Reduced delayed rectifier K+ current, altered electrophysiology, and increased ventricular vulnerability in MLP-deficient mice.
BACKGROUND
Mice with a knockout (KO) of muscle LIM protein (MLP) exhibit many morphologic and clinical features of human cardiomyopathy. In humans, MLP-expression is downregulated both in ischemic and dilative cardiomyopathy. In this study, we investigated the effects of MLP on the electrophysiologic phenotype in vivo and on outward potassium currents.


RESULTS
MLP-deficient (MLPKO) and wild-type (MLPWT) mice were subjected to long-term electrocardiogram (ECG) recording and in vivo electrophysiologic study. The whole-cell, patch-clamp technique was applied to measure voltage dependent outward K+ currents in isolated cardiomyocytes. Long-term ECG revealed a significant prolongation of RR mean (108 +/- 9 versus 99 +/- 5 ms), P (16 +/- 3 versus 14 +/- 1 ms), QRS (17 +/- 3 versus 13 +/- 1 ms), QT (68 +/- 8 versus 46 +/- 7 ms), QTc (66 +/- 6 versus 46 +/- 7 ms), JT (51 +/- 7 versus 34 +/- 7 ms), and JTc (49 +/- 5 versus 33 +/- 7 ms) in MLPKO versus MLPWT mice (P < .05). During EP study, QT (80 +/- 8 versus 58 +/- 7 ms), QTc (61 +/- 6 versus 45 +/- 5 ms), JT (62 +/- 9 versus 43 +/- 6 ms), and JTc (47 +/- 5 versus 34 +/- 5 ms) were also significantly prolonged in MLPKO mice (P < .05). Nonsustained VT was inducible in 9/16 MLPKO versus 2/15 MLPWT mice (P < .05). Analysis of outward K+ currents in revealed a significantly reduced density of the slowly inactivating outward K+ current IK, slow in MLPKO mice (11 +/- 5 pA/pF versus 18 +/- 7 pA/pF; P < .05).


CONCLUSIONS
Mice with KO of MLP exhibit significant prolongation of atrial and ventricular conduction and an increased ventricular vulnerability. A reduction in repolarizing outward K+ currents may be responsible for these alterations.
Gardiwal
Ajmal
A
Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
Klein
Gunnar
G
Kraemer
Kirsten
K
Durgac
Tolga
T
Koenig
Thorben
T
Niehaus
Michael
M
Heineke
Joerg
J
Mohammadi
Bahram
B
Krampfl
Klaus
K
Schaefer
Arnd
A
Wollert
Kai C
KC
Korte
Thomas
T
D000818:Animals; D051668:Delayed Rectifier Potassium Channels / Q000502:physiology*; D004594:Electrophysiology; D005260:Female; D060588:LIM Domain Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism*; D016276:Ventricular Function / Q000502:physiology
D051668:Delayed Rectifier Potassium Channels; D060588:LIM Domain Proteins; D009124:Muscle Proteins; C090114:cysteine and glycine-rich protein 3