Rationale:: Understanding atrial fibrillation (AF) requires integrated understanding of ionic currents and Ca ²⁺ transport in remodeled human atrium, but appropriate models are limited. Objective:: To study AF, we developed a new human atrial action potential (AP) model, derived from atrial experimental results and our human ventricular myocyte model. Methods and Results:: Atria versus ventricles have lower I _K1 , resulting in more depolarized resting membrane potential (≈7 mV). We used higher I _to,fast density in atrium, removed I _to,slow , and included an atrial-specific I _Kur . I _NCX and I _NaK densities were reduced in atrial versus ventricular myocytes according to experimental results. SERCA function was altered to reproduce human atrial myocyte Ca ²⁺ transients. To simulate chronic AF, we reduced I _CaL , I _to , I _Kur and SERCA, and increased I _K1 ,I _Ks and I _NCX . We also investigated the link between Kv1.5 channelopathy, [Ca ²⁺ ] _i , and AF. The sinus rhythm model showed a typical human atrial AP morphology. Consistent with experiments, the model showed shorter APs and reduced AP duration shortening at increasing pacing frequencies in AF or when I _CaL was partially blocked, suggesting a crucial role of Ca ²⁺ and Na ⁺ in this effect. This also explained blunted Ca ²⁺ transient and rate-adaptation of [Ca ²⁺ ] _i and [Na ⁺ ] _i in chronic AF. Moreover, increasing [Na ⁺ ] _i and altered I _NaK and I _NCX causes rate-dependent atrial AP shortening. Blocking I _Kur to mimic Kv1.5 loss-of-function increased [Ca ²⁺ ] _i and caused early afterdepolarizations under adrenergic stress, as observed experimentally. Conclusions:: Our study provides a novel tool and insights into ionic bases of atrioventricular AP differences, and shows how Na ⁺ and Ca ²⁺ homeostases critically mediate abnormal repolarization in AF.

Rationale:: In heart failure Ca/calmodulin kinase (CaMK)II expression and reactive oxygen species (ROS) are increased. Both ROS and CaMKII can increase late I _Na leading to intracellular Na accumulation and arrhythmias. It has been shown that ROS can activate CaMKII via oxidation. Objective:: We tested whether CaMKIIδ is required for ROS-dependent late I _Na regulation and whether ROS-induced Ca released from the sarcoplasmic reticulum (SR) is involved. Methods and Results:: 40 μmol/L H ₂ O ₂ significantly increased CaMKII oxidation and autophosphorylation in permeabilized rabbit cardiomyocytes. Without free [Ca] _i (5 mmol/L BAPTA/1 mmol/L Br ₂ -BAPTA) or after SR depletion (caffeine 10 mmol/L, thapsigargin 5 μmol/L), the H ₂ O ₂ -dependent CaMKII oxidation and autophosphorylation was abolished. H ₂ O ₂ significantly increased SR Ca spark frequency (confocal microscopy) but reduced SR Ca load. In wild-type (WT) mouse myocytes, H ₂ O ₂ increased late I _Na (whole cell patch-clamp). This increase was abolished in CaMKIIδ ^−/− myocytes. H ₂ O ₂ -induced [Na] _i and [Ca] _i accumulation (SBFI [sodium-binding benzofuran isophthalate] and Indo-1 epifluorescence) was significantly slowed in CaMKIIδ ^−/− myocytes (versus WT). CaMKIIδ ^−/− myocytes developed significantly less H ₂ O ₂ -induced arrhythmias and were more resistant to hypercontracture. Opposite results (increased late I _Na , [Na] _i and [Ca] _i accumulation) were obtained by overexpression of CaMKIIδ in rabbit myocytes (adenoviral gene transfer) reversible with CaMKII inhibition (10 μmol/L KN93 or 0.1 μmol/L AIP [autocamtide 2–related inhibitory peptide]). Conclusions:: Free [Ca] _i and a functional SR are required for ROS activation of CaMKII. ROS-activated CaMKIIδ enhances late I _Na , which may lead to cellular Na and Ca overload. This may be of relevance in hear failure, where enhanced ROS production meets increased CaMKII expression.

Compartmentalized cAMP/PKA signalling is now recognized as important for physiology and pathophysiology, yet a detailed understanding of the properties, regulation and function of local cAMP/PKA signals is lacking. Here we present a fluorescence resonance energy transfer (FRET)-based sensor, CUTie, which detects compartmentalized cAMP with unprecedented accuracy. CUTie, targeted to specific multiprotein complexes at discrete plasmalemmal, sarcoplasmic reticular and myofilament sites, reveals differential kinetics and amplitudes of localized cAMP signals. This nanoscopic heterogeneity of cAMP signals is necessary to optimize cardiac contractility upon adrenergic activation. At low adrenergic levels, and those mimicking heart failure, differential local cAMP responses are exacerbated, with near abolition of cAMP signalling at certain locations. This work provides tools and fundamental mechanistic insights into subcellular adrenergic signalling in normal and pathological cardiac function.

Calcium/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase expressed abundantly in the heart. CaMKII targets numerous proteins involved in excitation-contraction coupling and excitability, and its activation may simultaneously contribute to heart failure and cardiac arrhythmias. In this review, we summarize the modulatory effects of CaMKII on cardiac ion channel function and expression and illustrate potential implications in the onset of arrhythmias via a computer model.