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