Mechanism for Triggered Waves in Atrial Myocytes

Abstract

Excitation-contraction coupling in atrial cells is mediated by calcium (Ca) signaling between L-type Ca channels and Ryanodine receptors that occurs mainly at the cell boundary. This unique architecture dictates essential aspects of Ca signaling under both normal and diseased conditions. In this study we apply laser scanning confocal microscopy, along with an experimentally based computational model, to understand the Ca cycling dynamics of an atrial cell subjected to rapid pacing. Our main finding is that when an atrial cell is paced under Ca overload conditions, Ca waves can then nucleate on the cell boundary and propagate to the cell interior. These propagating Ca waves are referred to as "triggered waves" because they are initiated by L-type Ca channel openings during the action potential. These excitations are distinct from spontaneous Ca waves originating from random fluctuations of Ryanodine receptor channels, and which occur after much longer waiting times. Furthermore, we argue that the onset of these triggered waves is a highly nonlinear function of the sarcoplasmic reticulum Ca load. This strong nonlinearity leads to aperiodic response of Ca at rapid pacing rates that is caused by the complex interplay between paced Ca release and triggered waves. We argue further that this feature of atrial cells leads to dynamic instabilities that may underlie atrial arrhythmias. These studies will serve as a starting point to explore the nonlinear dynamics of atrial cells and will yield insights into the trigger and maintenance of atrial fibrillation.

Region-specific parasympathetic nerve remodeling in the left atrium contributes to creation of a vulnerable substrate for atrial fibrillation

“…For low I Ca conductance ( Figure 6A) we observed that the Ca 2+ transient and action potential (AP) was essentially periodic from beat-to-beat, and that Ca 2+ release occurred mainly at the cell boundary. As shown in our previous study (21), this response occurs because atrial myocytes have a poorly developed t-tubule system so that the bulk of Ca 2+ signaling occurs at the cell boundary. After a 10% increase in I Ca conductance ( Figure 6B), the Ca 2+ content in the cell is increased and Ca 2+ waves begin to penetrate into the cell interior intermittently.…”

“…These results demonstrate that sympathetic stimulation promotes an increased frequency of subcellular Ca 2+ waves that propagate inside the cell interior. These subcellular Ca 2+ waves have been studied extensively by our group (21,22) and have been shown to occur in normal atrial myocytes under rapid pacing conditions. In both cases, these waves originate under conditions of increased sarcoplasmic reticulum (SR) loading, where the interior of the atrial myocyte is sensitized and can support the propagation of Ca 2+ waves.…”

“…A spatially distributed atrial cell model. To model the spatiotemporal distribution of Ca 2+ in atrial myocytes, we implemented an established mathematical model by Restrepo et al (50,51), which was recently adapted by us to describe atrial myocytes (21). In this model, the cell interior is divided into a 3-D array of compartments that represent distinct intracellular spaces.…”

Alcoholism: A Multi-Systemic Cellular Insult to Organs

“…Heightened AF occurrence associated with elevated alcohol intake could be due to an increase in triggered atrial calcium waves induced by L-type calcium channels [ 38 ]. Thus, improper calcium channel expression and activity may contribute to alcohol-induced cardiomyopathy.…”

Alcoholism: A Multi-Systemic Molecular Insult to Organ Damage

“…al, 2017). This heightened AF occurrence with elevated alcohol intake could be due to an increase in triggered atrial calcium waves induced by L-type calcium channels (Shiferaw Y et al, 2017). Thus, improper calcium channel expression and activity may contribute to alcohol-induced cardiomyopathy.…”