Acute inhibition of the Na+/Ca2+ exchanger reduces proarrhythmia in an experimental model of chronic heart failure

Milberg, Peter; Pott, Christian; Frommeyer, Gerrit; Fink, Martin; Ruhe, M; Matsuda, Takehisa; Baba, Akemichi; Klocke, Rainer; Quang, Trong Hung; Nikol, Sigrid; Stypmann, Jörg; Osada, Nani; Müller, Frank; Breithardt, Günter; Noble, D; Eckardt, Lars

doi:10.1016/j.hrthm.2011.11.004

Cited by 43 publications

(38 citation statements)

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“…It is also the first study to investigate the effects of chronic and specific NCX inhibition on the generation of arrhythmia because synthetic NCX inhibitors lack specificity [19][20][21][22][23] and-to our knowledge-have only been applied acutely as single shot applications and not chronically in the investigation of arrhythmia. 23,24 …”

Section: Discussionmentioning

confidence: 99%

Suppression of Early and Late Afterdepolarizations by Heterozygous Knockout of the Na ⁺ /Ca ²⁺ Exchanger in a Murine Model

Bögeholz

Pauls

Bauer

et al. 2015

Circ: Arrhythmia and Electrophysiology

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Background-The Na + /Ca 2+ exchanger (NCX) has been implied to cause arrhythmias. To date, information on the role of NCX in arrhythmogenesis derived from models with increased NCX expression, hypertrophy, and heart failure. Furthermore, the exact mechanism by which NCX exerts its potentially proarrhythmic effect, ie, by promoting early afterdepolarization (EAD) or delayed afterdepolarization (DAD) or both, is unknown. Methods and Results-We investigated isolated cardiomyocytes from a murine model with heterozygous knockout of NCX (hetKO) using the patch clamp and Ca 2+ imaging techniques. Action potential duration was shorter in hetKO with I Ktot not being increased. The rate of spontaneous Ca 2+ release events and the rate of DADs were unaltered; however, DADs had lower amplitude in hetKO. A DAD triggered a spontaneous action potential significantly less often in hetKO when compared with wild-type. The occurrence of EADs was also drastically reduced in hetKO. I Ca activity was reduced in hetKO, an effect that was abolished in the presence of the Ca 2+ buffer BAPTA. Conclusions-Genetic suppression of NCX reduces both EADs and DADs. The following molecular mechanisms apply: (1) Although the absolute number of DADs is unaffected, an impaired translation of DADs into spontaneous action potentials results from a reduced DAD amplitude. (2) EADs are reduced in absolute number of occurrence, which is presumably a consequence of shortened action potential duration because of reduced NCX activity but also reduced I Ca the latter possibly being caused by a direct modulation of Ca 2+ -dependent I Ca inhibition by reduced NCX activity. This is the first study to demonstrate that genetic inhibition of NCX protects against afterdepolarizations and to investigate the underlying mechanisms. (Circ Arrhythm Electrophysiol.

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Section: Discussionmentioning

confidence: 99%

Suppression of Early and Late Afterdepolarizations by Heterozygous Knockout of the Na ⁺ /Ca ²⁺ Exchanger in a Murine Model

Bögeholz

Pauls

Bauer

et al. 2015

Circ: Arrhythmia and Electrophysiology

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“…Prior studies have demonstrated that a relatively specific inhibitor of the NCX, SEA-0400, suppressed dofetilide-induced torsade de pointes in anesthetized dogs (35) and in Langendorffperfused rabbit hearts with drug-and hypokalemia-induced models of LQT2 and LQT3 (36), possibly by reducing [Ca 2+ ] i ( Figure 6A). The efficacy of NCX inhibitors in AF, however, is unknown.…”

Section: Ncx Inhibition Reduces Frequency Of Atrial and Ventricular Amentioning

confidence: 94%

Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice

Wan¹,

Abrams²,

Weinberg³

et al. 2015

Journal of Clinical Investigation

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“…SEA0400 did not decrease QTc after dofetilide administration, and failed to prevent the development of Torsades de Pointes tachyarrhythmias (TdPs) in Langendorff-perfused rabbit hearts (30,32), while in another study it effectively reduced the amplitudes of EADs, without influencing APD (56). In contrast, Milberg et al reported considerable APD shortening effect of SEA0400, furthermore, sotalol or veratridine induced TdPs were also suppressed (57,60). Recently Jost et al (10) claimed that ORM-10103, a novel NCX inhibitor with improved selectivity decreased pharmacologically induced DADs and EADs, confirming previous results performed with SEA0400 (56).…”

Section: Transmural Heterogeneity In the Ventricular Myocardiummentioning

confidence: 90%

Characterization of different aspects of selective NCX inhibition in the heart

Kohajda

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Acute inhibition of the Na+/Ca2+ exchanger reduces proarrhythmia in an experimental model of chronic heart failure

Cited by 43 publications

References 36 publications

Suppression of Early and Late Afterdepolarizations by Heterozygous Knockout of the Na ⁺ /Ca ²⁺ Exchanger in a Murine Model

Suppression of Early and Late Afterdepolarizations by Heterozygous Knockout of the Na ⁺ /Ca ²⁺ Exchanger in a Murine Model

Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice

Characterization of different aspects of selective NCX inhibition in the heart

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Acute inhibition of the Na+/Ca2+ exchanger reduces proarrhythmia in an experimental model of chronic heart failure

Cited by 43 publications

References 36 publications

Suppression of Early and Late Afterdepolarizations by Heterozygous Knockout of the Na + /Ca 2+ Exchanger in a Murine Model

Suppression of Early and Late Afterdepolarizations by Heterozygous Knockout of the Na + /Ca 2+ Exchanger in a Murine Model

Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice

Characterization of different aspects of selective NCX inhibition in the heart

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Product

Resources

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Suppression of Early and Late Afterdepolarizations by Heterozygous Knockout of the Na ⁺ /Ca ²⁺ Exchanger in a Murine Model

Suppression of Early and Late Afterdepolarizations by Heterozygous Knockout of the Na ⁺ /Ca ²⁺ Exchanger in a Murine Model