Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene.
Long QT syndrome is the prototypical disorder of ventricular repolarization (VR), and a genotype-phenotype relation is postulated. Furthermore, although increased VR heterogeneity (dispersion) may be important in the arrhythmogenicity in long QT syndrome, this hypothesis has not been evaluated in humans and cannot be tested by conventional electrocardiography. In contrast, vectorcardiography allows assessment of VR heterogeneity and is more sensitive to VR alterations than electrocardiography. Therefore, vectorcardiography was used to compare the electrophysiological phenotypes of two mutations in the LQT1 gene with different in vitro biophysical properties, and with LQT2 mutation carriers and healthy control subjects. We included 99 LQT1 gene mutation carriers (57 Y111C, 42 R518X) and 19 LQT2 gene mutation carriers. Potassium channel function is in vitro most severely impaired in Y111C. The control group consisted of 121 healthy subjects. QRS, QT, and T-peak to T-end (Tp-e) intervals, measures of the QRS vector and T vector and their relationship, and T-loop morphology parameters were compared at rest. Apart from a longer heart rate-corrected QT interval (QT heart rate corrected according to Bazett) in Y111C mutation carriers, there were no significant differences between the two LQT1 mutations. No signs of increased VR heterogeneity were observed among the LQT1 and LQT2 mutation carriers. QT heart rate corrected according to Bazett and Tp-e were longer, and the Tp-e-to-QT ratio greater in LQT2 than in LQT1 and the control group. In conclusion, there was a marked discrepancy between in vitro potassium channel function and in vivo electrophysiological properties in these two LQT1 mutations. Together with previous observations of the relatively low risk for clinical events in Y111C mutation carriers, our results indicate need for cautiousness in predicting in vivo electrophysiological properties and the propensity for clinical events based on in vitro assessment of ion channel function alone.
Department of Public Health and Clinical Medicine, Heart Centre, Umeå University, Umeå, Sweden;
Ulla-Britt
UB
Diamant
Farzad
F
Vahedi
Annika
A
Winbo
Annika
A
Rydberg
Eva-Lena
EL
Stattin
Steen M
SM
Jensen
Lennart
L
Bergfeldt
D000200:Action Potentials; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006339:Heart Rate; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008133:Long QT Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011188:Potassium / Q000378:metabolism*; D029597:Romano-Ward Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013548:Sweden; D013997:Time Factors; D014672:Vectorcardiography; D055815:Young Adult
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D011188:Potassium
arrhythmia; diagnosis; electrocardiography; electrophysiology; genes; long QT syndrome; mutation