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

Sleep Apnea Syndromes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02725632
• Other study ID #: 411013
• Status: Completed
• Phase: N/A
• First received: March 14, 2016
• Last updated: April 25, 2017
• Start date: August 2015
• Est. completion date: March 2017

Study information

• Verified date: April 2017
• Source: Rhode Island Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: March 2017
• Est. primary completion date: March 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Apnea
• Sleep Apnea Syndromes
• Sleep Apnea, Obstructive

Intervention

Device:
• CPAP
The patients on CPAP treatment will be followed-up for 1 month.

Locations

Country	Name	City	State
United States	Brown University, Lifespan	Providence	Rhode Island

Sponsors (2)

Lead Sponsor	Collaborator
Rhode Island Hospital	University of Illinois at Chicago

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. Review. Erratum in: J Am Coll Cardiol. 2006 Apr 7;47(7):1503-1505. — View Citation

Kannel WB, Plehn JF, Cupples LA. Cardiac failure and sudden death in the Framingham Study. Am Heart J. 1988 Apr;115(4):869-75. — View Citation

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. Epub 2007 Dec 17. Erratum in: Circulation. 2010 Jul 6;122(1):e10. Kissela, Bret [corrected to Kissela, Brett]. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	The levels of potassium channels that are related to the severity of OSA, change from baseline to one month after CPAP treatment.		Four weeks