Triggered activity in atrial myocytes is influenced by Na+/Ca2+ exchanger activity in genetically altered mice

Bögeholz, Nils; Pauls, Paul; Kaese, Sven; Schulte, Jan S.; Lemoine, Marc D.; Dechering, Dirk G.; Frommeyer, Gerrit; Goldhaber, Joshua I.; Seidl, Matthias D.; Kirchhefer, Uwe; Eckardt, Lars; Müller, Frank; Pott, Christian

doi:10.1016/j.yjmcc.2016.11.004

Cited by 16 publications

(15 citation statements)

References 48 publications

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“…Investigated wild-type mice were on a combined genetic background (CD-1 and C57BL/6) as previously described ( Bögeholz et al, 2015 , 2016 ) at the age of 7.5–12.5 weeks. The applied experimental methods confirmed to the instructions of Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes and were approved by the local authorities (Landesamt für Natur, Umwelt und Verbraucherschutz NRW; permission number: 84-02.05.50.17.002).…”

Section: Methodsmentioning

confidence: 99%

Distinct Occurrence of Proarrhythmic Afterdepolarizations in Atrial Versus Ventricular Cardiomyocytes: Implications for Translational Research on Atrial Arrhythmia

et al. 2018

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Background: Principal mechanisms of arrhythmia have been derived from ventricular but not atrial cardiomyocytes of animal models despite higher prevalence of atrial arrhythmia (e.g., atrial fibrillation). Due to significant ultrastructural and functional differences, a simple transfer of ventricular proneness toward arrhythmia to atrial arrhythmia is critical. The use of murine models in arrhythmia research is widespread, despite known translational limitations. We here directly compare atrial and ventricular mechanisms of arrhythmia to identify critical differences that should be considered in murine models for development of antiarrhythmic strategies for atrial arrhythmia.Methods and Results: Isolated murine atrial and ventricular myocytes were analyzed by wide field microscopy and subjected to a proarrhythmic protocol during patch-clamp experiments. As expected, the spindle shaped atrial myocytes showed decreased cell area and membrane capacitance compared to the rectangular shaped ventricular myocytes. Though delayed afterdepolarizations (DADs) could be evoked in a similar fraction of both cell types (80% of cells each), these led significantly more often to the occurrence of spontaneous action potentials (sAPs) in ventricular myocytes. Interestingly, numerous early afterdepolarizations (EADs) were observed in the majority of ventricular myocytes, but there was no EAD in any atrial myocyte (EADs per cell; atrial myocytes: 0 ± 0; n = 25/12 animals; ventricular myocytes: 1.5 [0–43]; n = 20/12 animals; p < 0.05). At the same time, the action potential duration to 90% decay (APD90) was unaltered and the APD50 even increased in atrial versus ventricular myocytes. However, the depolarizing L-type Ca2+ current (ICa) and Na+/Ca2+-exchanger inward current (INCX) were significantly smaller in atrial versus ventricular myocytes.Conclusion: In mice, atrial myocytes exhibit a substantially distinct occurrence of proarrhythmic afterdepolarizations compared to ventricular myocytes, since they are in a similar manner susceptible to DADs but interestingly seem to be protected against EADs and show less sAPs. Key factors in the generation of EADs like ICa and INCX were significantly reduced in atrial versus ventricular myocytes, which may offer a mechanistic explanation for the observed protection against EADs. These findings may be of relevance for current studies on atrial level in murine models to develop targeted strategies for the treatment of atrial arrhythmia.

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Section: Methodsmentioning

confidence: 99%

Distinct Occurrence of Proarrhythmic Afterdepolarizations in Atrial Versus Ventricular Cardiomyocytes: Implications for Translational Research on Atrial Arrhythmia

et al. 2018

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“…Several changes favor the development of EADs in cAF, including SR Ca 2+ leak via RyR2 can promote I Ca,L reactivation, the upregulation of I Na,L , and enhancement of I NCX . 243, 253–255 Nevertheless, the potential role of late phase-3 EADs in the development of AF requires further investigation. Other mechanisms may contribute to the formation of triggered activity, including cytosolic Ca 2+ alternans (see below), which play a critical role in the initiation of AF in humans.…”

Section: Calcium-dependent Acquired Arrhythmiasmentioning

confidence: 99%

Calcium Signaling and Cardiac Arrhythmias

Landstrom

Dobrev

Wehrens

2017

Circulation Research

433

331

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There has been significant progress in our understanding of the molecular mechanisms by which calcium (Ca2+) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca2+-handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca2+ in normal cardiac function - in particular, excitation-contraction coupling and normal electrical rhythms. The functional involvement of Ca2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca2+-handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes.

