Vascular Endothelial Dysfunction in Sleep Apnea

Study Overview
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Brief Summary
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This double-blind placebo-controlled parallel group randomized study design will be used to test whether 4 weeks of atorvastatin 10 mg daily reduces levels of inflammatory markers in OSA patients treated with CPAP (standard of care). The purpose of this study is to investigate: 1) whether statins reduce endothelial inflammation and pro-thrombotic conditions in OSA, including in patients adherent to CPAP (Aim 1); and 2) whether statins reduce endothelial inflammation and pro-thrombotic conditions by improving endothelial cholesterol metabolism and trafficking in OSA (Aim 2).

Detailed Description
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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 the investigators' mechanistic observation that the abnormal cycle of endothelial inflammation can be disrupted with statin therapy, the investigators 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.

Official Title
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Vascular Endothelial Dysfunction in Sleep Apnea

Conditions
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Obstructive Sleep Apnea of Adult

Intervention / Treatment
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* Drug: Atorvastatin 10mg
* Drug: Placebo
* Other: Continuous Positive Airway Pressure Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥18 years Newly diagnosed with obstructive sleep apnea (OSA) who were never treated with CPAP. OSA is defined as apnea-hypopnea index (AHI) ≥5 events/hour of sleep. Exclusion Criteria: A history of coronary artery disease, heart failure, stroke, diabetes, malignancy, chronic pulmonary, kidney or rheumatologic disease, muscle pain/fatigue, smoking within the past 5 years Regular use of any medications

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized double blind design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment<br>OSA patients who adhered or did not adhere with CPAP who are randomized to receive atorvastatin 10 mg daily. | Drug: Atorvastatin 10mg<br>* Atorvastatin 10 mg daily for 28 days will be randomly allocated to OSA patients regardless of adherence with CPAP. Atorvastatin and placebo will be encapsulated to appear identical and dispensed by the research pharmacy.<br>* Other names: statin;Other: Continuous Positive Airway Pressure Therapy<br>* CPAP is a standard of care for OSA and will be prescribed by care providers not associated with this study based on clinical indications. The investigators will have no role in prescribing CPAP.<br>* Other names: CPAP;|
| Placebo Comparator: Control<br>OSA patients who adhered or did not adhere with CPAP who are randomized to receive placebo daily. | Drug: Placebo<br>* Placebo daily for 28 days will be randomly allocated to OSA patients regardless of adherence with CPAP. Atorvastatin and placebo will be encapsulated to appear identical and dispensed by the research pharmacy.<br>Other: Continuous Positive Airway Pressure Therapy<br>* CPAP is a standard of care for OSA and will be prescribed by care providers not associated with this study based on clinical indications. The investigators will have no role in prescribing CPAP.<br>* Other names: CPAP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Circulating levels of Angiopoietin-2 after 4 weeks of atorvastatin vs. placebo therapy | Mean circulating levels of Ang-2 will be quantified after 4 weeks of statin or placebo therapy by enzyme-linked immunosorbent assay (ELISA) | 4 weeks post-treatment | 
| Interaction of endoplasmic reticulum (ER)-bound vesicle-associated membrane protein-associated protein B (VAPB) with late endosome-bound ORP1L (proximity ligation assay fluorescence area in µm2) after 4 weeks of atorvastatin vs. placebo therapy | Mean Interactions ER-bound VAPB with late endosome-bound ORP1L in harvested endothelial cells (ECs) will be assessed using proximity ligation assay (DuoLink, fluorescence area in µm2) after 4 weeks of atorvastatin or placebo therapy | 4 weeks post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Circulating levels of von Willebrand factor cleavage products after 4 weeks of atorvastatin vs. placebo | Mean Circulating levels (count) of von Willebrand factor (vWF) cleavage products (low molecular weight (LMW), medium molecular weight (IMW), high molecular weight (HMW)) after 4 weeks of atorvastatin vs. placebo | 4 weeks post-treatment | 
| Circulating levels of von Willebrand factor (vWF) cleavage products (low, medium, high molecular weight) at baseline and after 4 weeks of CPAP | Mean Circulating levels (count) of vWF cleavage products (LMW, IMW, HMW) at baseline and after CPAP. | 4 weeks post-CPAP | 
| Endothelial cell free cholesterol levels after 4 weeks of atorvastatin vs. placebo | Mean Endothelial cell free cholesterol levels (fluorescence intensity) after 4 weeks of atorvastatin vs. placebo therapy | 4 weeks post-treatment | 
| Endothelial cell lipid droplets after 4 weeks of atorvastatin vs. placebo | Mean Endothelial cell lipid droplets (fluorescence area µm2) after 4 weeks of atorvastatin vs. placebo | 4 weeks post-treatment | 
| Endothelial cell interactions between CD59 and Weibel Palade Bodies (WPBs) after 4 weeks of atorvastatin vs. placebo | Mean Endothelial cell interactions between CD59 and Weibel Palade Bodies (fluorescence area µm2) after 4 weeks of atorvastatin vs. placebo | 4 weeks post-treatment | 
| Circulating levels of Angiopoietin-2 at baseline and after 4 weeks of CPAP therapy | Mean Circulating levels of Angiopoietin-2 after 4 weeks of CPAP therapy quantified by ELISA | 4 weeks post-CPAP | 
| Interaction of ER-bound VAPB with late endosome-bound ORP1L (proximity ligation assay fluorescence area in µm2) at baseline and after 4 weeks of CPAP therapy | Mean Interaction of ER-bound VAPB with late endosome-bound ORP1L (proximity ligation assay fluorescence area in µm2) after 4 weeks of CPAP therapy | 4 weeks post-CPAP | 
| Endothelial cell nuclear factor kappa B (NF-κB) nuclear fluorescence intensity after 4 weeks of atorvastatin vs. placebo | Mean Endothelial cell NF-kB nuclear fluorescence intensity after 4 weeks of atorvastatin vs. placebo | 4 weeks post-treatment | 
| Circulating levels of E-selectin after 4 weeks of atorvastatin vs. placebo therapy | Mean Circulating levels of E-selectin after 4 weeks of atorvastatin vs. placebo therapy quantified by ELISA | 4 weeks post-treatment | 
| Endothelial cell messenger ribonucleic acid (mRNA) expression of EC adhesion molecules after 4 weeks of atorvastatin vs. placebo | Mean Endothelial cell mRNA expression of EC adhesion molecules after 4 weeks of atorvastatin vs. placebo quantified by reverse transcription polymerase chain reaction (RT-PCR) | 4 weeks post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CPAP, Atorvastatin