Atrial fibrillation (AF) is the most common arrhythmia with a prevalence of 1-2% of the US population and it is the most important single risk factor for an ischemic stroke. Despite decades of research, successful termination of the arrhythmia remains difficult. The challenge is in part due to our incomplete understanding of atrial myocyte Ca2+ signaling and underlying disease mechanisms. In the atria, like all cardiac tissue, the conducted action potential (AP) underlies triggering of the [Ca2+]i transient, which is responsible for activating contraction. The process that links electrical activity to Ca2+ signaling and contraction is known as excitation-contraction coupling (ECC).

The objective of this dissertation is to understand the mechanism of excitation contraction coupling in atrial myocytes. To achieve this goal, we (1) developed tools to specifically study atrial cell biology, (2) we studied the role of altered Ca2+ buffering on ionic membrane currents and Ca2+ signaling, (3) we investigated the role that reactive oxygen species (ROS) plays in altered Ca2+ signaling and the morphology of the AP and (4) we measured intracellular sodium concentration ([Na+]i ) and studied Na+ and Ca2+ signaling in a transgenic murine model of AF. This work includes mathematical modeling of atrial cell electrical and Ca2+ signaling to define our quantitative understanding of the processes involved.

Our results indicate that increased Ca2+ buffering plays a major role in speeding the inactivation of the L type Ca2+ current (ICa,L ). This work also shows that low concentrations of H2O2 for a brief period increases atrial Ca2+ spark rate, changes spark characteristics and decreases the duration of the AP. We quantified for the first time the [Na+]i in murine atrial cells both at rest and during field stimulation in control and transgenic mice. Our results indicate that [Na+]i is significantly lower in atrial myocytes in comparison to their ventricular counterparts, which reveal important differences in how [Na+]i is regulated in atrial cells. Moreover, our work demonstrates that [Na+]i and [Ca2+]i homeostasis are profoundly affected during AF. The results further our understanding of mechanisms that modulate excitation-contraction coupling in atrial myocytes in normal and pathophysiological conditions.