A major role for HERG in determining frequency of reentry in neonatal rat ventricular myocyte monolayer.
BACKGROUND
the rapid delayed rectifier potassium current, I(Kr), which flows through the human ether-a-go-go-related (hERG) channel, is a major determinant of the shape and duration of the human cardiac action potential (APD). However, it is unknown whether the time dependency of I(Kr) enables it to control APD, conduction velocity (CV), and wavelength (WL) at the exceedingly high activation frequencies that are relevant to cardiac reentry and fibrillation.


OBJECTIVE
to test the hypothesis that upregulation of hERG increases functional reentry frequency and contributes to its stability.


RESULTS
using optical mapping, we investigated the effects of I(Kr) upregulation on reentry frequency, APD, CV, and WL in neonatal rat ventricular myocyte (NRVM) monolayers infected with GFP (control), hERG (I(Kr)), or dominant negative mutant hERG G628S. Reentry frequency was higher in the I(Kr)-infected monolayers (21.12 ± 0.8 Hz; n=43 versus 9.21 ± 0.58 Hz; n=16; P<0.001) but slightly reduced in G628S-infected monolayers. APD(80) in the I(Kr)-infected monolayers was shorter (>50%) than control during pacing at 1 to 5 Hz. CV was similar in both groups at low frequency pacing. In contrast, during high-frequency reentry, the CV measured at varying distances from the center of rotation was significantly faster in I(Kr)-infected monolayers than controls. Simulations using a modified NRVM model predicted that rotor acceleration was attributable, in part, to a transient hyperpolarization immediately following the AP. The transient hyperpolarization was confirmed experimentally.


CONCLUSIONS
hERG overexpression dramatically accelerates reentry frequency in NRVM monolayers. Both APD and WL shortening, together with transient hyperpolarization, underlies the increased rotor frequency and stability.
Center for Arrhythmia Research, University of Michigan, 5025 Venture Dr, Ann Arbor, MI 48108, USA.
Luqia
L
Hou
Makarand
M
Deo
Philip
P
Furspan
Sandeep V
SV
Pandit
Sergey
S
Mironov
David S
DS
Auerbach
Qiuming
Q
Gong
Zhengfeng
Z
Zhou
Omer
O
Berenfeld
José
J
Jalife
D000200:Action Potentials; D000818:Animals; D000831:Animals, Newborn; D018076:DNA, Complementary; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology*; D007700:Kinetics; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000502:physiology*; D011188:Potassium / Q000378:metabolism; D051381:Rats; D013611:Tachycardia, Atrioventricular Nodal Reentry; D054139:Tachycardia, Reciprocating; D014162:Transfection; D014693:Ventricular Fibrillation
D018076:DNA, Complementary; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D011188:Potassium