Sodium Channel Splicing in Obstructive Sleep Apnea (SOCS-OSA)

This study is designed to test whether SCN5A mRNA processing is altered in OSA patients, which may contribute to their increased arrhythmic risk, and whether processing of SCN5A mRNA is modulated by CPAP treatment.

Specific aims:

1. Compare sodium channel splicing variants in mild, moderate, or severe OSA patients at baseline to at 1 month after CPAP treatment. In addition, the baseline splicing variants of SCN5A in the OSA patients will be compared to an age-matched control group.
2. Hypoxia-associated upstream regulators of SCN5a mRNA splicing, Hypoxia-inducible factor 1-alpha (HIF-1α), RNA Binding Motif Protein 25 (RBM25) and LUC7-Like 3 Pre-MRNA Splicing Factor (LUC7L3), will be examined in OSA patients before and after 1 month of CPAP treatment.

Study Overview

• Status: Completed
• Conditions: Sleep Apnea Syndromes
• Intervention / Treatment: Device: CPAP

Detailed Description

BACKGROUND & SIGNIFICANCE Obstructive sleep apnea (OSA) is a common disease with an estimated prevalence of 3% to 7%. It is characterized by recurrent episodes of partial or complete collapse of the upper airway during sleep, resulting in hypopneas or apneas, respectively. The collapse of upper airway during obstructed events result in intermittent hypoxia, recurrent arousals from sleep, metabolic disturbance and poor quality of life. Cardiac arrhythmias are reportedly more frequent in patients with OSA and increase with the number of apneic episodes and the severity of the associated hypoxemia. Recent data from the Sleep Heart Health Study suggested that those with severe sleep disorders had a 2- to 4-fold-higher risk of nocturnal complex arrhythmias. Even after adjustment for age, sex, BMI, and prevalent coronary artery disease, patients with sleep disorders had increased likelihoods of atrial fibrillation, nonsustained ventricular tachycardia, and complex ventricular ectopy.

Continuous positive airway pressure (CPAP) is the first-line treatment for patients with OSA and acts as a pneumatic splint to the upper airway during sleep and corrects the obstruction, improving daytime sleepiness and quality of life. Observational studies suggest that CPAP treatment reduces the incidence of cardiovascular events in patients with moderate and sever OSA.

Sodium channel is an integral membrane protein that plays a central role in conduction of the cardiac impulse in myocytes and cells of the His-Purkinje system. It is a multimeric complex consisting of an α and an auxiliary β-subunit. The α subunit, SCN5A is sufficient to express a functional channel. However, β subunit co-expression increases the level of channel expression and alters the voltage dependence of inactivation. Mutations of the sodium channel result in type 3 long QT syndrome (LQT3), Brugada syndrome, atrial fibrillation, congenital sick sinus syndrome, multifocal premature ventricular contractions (PVCs), and dilated cardiomyopathy.

Recently, the investigators have discovered abnormal sodium channel messenger RNA (mRNA) processing in congestive heart failure (CHF) that results in reduced sodium channel to a range known to be associated with sudden cardiac death. Three truncated SCN5A mRNA splicing variants were identified (denoted variant B (E28B), variant C (E28C), and variant D (E28D)). Among them, E28C and E28D abundances were increased 14.2 fold and 3.8 fold respectively in CHF patients compared to controls. The full length SCN5A mRNA (E28A) was decreased by 24.7% in patients with CHF compared to control. Moreover, a key transcriptional regulatory molecule in hypoxia, hypoxia-induced factor 1α (HIF-1α), and hypoxia-induced mRNA splicing factors, such as RBM25 and LUC7L3, were elevated in human CHF tissue and mediated in vitro truncation of SCN5A mRNA.

Thus, this study is designed to test whether SCN5A mRNA processing is altered in OSA patients, which may contribute to their increased arrhythmic risk, and whether processing of SCN5A mRNA is modulated by CPAP treatment.

