Abstract Obstructive sleep apnea (OSA), a highly prevalent condition, triples the risk for cardiovascular disease. Observational studies suggested that continuous positive airway pressure (CPAP) therapy improves cardiovascular outcomes in OSA. However, 3 recent randomized clinical trials failed to confirm those findings, indicating that cardiovascular risk persists in OSA despite effective elimination of intermittent hypoxia (IH). Our preliminary data suggest that CPAP may unexpectedly exacerbate the pro-inflammatory milieu in OSA, which may contribute to the residual cardiovascular risk observed in randomized trials of CPAP therapy. Thus, alternative therapies for OSA-related cardiovascular risk are urgently needed. Using endothelial cells (ECs) freshly harvested from OSA patients, we identified increased deposition of the complement membrane attack complex (MAC) on ECs, a consequence of increased internalization of the complement inhibitor CD59 from the EC surface, as a trigger of endothelial inflammation in OSA. We showed that this process is mediated by alterations in EC cholesterol metabolism and trafficking in response to IH and is blocked by statins. We found that randomly allocated statin therapy protects ECs from MAC-induced inflammation compared to placebo, including in OSA patients adherent with CPAP. In the same study, CPAP had no impact on MAC deposition. Unlike CPAP, statins do not eliminate IH episodes in OSA. However, by lowering systemic and cellular cholesterol levels, statins may exert endothelial protection by inhibiting complement-mediated vascular injury in OSA, suggesting a novel therapeutic strategy that may allow OSA patients to continue to benefit from CPAP- mediated elimination of IH and fragmented sleep while reducing their cardiovascular risk. Statin use among OSA patients has been consistently low: only 8-13% of OSA patients are prescribed statins in studies spanning the last decade, indicating that this potentially beneficial therapy has been vastly underutilized in OSA patients. We will use rigorous randomized, double blind, parallel group, placebo controlled study design and ECs harvested from otherwise healthy OSA patients to assess the overall hypothesis that statins stabilize endothelial function by improving endothelial cholesterol metabolism and trafficking regardless of the adherence with CPAP therapy. To address this overall hypothesis, we will determine 1) whether statins reduce endothelial inflammation and pro-thrombotic conditions in OSA, including in patients adherent to CPAP who may express increased inflammatory markers (Aim 1), and 2) whether statins reduce endothelial inflammation and pro- thrombotic conditions by improving endothelial cholesterol metabolism and trafficking in OSA (Aim 2). These studies will advance our understanding of the mechanisms underlying endothelial dysfunction and cardiovascular risk in OSA that seem to persist despite effective CPAP therapy. Since a minority of OSA patients are currently treated with statins, our study will provide the mechanistic background to justify a practical clinical trial to determine if statin therapy improves cardiovascular outcomes in OSA.

Narrative Obstructive sleep apnea (OSA), a condition that affects a quarter of American adults, triples the risk for cardiovascular diseases and increases all-cause mortality. Standard therapy with continuous positive airway pressure (CPAP) does not improve cardiovascular risk. Based on our mechanistic observation that the abnormal cycle of endothelial inflammation can be disrupted with statin therapy, we now propose randomized clinical trial of statins vs. placebo to determine its effects on endothelial dysfunction in OSA patients treated with CPAP, which may provide the basis for practical clinical trials of statins for reducing cardiovascular risk in OSA.