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“…Generation of global homozygous NCX overexpressor (OE) (Adachi-Akahane et al, 1997 ) and heterozygous knockout (hetKO) (Jordan et al, 2010 ) mouse model has been described previously. The genetic background of OE mice is C57BL/6 (Pott et al, 2012 ), whereas hetKO mice are on a combined genetic background of C57BL/6 and CD-1 due to embryonic transfer (Bögeholz et al, 2016 ). Animals entering experimentation were <12.5 weeks of age, since up to this age there is no evidence for structural remodeling or heart failure in OE (Pott et al, 2012 ) or hetKO mice (Jordan et al, 2010 ; Bögeholz et al, 2015 ).…”

Section: Methodsmentioning

confidence: 99%

“…Experiments were performed at room temperature. The NCX function was assessed by the decay of caffeine (10 mM) induced Ca 2+ transients (Bassani et al, 1994 ; Bögeholz et al, 2015 , 2016 ) using fluo-4-AM (excitation: 488 nm, emission: 522 nm). The ratiometric fluorescent Ca 2+ indicator indo-1-AM was employed to record field-stimulated Ca 2+ transients and proarrhythmic spontaneous Ca 2+ activity (excitation: 344 nm, emission-ratio: 405/495 nm).…”

Section: Methodsmentioning

confidence: 99%

The Effects of SEA0400 on Ca2+ Transient Amplitude and Proarrhythmia Depend on the Na+/Ca2+ Exchanger Expression Level in Murine Models

et al. 2017

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Background/Objective: The cardiac Na+/Ca2+ exchanger (NCX) has been identified as a promising target to counter arrhythmia in previous studies investigating the benefit of NCX inhibition. However, the consequences of NCX inhibition have not been investigated in the setting of altered NCX expression and function, which is essential, since major cardiac diseases (heart failure/atrial fibrillation) exhibit NCX upregulation. Thus, we here investigated the effects of the NCX inhibitor SEA0400 on the Ca2+ transient amplitude and on proarrhythmia in homozygous NCX overexpressor (OE) and heterozygous NCX knockout (hetKO) mice compared to corresponding wild-types (WTOE/WThetKO).Methods/Results: Ca2+ transients of field-stimulated isolated ventricular cardiomyocytes were recorded with fluo-4-AM or indo-1-AM. SEA0400 (1 μM) significantly reduced NCX forward mode function in all mouse lines. SEA0400 (1 μM) significantly increased the amplitude of field-stimulated Ca2+ transients in WTOE, WThetKO, and hetKO, but not in OE (% of basal; OE = 98.7 ± 5.0; WTOE = 137.8 ± 5.2*; WThetKO = 126.3 ± 6.0*; hetKO = 140.6 ± 12.8*; *p < 0.05 vs. basal). SEA0400 (1 μM) significantly reduced the number of proarrhythmic spontaneous Ca2+ transients (sCR) in OE, but increased it in WTOE, WThetKO and hetKO (sCR per cell; basal/+SEA0400; OE = 12.5/3.7; WTOE = 0.2/2.4; WThetKO = 1.3/8.8; hetKO = 0.2/5.5) and induced Ca2+ overload with subsequent cell death in hetKO.Conclusion: The effects of SEA0400 on Ca2+ transient amplitude and the occurrence of spontaneous Ca2+ transients as a proxy measure for inotropy and cellular proarrhythmia depend on the NCX expression level. The antiarrhythmic effect of SEA0400 in conditions of increased NCX expression promotes the therapeutic concept of NCX inhibition in heart failure/atrial fibrillation. Conversely, in conditions of reduced NCX expression, SEA0400 suppressed the NCX function below a critical level leading to adverse Ca2+ accumulation as reflected by an increase in Ca2+ transient amplitude, proarrhythmia and cell death. Thus, the remaining NCX function under inhibition may be a critical factor determining the inotropic and antiarrhythmic efficacy of SEA0400.

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Triggered activity in atrial myocytes is influenced by Na+/Ca2+ exchanger activity in genetically altered mice

Cited by 16 publications

References 48 publications

Distinct Occurrence of Proarrhythmic Afterdepolarizations in Atrial Versus Ventricular Cardiomyocytes: Implications for Translational Research on Atrial Arrhythmia

Distinct Occurrence of Proarrhythmic Afterdepolarizations in Atrial Versus Ventricular Cardiomyocytes: Implications for Translational Research on Atrial Arrhythmia

Calcium Signaling and Cardiac Arrhythmias

The Effects of SEA0400 on Ca2+ Transient Amplitude and Proarrhythmia Depend on the Na+/Ca2+ Exchanger Expression Level in Murine Models

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