Imaging atrial arrhythmic intracellular calcium in intact heart

Abnormalities in intracellular Ca²⁺ signaling have been proposed to play an essential role in the pathophysiology of atrial arrhythmias. However, a direct observation of intracellular Ca²⁺ in atrial myocytes during atrial arrhythmias is lacking. Here, we have developed an ex vivo model of simultaneous Ca²⁺ imaging and electrocardiographic recording in cardiac atria. Using this system we were able to record atrial arrhythmic intracellular Ca²⁺ activities. Our results indicate that atrial arrhythmias can be tightly linked to intracellular Ca²⁺ waves and Ca²⁺ alternans. Moreover, we applied this strategy to analyze Ca²⁺ signals in the hearts of WT and knock-in mice harboring a 'leaky' type 2 ryanodine receptor (RyR2-R2474S). We showed that sarcoplasmic reticulum (SR) Ca²⁺ leak increases the susceptibility to Ca²⁺ alternans and Ca²⁺ waves increasing the incidence of atrial arrhythmias. Reduction of SR Ca²⁺ leak via RyR2 by acute treatment with S107 reduced both Ca²⁺ alternans and Ca²⁺ waves, and prevented atrial arrhythmias.