Endothelial Function in Obstructive Sleep Apnea

Vascular Endothelial Activation in Obstructive Sleep Apnea

Obstructive sleep apnea (OSA), a condition that affects a quarter of the Western adults, triples the risk for cardiovascular diseases and increases all-cause mortality. Intermittent hypoxia (IH) during transient cessation of breathing in OSA leads to endothelial inflammation, a key step in the initiation and progression of cardiovascular disease. However, the mechanisms that mediate IH-induced endothelial inflammation remain unclear and, consequently, no targeted therapy is available for vascular manifestations of OSA. Using endothelial cells (ECs) freshly harvested from OSA patients, they study team has identified impaired complement inhibition as an initial stimulus for endothelial inflammation in IH, thereby linking for the first time complement activation to vascular risk in OSA. The investigators found that a major complement inhibitor cluster of differentiation (CD59), a plasma membrane protein that inhibits the formation of the terminal complement membrane attack complex (MAC) and protects host cells from complement injury, is internalized from the EC surface in OSA patients. Consequent MAC deposition initiates endothelial inflammation in IH. Importantly, the investigators showed that IH does not significantly affect inflammation in ECs in the absence of complement, suggesting that complement activation has an essential role in endothelial inflammation in OSA. Interestingly, internalization of CD59 in IH appears to be cholesterol-dependent and statins prevent MAC deposition on ECs in IH in a CD59-dependent manner, suggesting a novel therapeutic strategy to reduce vascular risk in OSA. This led the study team to hypothesize that IH-induced cellular cholesterol accumulation reduces complement inhibition via increased internalization of CD59 from the EC surface leading to increased MAC deposition, and that treatment of OSA with continuous positive airway pressure (CPAP) and/or statins reverses endothelial dysfunction by restoring complement inhibition.

Study Overview

• Status: Completed
• Conditions: Obstructive Sleep Apnea of Adult
• Intervention / Treatment: Drug: Atorvastatin 10mg; Drug: Placebo

Detailed Description

To address the hypothesis, the investigators seek to determine whether statins prevent endothelial dysfunction in OSA by restoring complement inhibition. The preliminary data indicate that the expression of CD59 on the EC surface is preserved in OSA patients who are receiving statins and that statins prevent CD59 internalization and MAC deposition in IH leading to reduced inflammation. The study proposes to determine whether statins restore endothelial protection against complement activity in OSA patients using double-blind placebo-controlled parallel group randomized study design. The hypothesis: The proportion of CD59 on the EC surface is increased while MAC deposition is decreased after 4 weeks of atorvastatin 10 mg daily compared with placebo in OSA patients who adhere with CPAP or do not adhere with CPAP.

The proposed studies may advance our understanding of vascular dysfunction in OSA and provide the basis for large, long-term clinical trials of novel therapeutic strategies, such as addition of statins to the standard CPAP therapy, for preventing and/or reversing vascular risk in OSA.

• Study Type: Interventional
• Enrollment (Actual): 106
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients aged ≥18 years with newly diagnosed 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment; OSA patients who adhered or did not adhere with CPAP will be randomized 1:1 to treatment (atorvastatin 10 mg daily) or control group (placebo).	Drug: Atorvastatin 10mg; Atorvastatin 10 mg daily for 28 days will be randomly allocated to OSA patients regardless of adherence with CPAP. 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. Atorvastatin and placebo will be encapsulated to appear identical and dispensed by the research pharmacy.; Other Names: statin
Placebo Comparator: Control; OSA patients who adhered or did not adhere with CPAP will be randomized 1:1 to treatment (atorvastatin 10 mg daily) or control group (placebo).	Drug: Placebo; Placebo daily for 28 days will be randomly allocated to OSA patients regardless of adherence with CPAP. 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. Atorvastatin and placebo will be encapsulated to appear identical and dispensed by the research pharmacy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in proportion of CD59 on the endothelial cell (EC) surface (the percent [%] of the total cellular CD59 protein that is expressed on the endothelial cell surface).	Outcome 1 will be assessed before and after 4 weeks of atorvastatin or placebo. Each patient 28-day follow-up value will be compared with baseline value. There is no reference range for this marker of complement regulation. The percent of total CD59 located on the EC plasma membrane will be quantified using immunofluorescence and confocal microscopy. This is a single outcome measure. The unit is percent (%) of the total cellular CD59 protein that is expressed on the endothelial cell surface.	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MAC deposition on EC surface (measurement unit is fluorescent area quantified as micrometer square).	Outcome 2 will be assessed before and after 4 weeks of atorvastatin or placebo. Each patient 28-day follow-up value will be compared with baseline value. This is a single outcome measure. There is no reference range for this marker of complement regulation. MAC deposition on the EC plasma membrane will be quantified using immunofluorescence and confocal microscopy and expressed as the fluorescent area in micrometer square.	Up to 28 days
ORP1L (late endosome protein) and VAPB (endoplasmic reticulum protein) interaction (measurement unit is fluorescent area quantified as micrometer square).	Outcome 3 will be assessed at baseline between healthy control and OSA group.	1 day

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Sanja Jelic, MD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2017
• Primary Completion (Actual): January 30, 2020
• Study Completion (Actual): May 7, 2021

Study Registration Dates

• First Submitted: April 12, 2017
• First Submitted That Met QC Criteria: April 17, 2017
• First Posted (Actual): April 21, 2017

Study Record Updates

• Last Update Posted (Actual): October 18, 2023
• Last Update Submitted That Met QC Criteria: October 17, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Apnea; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: AAAR0444; 2R01HL106041-06A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No