Endothelial Function in Obstructive Sleep Apnea
| Status: | Recruiting |
|---|---|
| Conditions: | Insomnia Sleep Studies, Pulmonary, Pulmonary |
| Therapuetic Areas: | Psychiatry / Psychology, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 2/1/2019 |
| Start Date: | September 1, 2017 |
| End Date: | August 30, 2021 |
| Contact: | Sanja Jelic, MD |
| Email: | sj366@cumc.columbia.edu |
| Phone: | 2125438875 |
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.
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.
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.
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.
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 hypertension, 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.
We found this trial at
1
site
630 W 168th St
New York, New York
New York, New York
212-305-2862
Phone: 212-543-8875
Columbia University Medical Center Situated on a 20-acre campus in Northern Manhattan and accounting for...
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