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

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