Logo

American Heart Association

  2
  0


Final ID: MDP1252

Fluoxetine, a Novel Therapeutic Strategy for Early Repolarization Syndrome Caused by a KCND3 Gain-of-Function Variant

Abstract Body (Do not enter title and authors here): Introduction: Kv4.3 encoded by KCND3 is an α-subunit of the Ito channel and is highly expressed in both brain and heart. Several KCND3 variants have been shown to be related to inherited arrhythmias and neurological disorders. We have reported a gain-of-function (GOF) KCND3 variant, p.G306A, which was identified in a young patient with early repolarization syndrome (ERS) and refractory epilepsy (RE). The variant increased peak current densities and slowed inactivation of Ito. Micromolar quinidine inhibited increased Ito and accelerated its delayed inactivation. In addition, administration of quinidine to our patient prevented his lethal arrhythmia and epileptic attack. Thus, the suppression of increased Ito can be an effective treatment for ERS and RE. However, it remains unknown if other medicine except for quinidine is effective to suppress the GOF effect on Ito.
Hypothesis: Selective serotonin reuptake inhibitor, fluoxetine which has inhibitory effect for Ito normalizes the GOF effect caused by KCND3 variants.
Aims: To utilize the fluoxetine for the treatment of ERS and RE, we aimed to elucidate the pharmacological effect of fluoxetine on Kv4.3-G306A comparing those to Kv4.3-wild type (WT).
Methods: Plasmids with Kv4.3 WT or G306A were transiently transfected to Chinese Hamster Ovary cells with KChIP2, and reconstituted Ito was measured using whole-cell patch-clamp method at 370C degrees. Fluoxetine loading at 1-100 µM was applied externally.
Results: The peak current densities of Ito at +50 mV were 135.7±19.8 for WT and 321.0±116.7 pA/pF for G306A, and they were decreased to 101.1±20.9 and 199.6±63.6 pA/pF by application of 20 µM fluoxetine (Figure A and B). Fluoxetine inhibited Ito peak current with IC50 of 41.6±7.1 µM for WT and 83.7±16.7 µM for G306A. Although the inactivation in G306A was significantly slower than WT, they were almost normalized after 20 µM fluoxetine application (Figure A and Table). The inhibition effect of fluoxetine was concentration dependent for both peak current densities and inactivation time constants.
Conclusion: Fluoxetine rescued the GOF effect on Ito reconstituted by KCND3 G306A variant, suggesting that fluoxetine could be an effective therapeutic for ERS and RE.
  • Byambajav, Tserenlkham  ( National Cerebral and Cardiovascular Center , Suita , Japan )
  • Takayama, Koichiro  ( National Cerebral and Cardiovascular Center , Suita , Japan )
  • Zankov, Dimitar  ( National Cerebral and Cardiovascular Center , Suita , Japan )
  • Horie, Minoru  ( Shiga University of Medical Science , Otsu , Japan )
  • Ohno, Seiko  ( National Cerebral and Cardiovascular Center , Suita , Japan )
  • Author Disclosures:
    Tserenlkham Byambajav: DO NOT have relevant financial relationships | Koichiro Takayama: DO NOT have relevant financial relationships | Dimitar Zankov: No Answer | Minoru Horie: No Answer | Seiko Ohno: No Answer
Meeting Info:

Scientific Sessions 2024

2024

Chicago, Illinois

Session Info:

The Return of Antiarrhythmic Drug Therapy: A New Age with New Therapeutics

Sunday, 11/17/2024 , 11:10AM - 12:35PM

Moderated Digital Poster Session

More abstracts on this topic:
A Curious Complete Heart Block with Carfilzomib

Shah Mohammed, Rahman Naveed, Al-mohamad Talal, Batra Sejal, Vyas Apurva

1-year comparison of quadruple therapy sequencing strategies for heart failure with reduced ejection fraction using an individual-based state-transition microsimulation model

Turgeon Ricky, Van Minh Tri, Loewen Peter, Hawkins Nathaniel, Sadatsafavi Mohsen, Zhang Wei, Mackay Kelly

You have to be authorized to contact abstract author. Please, Login
Not Available