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 μM) reduced electrically evoked cytosolic Ca2+ transients yet increased the frequency of spontaneous Ca2+-release events. Diltiazem (1 μM) but not nifedipine (1 μM) 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.
Limited value of programmed electrical stimulation in patients with hypertrophic cardiomyopathy — experience in 71 patients