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Na+ Channel mRNA Regulation in Heart Failure

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ClinicalTrials.gov Identifier: NCT03313882
Recruitment Status : Active, not recruiting
First Posted : October 18, 2017
Last Update Posted : March 25, 2019
Sponsor:
Information provided by (Responsible Party):
University of Minnesota

Brief 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.

Condition or disease Intervention/treatment
Heart Failure Other: no intervention is involved

Detailed 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.


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Study Type : Observational
Actual Enrollment : 48 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Na+ Channel mRNA Regulation in Heart Failure
Actual Study Start Date : August 2011
Actual Primary Completion Date : April 2016
Estimated Study Completion Date : August 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Group/Cohort Intervention/treatment
donor
donor: normal heart samples from donor
Other: no intervention is involved
ICM
ICM: heart samples with ischemic cardiomyopathy
Other: no intervention is involved
NICM
NICM: heart samples with non-ischemic cardiomyopathy
Other: no intervention is involved



Primary Outcome Measures :
  1. ion channel expression [ Time Frame: Baseline ]
    mRNA and protein levels of cardiac ion channels, cardiac ion currents


Secondary Outcome Measures :
  1. HuR change [ Time Frame: Baseline ]
    mRNA, protein, phosphorylation, cleavage products, and localization



Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
heart samples from healthy donor or from patients with ischemic or non-ischemic cardiomyopathy
Criteria

Inclusion Criteria:

  • ischemic or non-ischemic cardiomyopathy Healthy Donor heart

Exclusion Criteria: N/A

  • Not diagnosed with ischemic or non-ischemic cardiomyopathy

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Responsible Party: University of Minnesota
ClinicalTrials.gov Identifier: NCT03313882     History of Changes
Other Study ID Numbers: Study00001184
First Posted: October 18, 2017    Key Record Dates
Last Update Posted: March 25, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Minnesota:
RNA Stability
HuR protein
SCN5A
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases