Download 2015 department of medicine research day

2015 DEPARTMENT OF MEDICINE RESEARCH DAY
Title of Poster: Cellular Electrophysiology in Heart Failure: the Role of Small
Conductance Potassium (SK) Channels
Presenter: Imesh Samarakoon
Division: Cardiology
☐Faculty ☐Fellow ☐Resident ☐Post-doc Research Fellow ☐Graduate Student ☐Medical Student ☒Other (Undergraduate)
Principal Investigator/Mentor: Alan Garfinkel
Co-Investigators: Luigi Perotti, Aditya Ponnaluri, Michael Liu
Thematic Poster Category: Neurobiology, Smooth, Striated and Cardiac Muscle Function, Cardiac Conduction Systems
and Arrhythmias, Biology of Perception and Pain, Psychoneuroimmunology
Abstract
Arrhythmias, like ventricular fibrillation (VF), are a major cause of sudden cardiac death (SCD) in
patients with heart failure (HF), yet the mechanisms by which it manifests are not well understood.
Fibrillation, and other types of arrhythmias, are caused by alternans at the cellular and tissue level. In
order to better understand the onset of alternans in HF, we reformed our rabbit ventricular myocyte
model to simulate a HF cell. These reformations involved altered calcium release, decreased
transmural gradients, gap junction remodeling, later sodium inactivation, increased sodium-calcium
exchanger (INCX) current, and decreased potassium currents: slow and fast outward (Itos / Itof), delayed
rectifier (IKr), and inward rectifier (IK1). Simulations were run at the cellular level under various
experimental conditions in order to better tease out the mechanisms by which alternans can arise and
contribute to arrhythmias. The HF cell models produced the expected physiological results: lengthened
action potential durations (APD), lower and slower calcium transients, elevated intracellular sodium,
reduced transmural gradients, allowed for a steeper restitution curve and produced alternans earlier.
HF also involves the heterogeneous upregulation of small conductance calcium-activated potassium
(SK) channels. This channel potentially has important anti-arrhythmic and pro-arrhythmic effects
which are currently poorly understood. Experiments with failing rabbit hearts have shown that apamin,
a very selective SK blocker, can eliminate VF under rapid pacing. However, the administration of
apamin to ventricles under slower pacing resulted in early afterdepolarizations (EADs) and torsades de
pointes (TdP). We seek to use computer modeling as a tool to investigate this apparent paradox.
Equations to model the SK current were formulated, and parameter spaces of SK and other potassium
currents were searched to find robust parameter regions that matched experimented results. The
inclusion of an SK current in the HF cell model resulted in decreased APD and the earlier onset of
alternans. Understanding how the ionic changes in HF relate to the mechanisms of arrhythmogenesis
will enable future studies to improve the prevention and treatment of arrhythmias in HF.