Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome
Michael Brunner, … , Manfred Zehender, Gideon Koren
Michael Brunner, … , Manfred Zehender, Gideon Koren
Published May 8, 2008
Citation Information: J Clin Invest. 2008;118(6):2246-2259. https://doi.org/10.1172/JCI33578.
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Research Article Cardiology

Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome

Abstract

Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of IKs and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type α subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.

Authors

Michael Brunner, Xuwen Peng, Gong Xin Liu, Xiao-Qin Ren, Ohad Ziv, Bum-Rak Choi, Rajesh Mathur, Mohammed Hajjiri, Katja E. Odening, Eric Steinberg, Eduardo J. Folco, Ekatherini Pringa, Jason Centracchio, Roland R. Macharzina, Tammy Donahay, Lorraine Schofield, Naveed Rana, Malcolm Kirk, Gary F. Mitchell, Athena Poppas, Manfred Zehender, Gideon Koren

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Figure 6

Cellular electrophysiology.

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Cellular electrophysiology. (A) APD of rabbit ventricular myocytes. Left...
(A) APD of rabbit ventricular myocytes. Left panel shows typical action potential recordings (0.1 Hz) from LMC, LQT1, and LQT2 rabbits. Right shows averaged APD (APD90, mean ± SEM) of LMC (354.05 ± 30.07 ms, n = 22), LQT1 (499.88 ± 45.71 ms, n = 14), and LQT2 rabbits (533.14 ± 54.22 ms, n = 14); *P < 0.05. (B) Isolation and quantification of IKr and IKs. Left panel shows original recordings of control, LQT1, and LQT2 rabbits as indicated. After a recording without drugs (a), the cells were perfused with 5 μM E-4031 (b) and IKr was defined as the E4031-sensitive current (d). Secondary to E4031 application, the cells were further perfused with 30 μM chromanol 293B (c) and IKs was defined as chromanol-sensitive current (e). Right panels shows quantification of IKr and IKs . Current amplitudes measured at the end of repolarization (IKs or IKr) and the peak of the tail (IKs tail or IKr tail) were plotted against membrane voltages. All currents were normalized to cell capacitance. Open circles depict control myocytes (n = 20 from 6 rabbits), filled circles depict LQT1 myocytes (n = 17 from 5 rabbits), and filled triangles depict LQT2 myocytes (n = 12 from 3 rabbits). The downregulation of IKr (in LQT1) or IKs (in LQT2) was significant compared with controls (P < 0.05 by 2-way ANOVA). (C) Ito current and IK1 currents. Standard current-voltage relationship (IV curve) of Ito (left panel) or quasi-IV curve of IK1 (right panel) revealed no significant differences in peak Ito currents (n = 6–8) or IK1 currents (right, n = 10–12) among LMC, LQT1, and LQT2 rabbits.