Abstract
Clusters of ryanodine receptors within atrial myocytes are confined to spatially separated layers. In many species, these layers are not juxtaposed by invaginations of the plasma membrane (transverse tubules; ‘T-tubules’), so that calcium-induced-calcium signals rely on centripetal propagation rather than voltage-synchronized channel openings to invade the interior of the cell and trigger contraction. The combination of this specific cellular geometry and dynamics of calcium release can lead to novel autonomous spatio-temporal calcium waves, and in particular ping waves. These are waves of calcium release activity that spread as counter-rotating sectors of elevated calcium within a single layer of ryanodine receptors, and can seed further longitudinal calcium waves. Here we show, using a computational model, that these calcium waves can dominate the response of a cell to electrical pacing and hence are pro-arrhythmic. This highlights the importance of modeling internal cellular structures when investigating mechanisms of cardiac dysfunction such as atrial arrhythmia.
Highlights
The most common form of cardiac dysrhythmia in humans is “atrial fibrillation.” This pathology arises when electrical impulses occur spontaneously, and with high frequency, from sites around the atria
To explore the factors controlling Ca2+ homeostasis and signaling in atrial myocytes, we have developed a mathematical model based on the established geometry of the cells (Thul et al, 2012)
Following each systolic Ca2+ transient ryanodine receptor (RyR) are refractory for a period of time (DelPrincipe et al, 1999; Terentyev et al, 2002; Szentesi et al, 2004; Sobie et al, 2005; Ramay et al, 2011; Kornyeyev et al, 2012)
Summary
The most common form of cardiac dysrhythmia in humans is “atrial fibrillation.” This pathology arises when electrical impulses occur spontaneously, and with high frequency, from sites around the atria (typically 350 discharges per minute compared to the normal sinoatrial rhythm of 60–80 beats per minute; Dobrev, 2010). The most common form of cardiac dysrhythmia in humans is “atrial fibrillation.”. This pathology arises when electrical impulses occur spontaneously, and with high frequency, from sites around the atria (typically 350 discharges per minute compared to the normal sinoatrial rhythm of 60–80 beats per minute; Dobrev, 2010). Due to these irregular electrical discharges, the atria do not display coordinated contractions required to propel blood into the ventricles. The loss of atrial contraction can be debilitating when greater output from the heart is required, for example during physical exertion. Substantial evidence points to dysregulation of calcium (Ca2+) signaling as being a causal factor in genesis and maintenance of atrial fibrillation (Hove-Madsen et al, 2004; Dobrev and Nattel, 2008; Yeh et al, 2008; Wakili et al, 2010; Greiser et al, 2011)
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