Na+ Channel mRNA Regulation in Heart Failure

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.

Completed

Looking for future studies?

Notify Me

Key information

Conditions

Heart Failure Cardiovascular Diseases Heart Diseases

Sex eligibility

All sexes

Study type

Observational

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

ischemic or non-ischemic cardiomyopathy Healthy Donor heart

Exclusion criteria

N/A

Not diagnosed with ischemic or non-ischemic cardiomyopathy

Treatment and study plan

No intervention is involved

Other

Primary outcomes

ion channel expression

Time frame: Baseline

mRNA and protein levels of cardiac ion channels, cardiac ion currents

Secondary outcomes

HuR change

Time frame: Baseline

mRNA, protein, phosphorylation, cleavage products, and localization

Sponsors and collaborators

Lead sponsor

University of Minnesota

Other

Registry information

Important dates

Study start: 2011
Primary completion: 2016
Study completion: 2021
First posted: Oct 18, 2017
Registry last updated: Mar 2, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Published trials that share one or more normalized conditions with this study.

Completed