# SK current and ventricular arrhythmias.

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $557,134

## Abstract

The broad and long term goal of this research project is to explore the roles of small conductance Ca2+-
activated K (SK) channels in the mechanisms of ventricular arrhythmogenesis. We hypothesize that the SK
current upregulation is an endogenous compensatory mechanism to protect the heart from arrhythmias related
to reduced repolarization reserve, but under some conditions can result in excess repolarization reserve and
proarrhythmic effects. The SK channel became a focus of our research after we discovered that the apamin-
sensitive potassium current (IKAS, or SK current) is increased in both the rabbit and human ventricles with heart
failure (HF). We also discovered that SK current is acutely increased in normal ventricles with hypokalemia, in
a manner that depends on the ventricular activation sequence. These findings raise the intriguing possibility
that SK current is a rescue current that compensates for the electrophysiological effects of increased
intracellular Ca2+ load. While maintaining repolarization reserve in HF may be antiarrhythmic, we also found
that excessive or heterogeneous shortening of the APD by SK current may be proarrhythmic. Our recent
preliminary results indicate that IKAS is activated by isoproterenol, and that female rabbit ventricles express
more SK current during early phase 2 than male ventricles. CyPPA activation of SK2 and SK3 causes ECG J
point elevation, heterogeneous APD distribution, phase 2 reentry and spontaneous VF in normal rabbit
ventricles. The latter finding suggests that SK current may also contribute to proarrhythmia in certain clinical
conditions by creating excess repolarization reserve, such as in the J-wave syndromes. The incorporation of
IKAS in computer models will generate important new insights into the dynamical effects of IKAS in ventricular
repolarization. A combined mapping and computer simulation approach will be needed to fully understand the
importance of IKAS in cardiac arrhythmogenesis, including both the proarrhythmic and antiarrhythmic potentials.
We propose the following specific aims: Aim 1: Antiarrhythmic and proarrhythmic mechanisms of SK current in
rabbit ventricles. The Aim 1A is designed to study the Purkinje cells (PCs) in both normal and failing rabbit
ventricles to test the hypothesis that the SK current is increased in PCs and that blocking the SK current
decreases the Ca2+-membrane potential coupling gain and promotes Ca2+ induced arrhythmias. The Aim 1B is
designed to study SK current and J-wave syndrome. We hypothesize that (a) SK current is in part responsible
for J-wave elevation and VF during hypothermia, and apamin reverses these proarrhythmic effects and (b)
heterogeneous SK current activation can cause J wave elevation and spontaneous VF through heterogeneous
shortening of APD and phase 2 reentry. Aim 2: Antiarrhythmic and proarrhythmic mechanisms of SK current in
computer simulation. Aim 2A will systematically investigate the mechanisms of SK currents as a resc...

## Key facts

- **NIH application ID:** 9838804
- **Project number:** 5R01HL139829-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** PENG-SHENG CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $557,134
- **Award type:** 5
- **Project period:** 2017-12-15 → 2020-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838804

## Citation

> US National Institutes of Health, RePORTER application 9838804, SK current and ventricular arrhythmias. (5R01HL139829-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9838804. Licensed CC0.

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