Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT

London, Barry; Baker, Linda C.; Petkova-Kirova, Polina; Nerbonne, Jeanne M.; Choi, Bum‐Rak; Salama, Guy

doi:10.1113/jphysiol.2006.122622

Cited by 40 publications

(46 citation statements)

References 48 publications

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“…In congenital or acquired human LQTS, increased spatial dispersion of repolarization plays a major role in propagating and maintaining malignant arrhythmias (37,38), and EADs due to prolonged APD have been assumed to trigger these arrhythmias. Experimental models in transgenic mice have shown increased apexto-base dispersion of repolarization underlying mouse arrhythmias (17,39), and pharmacological LQT models in rabbits and dogs have reproduced this finding as transmural dispersion of repolarization in wedge preparations (40)(41)(42)(43). Studies in experimental models (43,44), in mathematical simulations (45,46), and in affected humans with LQTS (47) have demonstrated the occurrence of phase 2 and 3 EADs in vitro, in silico, and in vivo, hinting toward M cells and/or Purkinje fibers as the origin of EADs (44,46).…”

Section: Discussionmentioning

confidence: 99%

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

Brunner¹,

Peng²,

Liu³

et al. 2008

J. Clin. Invest.

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144

277

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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 I Ks and I Kr 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 I Kr and I Ks 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.

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Section: Discussionmentioning

confidence: 99%

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

Brunner¹,

Peng²,

Liu³

et al. 2008

J. Clin. Invest.

Self Cite

144

277

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“…Although AP prolongation underlying prolongation of the QT interval could promote reentrant arrhythmias through early afterdepolarizations (EADs) [as in Torsade de Pointes (53)], mice studies reveal that QT prolongation alone is not sufficient to create a proarrhythmic substrate and that gradients of refractoriness across the wall of the ventricle (epicardium to endocardium) as well as along the wall (base to apex) reflecting differential expression of ion channels (2,12,39) are critical to assess arrhythmia vulnerability (58). A most conspicuous example are Kv4.2DN dominant-negative TG mice, lacking a major repolarization current, the rapidly recovering component of I to .…”

Section: Differences In Aps and Ca 2ϩ Handling In Isolated Ventriculamentioning

confidence: 99%

“…A most conspicuous example are Kv4.2DN dominant-negative TG mice, lacking a major repolarization current, the rapidly recovering component of I to . These mice have a significant prolongation of AP in isolated myocytes and QT intervals in electrocardiogram recordings (5) but show an anti-arrhythmic phenotype due to uniform refractory periods along the epicardium (39). Our simulations confirmed a protective role for AP prolongation in TNF-␣-overexpressing mice: in the model tissue with TG AP and WT conductance, reentry was triggered in a smaller time window for S2 (ϳ0.01 ms) compared with WT tissue with normal AP and conduction (ϳ0.12 ms), and the resulting reentry was not sustained.…”

Section: Differences In Aps and Ca 2ϩ Handling In Isolated Ventriculamentioning

confidence: 99%

Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α

Petkova-Kirova

London

Salama

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Transgenic mice overexpressing tumor necrosis factor-α (TNF-α mice) possess many of the features of human heart failure, such as dilated cardiomyopathy, impaired Ca2+ handling, arrhythmias, and decreased survival. Although TNF-α mice have been studied extensively with a number of experimental methods, the mechanisms of heart failure are not completely understood. We created a mathematical model that reproduced experimentally observed changes in the action potential (AP) and Ca2+ handling of isolated TNF-α mice ventricular myocytes. To study the contribution of the differences in ion currents, AP, Ca2+ handling, and intercellular coupling to the development of arrhythmias in TNF-α mice, we further created several multicellular model tissues with combinations of wild-type (WT)/reduced gap junction conductance, WT/prolonged AP, and WT/decreased Na+ current ( INa) amplitude. All model tissues were examined for susceptibility to Ca2+ alternans, AP propagation block, and reentry. Our modeling results demonstrated that, similar to experimental data in TNF-α mice, Ca2+ alternans in TNF-α tissues developed at longer basic cycle lengths. The greater susceptibility to Ca2+ alternans was attributed to the prolonged AP, resulting in larger inactivation of INa, and to the decreased SR Ca2+ uptake and corresponding smaller SR Ca2+ load. Simulations demonstrated that AP prolongation induces an increased susceptibility to AP propagation block. Programmed stimulation of the model tissues with a premature impulse showed that reduced gap junction conduction increased the vulnerable window for initiation reentry, supporting the idea that reduced intercellular coupling is the major factor for reentrant arrhythmias in TNF-α mice.

