Changes in ionic currents and reduced conduction velocity in hypertrophied ventricular myocardium of Xin alpha-deficient mice.
OBJECTIVE
mXin alpha, a downstream target gene of Nkx2.5 transcription factor, was shown to encode a proline-rich and Xin repeats-containing protein which localizes to the intercalated disc of adult hearts. Our previous voltage-clamp studies have shown that the ventricular myocytes of mXin alpha -deficient mice exhibited a significant reduction in K+ currents (Ito and IK1), L-type Ca2+ currents, and maximum diastolic potential, leading to the development of early afterdepolarization (EAD) and arrhythmias. However, changes in cationic inward currents could also contribute to the genesis of EAD and arrhythmias in mXin alpha -deficient mice.


METHODS
The present study aims to characterize changes in Na+ currents on depolarization and transient inward currents (Iti) on repolarization. Conduction velocity (CV) on the frontal surface of ventricles were also measured and compared.


RESULTS
Results of optical mapping on the Langendorff-perfused hearts at 37oC revealed a 36% reduction of CV in mXin alpha -/- ventricle. Pacing (3 Hz)-induced tachyarrhythmias were more frequently found and ventricular fibrillation (VF, 21 Hz for 5 min) occurred in one out of 8 mXin alpha-/- heart. When perfused at 30 degrees C, no VF was observed in both types of preparations. Voltage-clamp study on isolated ventricular myocytes at 37 degrees C shows increase in INa and Iti in mXin alpha -/- cardiomyocytes thus could explain the occurrence of re-entrant triggered arrhythmias.


CONCLUSIONS
The present results revealed that the CV was slower, but INa and Iti were increased in mXin alpha -/-cardiomyocytes thus were prone to reentrant triggered arrhythmias. Hypothermia could reduce the occurrence of arrhythmias.
Lai
Yu-Jun
YJ
Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.
Chen
Ya-Yu
YY
Cheng
Chio-Pei
CP
Lin
Jim Jung-Ching
JJ
Chudorodova
Svetlana L
SL
Roshchevskaya
Irina M
IM
Roshchevsky
Mikhail P
MP
Chen
Yao-Chang
YC
Lin
Cheng-I
CI
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D004268:DNA-Binding Proteins; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology*; D007473:Ion Channels / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D032342:Muscle Cells / Q000502:physiology; D009206:Myocardium / Q000166:cytology; D009687:Nuclear Proteins; D018408:Patch-Clamp Techniques
D004268:DNA-Binding Proteins; D007473:Ion Channels; D009687:Nuclear Proteins; C118478:Xin protein, mouse