Upregulation of KCNE1 induces QT interval prolongation in patients with chronic heart failure.
BACKGROUND
Prolongation of the action potential duration (APD) is observed in ventricular myocytes isolated from the failing heart. The rapid component (I(Kr)) and the slow component (I(Ks)) of the delayed-rectifier potassium current (I(K)) are major determinants of the APD, but less information is available on the genomic modulation of I(K) in the remodeled human heart. The aim of the current study was to examine the relationship between I(K) transcripts and QT interval in surface electrocardiogram in patients with chronic heart failure (CHF).


RESULTS
Total RNA was extracted from right ventricle endomyocardial biopsy samples in 21 CHF patients (age: 53+/-4 years, mean +/- SEM). The KCNH2 and KCNQ1 levels did not differ significantly between controls (New York Heart Association (NYHA) I, n=10) and CHF patients (NYHA II or III, n=11), whereas the KCNE1 level was significantly higher in CHF patients than in controls (relative mRNA levels normalized to GAPDH expression: 6.16+/-0.31 vs 7.70+/-0.46, p<0.05). The KCNE1/KCNQ1 ratio was higher in CHF patients than in controls (0.92+/-0.02 vs 1.06+/-0.05, p<0.05) and the KCNE1-KCNQ1 ratio was positively correlated with QT interval (r=0.70, p<0.05). Increasing the KCNE1 concentration caused a shift in activation voltage and slowed the activation kinetics of the KCNE1-KCNQ1 currents expressed in Xenopus oocytes. Prolongation of the APD and decrease in I(Ks) with increasing the amount of KCNE1 concentration were well predicted in a computer simulation.


CONCLUSIONS
In mild-to-moderate CHF patients, the relative abundance of KCNE1 compared to KCNQ1 genes, at least in part, might contribute to the preferential prolongation of QT interval through reducing the net outward current during the plateau of the action potential.
Watanabe
Eiichi
E
Division of Cardiology, Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake.
Yasui
Kenji
K
Kamiya
Kaichiro
K
Yamaguchi
Takahiro
T
Sakuma
Ichiro
I
Honjo
Haruo
H
Ozaki
Yukio
Y
Morimoto
Shinichiro
S
Hishida
Hitoshi
H
Kodama
Itsuo
I
D000200:Action Potentials / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002303:Cardiac Output, Low / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002908:Chronic Disease; D051668:Delayed Rectifier Potassium Channels / Q000235:genetics / Q000378:metabolism; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*; D014982:Xenopus laevis
D051668:Delayed Rectifier Potassium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger