Alternans in Mouse Atrial Cardiomyocytes: A Computational Study on the Influence of Cell-Cell Coupling and β-Adrenergic Stimulation

Abstract

Cardiac alternans is a dynamical phenomenon in cardiomyocytes, which is linked to the genesis of cardiac mechanical dysfunction and lethal arrhythmias. The beat-to-beat alteration may occur in the amplitude of Ca2+ transients (CaT) or the action potential duration (APD). Typically, APD alternans is a secondary consequence of the CaT alternans and the generation of CaT alternans is relevant to the imbalance of the sarcoplasmic reticulum (SR) Ca2+ release and uptake. However, the effect of cell-cell coupling and $\beta $ -adrenergic receptor ($\beta $ -AdR) stimulation on the initiation and inhibition of CaT alternans is not fully understood. Here, we used a biophysically detailed mathematical model of the mouse atrial myocyte to study the mechanism underlying alternans and the effects of $\beta $ -AdR stimulation. The cell exhibited obvious CaT alternans under fast pacing due to sarcolemmal Ca2+ flux imbalance leaded SR Ca2+ flux imbalance, while no noticeable APD alternans was seen. The $\beta $ -AdR agonist isoproterenol (ISO) inhibited CaT alternans by its regulatory role on amplifying the L-type Ca2+ current. On a one-dimensional strand, cell-cell coupling indirectly alleviated CaT alternans by affecting the overshoot and APD, reducing the triggered SR Ca2+ release. Variation in the cell-cell coupling did not change the pattern of CaT alternans or interfere with the alternans inhibitory effect of $\beta $ -AdR stimulation. Taken together, our results imply a potentially anti-arrhythmic effect of $\beta $ -AdR stimulation and shed new light on the mechanisms behind the cardiac alternans.

Keywords

• Alternans
• Calcium
• gap junction
• β-adrenergic receptor stimulation