Caffeine-induced arrhythmias in murine hearts parallel changes in cellular Ca(2+) homeostasis

Richard Balasubramaniam, Sangeeta Chawla, Andrew A Grace, Christopher L-H Huang

Research output: Contribution to journalArticlepeer-review


Heart failure leading to ventricular arrhythmogenesis is a major cause of clinical mortality and has been associated with a leak of sarcoplasmic reticular Ca(2+) into the cytosol due to increased open probabilities in cardiac ryanodine receptor Ca(2+)-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 Ca(2+) concentration in isolated mouse ventricular cells to investigate parallel changes in Ca(2+) homeostasis associated with these arrhythmias. Both caffeine (1 mM) and FK506 (30 microM) reduced electrically evoked cytosolic Ca(2+) transients yet increased the frequency of spontaneous Ca(2+)-release events. Diltiazem (1 microM) but not nifedipine (1 microM) 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 Ca(2+) waves in triggered arrhythmogenesis in intact hearts.
Original languageEnglish
Pages (from-to)H1584-93
JournalAmerican journal of physiology. Heart and circulatory physiology
Issue number4
Publication statusPublished - 2005


  • Animals
  • Caffeine
  • Calcium
  • Calcium Channel Blockers
  • Cytosol
  • Diltiazem
  • Electric Stimulation
  • Homeostasis
  • Immunosuppressive Agents
  • Mice
  • Mice, Inbred Strains
  • Myocytes, Cardiac
  • Nifedipine
  • Perfusion
  • Phosphodiesterase Inhibitors
  • Ryanodine Receptor Calcium Release Channel
  • Tachycardia, Ventricular
  • Tacrolimus

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