Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT03313882 |
Other study ID # |
Study00001184 |
Secondary ID |
|
Status |
Completed |
Phase |
|
First received |
|
Last updated |
|
Start date |
August 2011 |
Est. completion date |
August 1, 2021 |
Study information
Verified date |
February 2022 |
Source |
University of Minnesota |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Observational
|
Clinical Trial Summary
Human heart failure (HF) has been associated with reduced cardiac sodium channel current and
other electrical remodeling. Recently, the investigators have shown that downregulation of
cardiac Na+ channels (SCN5A) can contribute to arrhythmic risk and that upregulation can
mitigate that risk. Furthermore, the investigators have shown that the reduction in cardiac
SCN5A mRNA abundance is reflected in circulating white blood cells (WBCs), which also express
SCN5A, and that a reduction in SCN5A is highly predictive of appropriate implanted cardiac
defibrillator (ICD) therapy. These data suggest that SCN5A regulation contributes to
arrhythmic risk in HF. Other electrical remodeling events thought to contribute to arrhythmic
risk include reductions in K+ currents, including Ito, IK1 and IKs are responsible. These
current reductions have been linked to reduced transcription, translation and expression of
the corresponding channel subunits, such as Kv4.3, Kir2.1, KvLQT1, and accessory proteins
including minK and K+ channel interacting protein 2. That all these ion channels are
downregulated may suggest a common mechanism to reduce ion channel expression. In this
application, the investigators intend to explore an entirely novel mechanism by which SCN5A
and other ion channel mRNA abundances are reduced in HF.
Description:
Altered gene expression has been traditionally focused on transcriptional regulation.
Nevertheless, recent large-scale analyses have revealed that as many as half of all changes
in the amounts of mRNA in responses to cellular signals can be attributed to altered rates of
mRNA decay. In preliminary data, we show that HuR, a member of a class of RNA stabilizing
proteins that bind to AU-rich elements (ARE), is expressed in the heart and contributes to
Na+ channel mRNA stability by binding to SCN5A transcript. Furthermore, HuR appears to be
downregulated in human HF, perhaps contributing to the downregulation of ion channels and
increased arrhythmic risk seen in HF. We propose that HuR is downregulated in HF, that this
downregulation contributes to reduced Na+ and other currents and increased arrhythmic risk,
and that upregulation of HuR will reduce ion channel downregulations and arrhythmic risk in
HF. The investigators specific aims are:
Aim 1: Determine the extent to which HuR can regulate ion currents in cardiomyocytes.
Aim 2: Determine the relative contributions of known ion channel posttranscriptional control
mechanisms.
Aim 3: Determine the mechanism and extent to which HuR activity is downregulated in ischemic
and nonischemic cardiomyopathy and the correlation with ion channel mRNA, protein, and
current.
Aim 4: Determine the extent to which overexpression of HuR can raise ion channel mRNA, raise
ion channel current, and reduce arrhythmic risk in ischemic and nonischemic cardiomyopathy.
Please be notified that only Aim 2 involves the usage of de-identified human heart samples.