Distinct gene-specific mechanisms of arrhythmia revealed by cardiac gene transfer of two long QT disease genes, HERG and KCNE1
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Key result
In vivo gene transfer of the KCNE1-D76N mutant markedly suppressed IKs and prolonged the QTc interval by approximately 23% in guinea pigs, whereas the HERG-G628S mutant suppressed IKr and increased beat-to-beat variability leading to early afterdepolarizations without prolonging the QT interval.
Why the study?
Does in vivo gene transfer of HERG and KCNE1 mutants alter cardiac repolarization in adult guinea pigs?
Population
Adult guinea pigs (200-250 g)
Comparison
Intramyocardial injection of adenoviral vectors… vs Noninfected myocytes or immediate postoperative…
Design
Preclinical
Follow-up
48-72 hours
Authors
Discussion
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Implication
Preclinical guinea pig models show distinct IKs vs IKr effects on repolarization; hypothesis-generating for genotype-specific LQTS mechanisms pending human validation.
Structured PICO
Does in vivo gene transfer of HERG and KCNE1 mutants alter cardiac repolarization in adult guinea pigs?
P
Population
Adult guinea pigs subjected to intramyocardial adenovirus injection to express wild-type or LQT mutants of HERG and KCNE1, evaluated at 48-72 hours.
I
Intervention
Intramyocardial injection of adenoviral vectors expressing wild-type or LQT mutants of HERG (HERG-G628S) and KCNE1 (KCNE1-D76N)
C
Comparator
Noninfected myocytes or immediate postoperative baseline
O
Outcome
Electrophysiological properties (IKr, IKs, action potential duration, refractoriness, beat-to-beat variability) and in vivo QTc interval at 48-72 hourssurrogate
Main Result
Absolute Event Rate: 353.3% vs 286.7%
p-value: p=0.04
Somatic gene transfer of LQTS mutants HERG-G628S and KCNE1-D76N in guinea pigs reveals distinct arrhythmogenic mechanisms, demonstrating the utility of in vivo gene transfer for creating genotype-specific disease models.
Limitations
- The relative contribution of different ionic currents to repolarization is variable between species, so IKs suppression may not entirely undermine repolarization in humans.
- Survival rate and long-term risk for arrhythmias were not evaluated as endpoints in this study.
- Survival rate was not an endpoint
- Relative contribution of different ionic currents to repolarization is variable between species
Cite This Study
Hoppe et al. (2001) studied Long QT syndrome (LQTS). Adenoviral gene transfer of HERG and KCNE1 mutants vs. Noninfected cells or immediate postoperative baseline was evaluated on QTc interval duration (KCNE1-D76N mutant vs baseline) (p=0.04). In vivo gene transfer of the KCNE1-D76N mutant markedly suppressed IKs and prolonged the QTc interval by approximately 23% in guinea pigs, whereas the HERG-G628S mutant suppressed IKr and increased beat-to-beat variability leading to early afterdepolarizations without prolonging the QT interval.
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