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.