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

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.

Development of a robust induced pluripotent stem cell atrial cardiomyocyte differentiation protocol to model atrial arrhythmia

“…S3B, C). The fixed cTnT+ cells from the Atrial (D1RA) differentiations were also significantly smaller than the fixed cells from the ventricular differentiations (7.9 µm vs. 13.4 µm, respectively), similar to what has been reported elsewhere [ 41 , 42 ], with relative profiles similar to freshly dissociated cells (Additional file 4 : Fig. S3A, D).…”

HFpEF and Atrial Fibrillation: The Enigmatic Interplay of Dysmetabolism, Biomarkers, and Vascular Endothelial Dysfunction

“…Similarly, we have shown that leptin levels were significantly lower in patients with HFpEF and AF as compared to HFpEF without AF [ 24 ]. The mechanisms by which leptin impacts atrial electrophysiology remain incompletely understood.…”

“…Moreover, the association of AF with the lower plasma concentrations of irisin may be due to the absence of irisin's inhibitory action on the sympathetic nervous system. Consequently, the imbalance in sympathetic tone to the heart creates a transitory dynamic proarrhythmogenic substrate which may trigger and initiate the AF [22][23][24].…”

Molecular Basis of Atrial Fibrillation Initiation and Maintenance

“…Basically, a DAD occurs in response to a spontaneous SR Ca 2+ release event, expanding as a Ca 2+ wave through the cytosol and depolarizing the membrane, due to part of Ca 2+ being expelled from the myocytes via Na + /Ca 2+ exchanger (NCX) [15,16]. Repetitive ectopic activity initiates atrial arrhythmias in myocytes [17] and in whole hearts [18]. Thus, the most prominent channels causing ectopic activity are the ones responsible of the magnitude of the SR Ca 2+ loading and release, the SR Ca 2+ ATPase (SERCA2a) and ryanodine receptor 2 (RyR2) [14].…”