Abstract
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.
Highlights
Triggered arrhythmia originates from early (EADs) and delayed (DADs) afterdepolarizations on the cellular level (Damiano and Rosen, 1984; Levine et al, 1985; January and Riddle, 1989)
There is a lack of studies, which directly compare proarrhythmic substrates and their molecular basis in atrial versus ventricular cardiomyocytes of murine models, which appears unexpected in the face of the high clinical and translational relevance of atrial arrhythmia and the widespread use of murine models in the research of atrial arrhythmia
Since murine models are frequently used in translational research on atrial arrhythmia, but data on the manifestation of proarrhythmic afterdepolarizations in atrial myocytes and their differences to ventricular myocytes is sparse, we investigated afterdepolarizations and their molecular bases in atrial and ventricular myocytes in a murine model
Summary
Triggered arrhythmia originates from early (EADs) and delayed (DADs) afterdepolarizations on the cellular level (Damiano and Rosen, 1984; Levine et al, 1985; January and Riddle, 1989). Murine models are frequently used to investigate proarrhythmic substrates or to evaluate potential antiarrhythmic strategies to counter atrial arrhythmia even on multicellular or whole-heart level (Bao et al, 2016; Syeda et al, 2016; Wan et al, 2016; Chang et al, 2017; Wang et al, 2017). There is a lack of studies, which directly compare proarrhythmic substrates and their molecular basis in atrial versus ventricular cardiomyocytes of murine models, which appears unexpected in the face of the high clinical and translational relevance of atrial arrhythmia and the widespread use of murine models in the research of atrial arrhythmia. 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
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