Abstract
Alternans is a risk factor for cardiac arrhythmia, including atrial fibrillation. At the cellular level alternans is observed as beat-to-beat alternations in contraction, action potential (AP) morphology and magnitude of the Ca2+ transient (CaT). It is widely accepted that the bi-directional interplay between membrane voltage and Ca2+ is crucial for the development of alternans, however recently the attention has shifted to instabilities in cellular Ca2+ handling, while the role of AP alternation remains poorly understood. This study provides new insights how beat- to-beat alternation in AP morphology affects occurrence of CaT alternans in atrial myocytes.Pacing-induced AP and CaT alternans were studied in rabbit atrial myocytes using combined Ca2+ imaging and electrophysiological measurements. To determine the role of AP morphology for the generation of CaT alternans, trains of two voltage commands in form of APs recorded during large and small alternans CaTs were applied to voltage-clamped cells. APs of longer duration (as observed during small amplitude alternans CaT) and especially beat-to-beat alternations in AP morphology (AP alternans) reduced the pacing frequency threshold and increased the degree of CaT alternans. AP morphology contributes to the development of CaT alternans by two mechanisms. First, the AP waveform observed during small alternans CaTs coincided with higher end-diastolic sarcoplasmic reticulum Ca2+ levels ([Ca2+]SR), and AP alternans resulted in beat-to-beat alternations in end-diastolic [Ca2+]SR. Second, L-type Ca2+ current was significantly affected by AP morphology, where the AP waveform observed during large CaT elicited L-type Ca2+ currents of higher magnitude and faster kinetics, resulting in more efficient triggering of SR Ca2+ release.In conclusion, alternation in AP morphology plays a significant role in the development and stabilization of atrial alternans. The demonstration that CaT alternans can be controlled or even prevented by modulating AP morphology has important ramifications for arrhythmia prevention and therapy strategies.
Highlights
Cardiac alternans is linked causally to cardiac arrhythmias, including atrial fibrillation [1,2,3,4], and sudden cardiac death [5,6,7]
To date the vast majority of the studies focusing on cardiac alternans mechanisms were performed on ventricular tissue, despite the established notion that atrial alternans is causally linked to atrial fibrillation, the most frequent cardiac arrhythmia [1,2,3,4]
While the importance of the bi-directional coupling between Vm and Ca2+ for the development of cardiac alternans is widely accepted and cannot be stressed enough, recently the attention has shifted to instabilities in cellular Ca2+ handling as the cause of alternans, leaving the role of Vm instabilities increasingly neglected
Summary
Cardiac alternans is linked causally to cardiac arrhythmias, including atrial fibrillation [1,2,3,4], and sudden cardiac death [5,6,7]. The demonstration that CaT alternans can be elicited in voltage-clamped myocytes without beat-to-beat variation in Vm [8, 15, 16] provided strong evidence that AP alternation is not an absolute requirement for CaT alternans to occur, and instabilities of Ca2+ handling that lead to alternans are an inherent property of the cardiac myocytes These observations cannot rule out a role of beat-to-beat alternations of membrane voltage dynamics for the development of cardiac alternans. Because of the complexity of the bi-directional coupling between Vm dynamics and intracellular Ca2+ handling the experimental distinction between effects of Ca2+ and Vm is complicated and experimental data on how AP morphology affects development of CaT alternans is scarce
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
