The document summarizes a study that used a computational model of ventricular myocytes to evaluate the effect of small-conductance calcium-activated potassium (SK) channels on failing cardiac cells. The model included 20,000 calcium release units and simulated changes in failing cells. Adding SK channels to failing cells with T-tubule disruption caused earlier calcium alternans and varying severity of alternans depending on SK conductance. Therefore, upregulation of SK channels has proarrhythmic effects in failing myocytes with T-tubule disruption. Future work is needed to better understand mechanisms and translate single-cell effects to tissue-level models.

1. To evaluate the effect of SK on failing ventricular cells, a
spatiotemporal calcium cycling ventricular myocyte
model was used consisting of a network of 20,000 Ca
Release Units (CRUs)3
.Ionic changes from the normal
cell to the failing cell were taken from Ponnaluri et al4
.
T-tubule disruption was modeled by moving RyR
clusters at random from the dyadic calcium space into
the myoplasm to simulate the real loss of physical
structure seen in HF.
The SK channel was modeled as:
Where gSK
is the conductance of the channel, EK
is the
Nernst potential of potassium, and Cai
is the
cytoplasmic calcium concentration. h is the half-maxial
concentration constant, which is different between
healthy and failing hearts:
hnormal
= 0.605
hfailing
= 0.320
Simulations were
conducted on Tesla
K20c GPUs (NVIDIA
Corporation).
Arrhythmogenic Effects of Ca-activated Small-Conductance Potassium Channels in
Failing Myocytes
Introduction
Imesh C. Samarakoon, Michael B Liu, Alan Garfinkel, James N. Weiss, Zhilin Qu
Department of Medicine (Cardiology), University of California, Los Angeles, California 90095, USA
Results
Heart Failure (HF) is the number one cause of hospitalization in people over the age of 65, and Sudden Cardiac Death (SCD) from lethal arrhythmias is the leading cause of
death in early to mid-stage HF. HF has been previously characterized by changes in various ionic currents, and the presence of T-tubule disruption (TTD), which orphans RyR
Clusters due to the loss of the physical geometrical structure of the T-tubule.
Among the channels upregulated in HF are Small Conductance Calcium-Gated Potassium Channels, more commonly known as SK channels. The channel is strongly blocked by
the drug apamin, but normally the channels have negligible effects upon the behavior of healthy ventricles. However, there is substantial upregulation of SK2 channels in
Epicardial and Endocardial cells in HF. SK has been shown to have both proarrhythmic and antiarrhythmic consequences under different circumstances.
This study provides insights into SK2 induced behaviors in failing ventricular cells, as well as apamin’s possible role as an antiarrhythmic agent.
Materials and Methods
Normal Cell Failing without TTD Failing with TTD
PCL=500ms
6
Conclusions
● Under the effects of T-tubule disruption, the
addition of an SK current can generate calcium
alternans at slower pacing.
● At slower pacing, the addition of the SK current
to a cell with T-tubule disruption can cause
varying severity of alternans depending on the
strength of the SK current.
● Addition of SK to a failing cell with T-tubule
disruption results in earlier alternans.
● SK has a proarrhythmic effect.
1
- = Normal
- = HF w/o TTD
- = HF w/ TTD
- = no SK
- = SK
The addition of SK has proarrhthymic effects when the myocyte has t-tubule disruption. We currently have no mechanism to explain
the oscillations in alternans magnitude seen in the failing cell with t-tubule disruption as SK conductance i increased.
When a cell has t-tubule disruption, the addition of SK initiates alternans earlier.
2
5
gSK
=0.005
[1] Chua et al, Circ Res 2011
[2] Hsieh et al, Circ Arrhythm Electrophys 2013
[3] Nivala et al, Frontiers Physiology 2012
[4] Ponnaluri et al, PLOS Computational Biology
2016
[5] Guo et al, Cardiovascular Res 2013
[6] Chang et al, JAHA 2013
As expected, the heart failure cell model has a longer action potential, with a larger and slower calcium transient. T-tubule disruption
potentiates the action potential further, and makes the calcium transient even larger and slower. Since the SK current is an inward
potassium current, it abbreviates the action potential. Upregulation of the channel can result in voltage and calcium alternans under
different conditions.
Future Work
● For future studies, we would like to evaluate
how the inclusion of a time delay within the SK
channel gates would affect behavior.
Preliminary single-cell simulations suggest that
a time delay is needed for calcium alternans in
certain cases.
● We would like to elucidate the mechanism by
which oxcillations occur in alternans magnitude
when a failing cell has its SK conductance
gradually increased.
● Additionally, we would like to discern how
SK-induced behaviors in the single cell model
translate to phenomena in the spatio-temporal
1-D cable.
References