Aims: Atrial fibrillation (AF) has been associated with the down-regualtion of L-type calcium current (I_Ca) and up-regulation of spontaneous calcium release from the sarcoplasmic reticulum (SR). Here we tested the hypothesis that these changes in calcium handling are associated with the remodelling of cyclic AMP (cAMP)-dependent signalling in AF.

Methods and Results: Patch-clamp recordings revealed a higher frequency of transient inward currents (I_TI) activated by spontaneous calcium release in myocytes from 46 patients with AF than in 86 without AF (1.9±0.3/min vs. 1.1±0.2/min, p<0.05), and protein kinase A inhibition with H-89 had a stronger effect in AF-patients (3.2±1.5 to 0.1±0.1/min) than in patients without AF (1.3±0.6 to 0.2±0.1/min). Furthermore, the β-agonist isoproterenol (ISO) increased I_TI 13.3-fold in patients without AF (0.2±0.1 to 2.9±1.2/min, p<0.01) but only 4.6-fold in AF (0.8±0.2 to 3.7±1.1/min, p<0.05). Inmunofluorescent labelling showed that ISO also increased the ratio of ser2808 phosphorylated : total ryanodine receptors. At baseline I_Ca was larger in patients without AF (2.1±0.1 vs. 1.4±0.1 pA/pF in AF, p<0.05), and H-89 reduced I_Ca in AF-free patients (from 2.4±0.4 to 1.4±0.3pA/pF, p=0.001) to levels recorded in AF-patients without and with H-89 (1.4±0.4 and 1.2±0.4pA/pF). Interestingly, Calmodulin kinase II inhibition significanly reduced I_Ca by 32% but had no effect on I_TI, and the treatment of either patient group with beta-blockers did not modify I_Ca density or I_TI frequency.

Conclusion: Our results associated atrial fibrillation with opposite changes in cAMP-dependent regulation of I_Ca (downregulation) and spontaneous SR calcium release (upregulation) but these changes  not affected by the treatment with β-blockers.