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

¹Physiological Laboratory, ²Section of Cardiovascular Biology, Department of Biochemistry, and ³Department of Pharmacology, University of Cambridge, United Kingdom

Submitted 12 December 2004 ; accepted in final form 25 May 2005

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.

mouse; ryanodine receptor; programmed electrical stimulation; ventricular tachycardia; arrhythmia

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