The Role of Oxidative Stress in the Cardiovascular Consequences of Sleep Apnea

Obstructive Sleep Apnea (OSA) is the most common sleep disorder affecting up to 9-24 percent of middle aged adults, and is becoming increasingly implicated in the pathogenesis of hypertension, and other cardiovascular disorders. Up to half of patients with OSA have hypertension, and their risk of developing hypertension increases with the increasing severity of Sleep Apnea. Patients with OSA and no hypertension have endothelial dysfunction, which is believed to be the precursor for most cardiovascular disorders.

The upper airway collapse and obstruction that occur in OSA result in a pattern of intermittent hypoxia, that has been shown to be the cause of the hypertension, and endothelial dysfunction found in patients with OSA. Intermittent hypoxia results in oxidative stress, which in turn is linked to the pathogenesis of hypertension and endothelial dysfunction.

This protocol evaluates the role of the oxidative stress in endothelial function and blood pressure in patients with OSA. This is a pilot clinical study that will compare oxidative stress parameters, and endothelial function in patients with OSA before starting treatment with continuous positive airway pressure (CPAP) and 12 weeks post being on CPAP. These patients will be compared to control patients with no history of OSA. the study does not involve assignement to different treatments. All patients will receive the indicated treatment for OSA and measurements will be collected before and 12 weeks after adequate treatment.

Study Overview

• Status: Completed
• Conditions: Sleep Apnea

Detailed Description

Obstructive Sleep Apnea (OSA) is increasingly recognized as a cardiovascular risk factor. OSA is a cause of hypertension and has strong association with atherosclerosis, coronary heart disease, diabetes stroke , and fatal cardiovascular events. Endothelial dysfunction is a preclinical vascular abnormality that predicts subsequent development of vascular disease . Patients with OSA demonstrate endothelial dysfunction in the absence of any manifested vascular disease . The mechanism of endothelial dysfunction in OSA is largely unknown. Endothelial dysfunction in OSA is reversible with antioxidants, suggesting a role for oxidant overproduction in the decreased NO availability in OSA. This provides parallels to other cardiovascular diseases in which oxidative stress induced endothelial dysfunction is important.

Recent studies reported evidence of dysfunction or decreased expression of endothelial nitric oxide synthase (eNOS) in association with increased peroxynitrite in harvested venous endothelial cells of OSA patients. We endeavored to perform the first direct quantification of microvascular endothelial genes from OSA patients. We hypothesized that patients with OSA who are free of any cardiovascular disease will have early functional changes in the microcirculatory endothelial cells that are associated with OSA, and therefore would resolve with treatment. Given the role of oxidative stress in the vascular disease of OSA, we expected to find evidence of superoxide overproduction in the microcirculatory vessels. We expected these functional changes to be reversible with treatment of OSA.

Measurement of superoxide will be done on the subcutaneous biopsy tissue using quantitative Polymerase Chain Reaction (qPCR) and immunohistochemistry techniques and image analysis software. Measurement of endothelial function will be done using Doppler ultrasound.

• Study Type: Observational
• Enrollment (Actual): 25

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43212
      • The Ohio State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

People screened for sleep apnea with a completed sleep study who do not have hypertension or coronary artery disease.

Description

Inclusion Criteria:

• Completed sleep study - Older than 18

Exclusion Criteria:

• Hypertension
• Diabetes
• coronary disease
• Peripheral vascular disease
• High cholesterol
• Smoking
• Pregnancy
• Use of erectile dysfunction medications or supplements

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Control group: healthy individuals without OSA; healthy individuals without OSA who are matched in weight and age to the participating OSA patients
OSA group; Patients in the OSA group receive CPAP for 12 weeks as part of their care. patients with OSA provide measures at baseline and after 12 weeks of CPAP treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Flow Mediated Dilation	A non-invasive test using an ultrasound to measure baseline resting vessel diameter and vessel wall dilation in upper arm post application of an inflated blood pressure cuff for five minutes. The percentage change in vessel wall dilation due to stimulation from the resting vessel diameter will be calculated for each group of participants. The results will be compared relative to each group of participants.	Baseline and 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peroxynitrite Deposition in the Vascular Walls	A forearm biopsy will be collected to isolate human microcirculatory endothelial cells. The stain density of peroxynitrite, an indicator of oxidative stress, in the vascular walls is compared between pre-treatment and post treatment patient tissue. Also another comparison is made between pre-treatment and control tissue. The stain density is a software-generated measurement of pixel intensity and is considered to be an arbitrary unit. Higher numbers indicate greater density	baseline and 12 weeks

Collaborators and Investigators

• Sponsor: Rami Khayat

Publications and helpful links

General Publications

• Patt BT, Jarjoura D, Haddad DN, Sen CK, Roy S, Flavahan NA, Khayat RN. Endothelial dysfunction in the microcirculation of patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2010 Dec 15;182(12):1540-5. doi: 10.1164/rccm.201002-0162OC. Epub 2010 Jul 23.

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (Actual): June 1, 2010
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: May 15, 2008
• First Submitted That Met QC Criteria: June 17, 2008
• First Posted (Estimate): June 19, 2008

Study Record Updates

• Last Update Posted (Estimate): October 30, 2013
• Last Update Submitted That Met QC Criteria: October 29, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: oxidative stress; sleep apnea,
• 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; Apnea
• Other Study ID Numbers: 2005H0221