Calcium- and voltage-driven atrial alternans: Insight from [Ca]_i and V_m asynchrony

Cardiac alternans is defined as beat-to-beat alternations in contraction strength, action potential duration (APD), and Ca transient (CaT) amplitude. Cardiac excitation-contraction coupling relies on the activity of two bidirectionally coupled excitable systems, membrane voltage (V_m ) and Ca release. Alternans has been classified as V_m - or Ca-driven, depending whether a disturbance of V_m or [Ca]_i regulation drives the alternans. We determined the primary driver of pacing induced alternans in rabbit atrial myocytes, using combined patch clamp and fluorescence [Ca]_i and V_m measurements. APD and CaT alternans are typically synchronized; however, uncoupling between APD and CaT regulation can lead to CaT alternans in the absence of APD alternans, and APD alternans can fail to precipitate CaT alternans, suggesting a considerable degree of independence of CaT and APD alternans. Using alternans AP voltage clamp protocols with extra APs showed that most frequently the pre-existing CaT alternans pattern prevailed after the extra-beat, indicating that alternans is Ca-driven. In electrically coupled cell pairs, dyssynchrony of APD and CaT alternans points to autonomous regulation of CaT alternans. Thus, with three novel experimental protocols, we collected evidence for Ca-driven alternans; however, the intimately intertwined regulation of V_m and [Ca]_i precludes entirely independent development of CaT and APD alternans.