TY - JOUR
T1 - A major role for hERG in determining frequency of reentry in neonatal rat ventricular myocyte monolayer
AU - Hou, Luqia
AU - Deo, Makarand
AU - Furspan, Philip
AU - Pandit, Sandeep V.
AU - Mironov, Sergey
AU - Auerbach, David S.
AU - Gong, Qiuming
AU - Zhou, Zhengfeng
AU - Berenfeld, Omer
AU - Jalife, José
PY - 2010/12/10
Y1 - 2010/12/10
N2 - Rationale: The rapid delayed rectifier potassium current, IKr, 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 IKr 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. Methods and results: Using optical mapping, we investigated the effects of IKr upregulation on reentry frequency, APD, CV, and WL in neonatal rat ventricular myocyte (NRVM) monolayers infected with GFP (control), hERG (IKr), or dominant negative mutant hERG G628S. Reentry frequency was higher in the IKr-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. APD80 in the IKr-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 IKr-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.
AB - Rationale: The rapid delayed rectifier potassium current, IKr, 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 IKr 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. Methods and results: Using optical mapping, we investigated the effects of IKr upregulation on reentry frequency, APD, CV, and WL in neonatal rat ventricular myocyte (NRVM) monolayers infected with GFP (control), hERG (IKr), or dominant negative mutant hERG G628S. Reentry frequency was higher in the IKr-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. APD80 in the IKr-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 IKr-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.
KW - delayed rectifier potassium channel
KW - hERG
KW - optical mapping
KW - reentry
KW - ventricular fibrillation
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U2 - 10.1161/CIRCRESAHA.110.232470
DO - 10.1161/CIRCRESAHA.110.232470
M3 - Article
C2 - 20947828
AN - SCOPUS:78650717034
SN - 0009-7330
VL - 107
SP - 1503
EP - 1511
JO - Circulation research
JF - Circulation research
IS - 12
ER -