


As shown in Table 15.1, posttreatment systolic blood pressure was predicted by pretreatment systolic blood pressure, posttreatment NE clearance, and posttreatment NE release rate, yielding a regression model of r = 0.687, F =16.1, p <0.001, with all other predictor variables dropping out as not significant. Thus, a lower posttreatment systolic blood pressure was associated with a lower pretreatment systolic blood pressure, a higher posttreatment NE clearance, and a lower posttreatment NE release rate.

Table 15.1. Predictors of systolic blood pressure following CPAP. Pretreatment systolic blood pressure (ß = 0.450, p = 0.005) Posttreatment NE clearance (ß = -0.836, p = 0.001) Posttreatment NE release rate (ß = 0.717, p = 0.005) Full regression model: r = 0.687, F = 16.1, p <0.001

Posttreatment diastolic blood pressure was best predicted by pretreatment diastolic blood pressure (full regression model: r = 0.284, F = 10.5,p <0.01).

To summarize this treatment study, we observed that in patients treated with CPAP, in addition to reductions in circulating NE and NE excretion, daytime NE clearance was increased. We did not observe a change in daytime NE release rate, although prior studies have shown that OSA patients have increased sympathetic nerve activity in the daytime and that CPAP leads to a reduction in sympathetic neural activity during sleep. Our measures help specify where CPAP induces changes in daytime sympathetic nerve activity. The major site for NE release is in muscle vascular beds and we did not find a change in NE release with CPAP. On the other hand, there was a clear reduction in urine NE with CPAP. NE in the urine comes from the blood and from NE released by sympathetic nerves in the kidney. Our findings suggest that CPAP causes a reduction in renal sympathetic neuronal activity. CPAP also led to an increase in the volume of distribution for NE. This could be due to more active diffusion of NE out of the bloodstream, enhanced reversible transport of NE by uptake-1 and uptake-2 mechanisms, or enhanced binding of NE by plasma proteins and cellular structures. Our study did not indicate which of these potential mechanisms predominates, but we have previously found a suggestion of enhanced binding to receptors following CPAP (Ziegler et al. 2001).

15.5.3 CPAP Effects on Inflammation

In addition to reducing sympathetic activation, studies show that CPAP is effective in reducing inflammatory markers. The elevations of circulating levels of IL-6 and TNF-a and the production of TNF-a by monocytes in OSA are significantly reduced by CPAP treatment (Minoguchi et al. 2004; Kobayashi et al. 2006). In these studies, all patients were assigned to active CPAP, with no nonactive treatment arm (e.g., placebo CPAP) for comparison. CPAP has also been shown to reduce circulating levels of soluble CD40 ligand (sCD40L) (Yokohama 2006). The reduction of sCD40L is significant because it suggests a potential mechanism of CPAP's reduction of inflammation. CD40L is expressed on many cell types, including endothelial cells, monocytes, and macrophages. CD40L signaling triggers the expression of many proinflammatory mediators including cytokines IL-6 and TNF-a and adhesion molecules ICAM-1 and VCAM-1 (Yokohama 2006).

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