Caffeine-induced arrhythmias in murine hearts parallel changes in cellular Ca2+ homeostasis

Heart failure leading to ventricular arrhythmogenesis is a major cause of clinical mortality and has been associated with a leak of sarcoplasmic reticular Ca2+ into the cytosol due to increased open probabilities in cardiac ryanodine receptor Ca2+-release channels. Caffeine similarly increases such open probabilities, and so we explored its arrhythmogenic effects on intact murine hearts. A clinically established programmed electrical stimulation protocol adapted for studies of isolated intact mouse hearts demonstrated that caffeine ( 1 mM) increased the frequency of ventricular tachycardia from 0 to 100% yet left electrogram duration and latency unchanged during programmed electrical stimulation, thereby excluding slowed conduction as a cause of arrhythmogenesis. We then used fluorescence measurements of intracellular Ca2+ concentration in isolated mouse ventricular cells to investigate parallel changes in Ca2+ homeostasis associated with these arrhythmias. Both caffeine ( 1 mM) and FK506 ( 30 mu M) reduced electrically evoked cytosolic Ca2+ transients yet increased the frequency of spontaneous Ca2+-release events. Diltiazem ( 1 mu M) but not nifedipine ( 1 mu M) pretreatment suppressed these increases in frequency. Identical concentrations of diltiazem but not nifedipine correspondingly suppressed the arrhythmogenic effects of caffeine in whole hearts. These findings thus directly implicate spontaneous Ca2+ waves in triggered arrhythmogenesis in intact hearts.