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

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 <inline-formula> <tex-math notation="LaTeX">$\beta $ </tex-math></inline-formula>-adrenergic receptor (<inline-formula> <tex-math notation="LaTeX">$\beta $ </tex-math></inline-formula>-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 <inline-formula> <tex-math notation="LaTeX">$\beta $ </tex-math></inline-formula>-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 <inline-formula> <tex-math notation="LaTeX">$\beta $ </tex-math></inline-formula>-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 <inline-formula> <tex-math notation="LaTeX">$\beta $ </tex-math></inline-formula>-AdR stimulation. Taken together, our results imply a potentially anti-arrhythmic effect of <inline-formula> <tex-math notation="LaTeX">$\beta $ </tex-math></inline-formula>-AdR stimulation and shed new light on the mechanisms behind the cardiac alternans.