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“…Regional differences in current densities 15 have been suggested to contribute to the native transmural repolarization gradient. 21 There were also marked regional differences in the cellular effects of LVH. The reduction in I peak densities was more pronounced in TAC EPI, than ENDO, LV myocytes in spite of the fact that meanϮSEM C m was higher in TAC ENDO cells (Figure 4A through 4C and the Table).…”

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confidence: 99%

Distinct Cellular and Molecular Mechanisms Underlie Functional Remodeling of Repolarizing K ⁺ Currents With Left Ventricular Hypertrophy

Marionneau

Brunet

Flagg

et al. 2008

Circulation Research

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102

126

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Abstract-Left ventricular hypertrophy (LVH) is associated with electric remodeling and increased arrhythmia risk, although the underlying mechanisms are poorly understood. In the experiments here, functional voltage-gated (Kv) and inwardly rectifying (Kir) K ϩ channel remodeling was examined in a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC). Action potential durations (APDs) at 90% repolarization in TAC LV myocytes and QT c intervals in TAC mice were prolonged. Mean whole-cell membrane capacitance (C m ) was higher, and I to,f , I K,slow , I ss , and I K1 densities were lower in TAC, than in sham, LV myocytes. Although the primary determinant of the reduced current densities is the increase in C m , I K,slow amplitudes were decreased and I ss amplitudes were increased in TAC LV cells. Further experiments revealed regional differences in the effects of LVH. Cellular hypertrophy and increased I ss amplitudes were more pronounced in TAC endocardial LV cells, whereas I K,slow amplitudes were selectively reduced in TAC epicardial LV cells. Consistent with the similarities in I to,f and I K1 amplitudes, Kv4.2, Kv4.3, and KChIP2 (I to,f ), as well as Kir2.1 and Kir2.2 (I K1 ), transcript and protein expression levels were similar in TAC and sham LV. Unexpectedly, expression of I K,slow channel subunits Kv1.5 and Kv2.1 was increased in TAC LV. Biochemical experiments also demonstrated that, although total protein was unaltered, cell surface expression of TASK1 was increased in TAC LV. Functional changes in repolarizing K ϩ currents with LVH, therefore, result from distinct cellular (cardiomyocyte enlargement) and molecular (alterations in the numbers of functional channels) mechanisms. (Circ Res. 2008;102:1406-1415.)Key Words: hypertrophy Ⅲ arrhythmia Ⅲ heart failure L eft ventricular hypertrophy (LVH) is an adaptive response of the myocardium to an increase in load. 1 LVH is seen in various disease states including hypertension and myocardial infarction, as well as in valvular and congenital heart diseases. 1 LVH is also observed in physiological states following rigorous, prolonged exercise. 2 Although physiological LVH does not confer increased morbidity and mortality, pathological LVH is consistently associated with prolongation of ventricular action potentials and alterations in the dispersion of repolarization, both of which result in electric instability and increase the propensity to develop lifethreatening arrhythmias. 3 Several lines of evidence suggest that these electric changes reflect, at least in part, alterations in the functioning of the K ϩ channels that underlie ventricular action potential repolarization. 3,4 Various experimental models of LVH, 5-7 including pressure overload-induced LVH, 8,9 have been developed to explore the mechanisms underlying K ϩ current remodeling.Although several studies have examined regional differences in remodeling, 8 -11 few have probed the underlying molecular and cellular mechanisms. In the studies here, a mouse mo...

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Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT

Cited by 40 publications

References 48 publications

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

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

Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α

Distinct Cellular and Molecular Mechanisms Underlie Functional Remodeling of Repolarizing K ⁺ Currents With Left Ventricular Hypertrophy

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Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT

Cited by 40 publications

References 48 publications

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

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

Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α

Distinct Cellular and Molecular Mechanisms Underlie Functional Remodeling of Repolarizing K + Currents With Left Ventricular Hypertrophy

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Distinct Cellular and Molecular Mechanisms Underlie Functional Remodeling of Repolarizing K ⁺ Currents With Left Ventricular Hypertrophy