SPECIFIC AIMS

1. Compare sodium channel splicing variants in mild, moderate, or severe OSA patients at baseline to at 1 month after CPAP treatment. In addition, the baseline splicing variants of SCN5A in the OSA patients will be compared to an age-matched control group.
2. Hypoxia-associated upstream regulators of SCN5a mRNA splicing, HIF-1α, RBM25 and LUC7L3, will be examined in OSA patients before and after 1 month of CPAP treatment.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Brown University, Lifespan

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

OSA Eligibility Criteria:

1. Age greater than 18 years
2. Able to provide informed consent
3. New diagnosis of OSA by polysomnogram
4. Agree with CPAP treatment

Control Eligibility Criteria:

1. Age greater than 18 years
2. Without OSA
3. Able to provide informed consent

Exclusion Criteria:

1. Not able to give informed consent due to psychological incapacity
2. Chronic use of hypnotics for more than 6 weeks
3. Current drug or alcohol addiction
4. Rhythm other than sinus at enrollment
5. Mandatory and biventricular pacing
6. History of heart transplant or left ventricular assist device (LVAD)
7. Active use of intravenous vasodilators, vasopressors or inotropes
8. Hemodialysis or peritoneal dialysis
9. Active infection including bacteremia
10. Acute coronary syndrome (ACS) within 6 weeks
11. Major trauma or surgery within 6 weeks
12. Malignant neoplastic disease on active treatment including chemotherapy and radiation therapy, or life expectancy less than 1 year
13. Collagen vascular disease on active treatment including steroids and other immunomodulating drugs
14. Systemic steroid use within 6 weeks
15. Concomitant use of investigational drug within 6 weeks

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; An age-matched control group will be enrolled and consented. A Data Collection Sheet will be used to document data from the subject's medical records including history, physical exam, active medications, laboratory data, polysomnogram, electrocardiogram, echocardiography and cardiac catheterization. At the time of enrollment, one blood drawn through peripheral venipuncture will be collected. Another blood drawn will be collected after one month. The blood samples will be processed and analyzed to assess for levels of SCN5A mRNA splicing variants.
Active Comparator: OSA; Newly diagnosed OSA patients will be enrolled and consented. A Data Collection Sheet will be used to document data from the patient's medical records including history, physical exam, active medications, laboratory data, polysomnogram, electrocardiogram, echocardiography and cardiac catheterization. At the time of enrollment, one blood drawn through peripheral venipuncture will be collected. The patients on CPAP treatment will be followed-up for 1 month. Another blood drawn will be collected after one month of CPAP treatment. The blood samples will be processed and analyzed to assess for levels of SCN5A mRNA splicing variants.	Device: CPAP; The patients on CPAP treatment will be followed-up for 1 month.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The levels of sodium channel splicing variants that are related to the severity of OSA, change from baseline to one month after CPAP treatment.	Four weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
The levels of potassium channels that are related to the severity of OSA, change from baseline to one month after CPAP treatment.	Four weeks

Collaborators and Investigators

• Sponsor: Rhode Island Hospital
• Collaborators: University of Illinois at Chicago
• Investigators: Principal Investigator: Richard Millman, MD, Rhode Island Hospital

Publications and helpful links

General Publications

• Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O'Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, Wilson M, Hong Y; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008 Jan 29;117(4):e25-146. doi: 10.1161/CIRCULATIONAHA.107.187998. Epub 2007 Dec 17. No abstract available. Erratum In: Circulation. 2010 Jul 6;122(1):e10. Kissela, Bret [corrected to Kissela, Brett].
• Hunt SA; American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2005 Sep 20;46(6):e1-82. doi: 10.1016/j.jacc.2005.08.022. No abstract available. Erratum In: J Am Coll Cardiol. 2006 Apr 7;47(7):1503-1505.
• Kannel WB, Plehn JF, Cupples LA. Cardiac failure and sudden death in the Framingham Study. Am Heart J. 1988 Apr;115(4):869-75. doi: 10.1016/0002-8703(88)90891-5.

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): March 1, 2017

Study Registration Dates

• First Submitted: March 14, 2016
• First Submitted That Met QC Criteria: March 31, 2016
• First Posted (Estimate): April 1, 2016

Study Record Updates

• Last Update Posted (Actual): April 26, 2017
• Last Update Submitted That Met QC Criteria: April 25, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: sleep apnea syndrome; Sodium channel; splicing variant
• 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
• Other Study ID Numbers: 411013

Plan for Individual participant data (IPD)

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