Ignite Creation Date:
2024-05-06 @ 8:23 AM
Last Modification Date:
2024-10-26 @ 11:59 AM
Study NCT ID:
NCT02725632
Status:
COMPLETED
Last Update Posted:
2017-04-26
First Post:
2016-03-14
Brief Title:
Sodium Channel Splicing in Obstructive Sleep Apnea SOCS-OSA
Sponsor:
Rhode Island Hospital
Organization:
Rhode Island Hospital
Study Overview
Official Title:
Sodium Channel Splicing in Obstructive Sleep Apnea SOCS-OSA
Status:
COMPLETED
Status Verified Date:
2017-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
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
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 142 fold and 38 fold respectively in CHF patients compared to controls The full length SCN5A mRNA E28A was decreased by 247 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
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 142 fold and 38 fold respectively in CHF patients compared to controls The full length SCN5A mRNA E28A was decreased by 247 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None