tacrolimus and Tachycardia--Ventricular

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.

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

A 42-year-old woman who underwent single lung transplantation who received tacrolimus and a 58-year-old woman with pneumonia and multiple comorbidities who received haloperidol both experienced drug-induced prolongation of cardiac repolarization. The second woman also developed torsade de pointes. Critically ill patients are particularly susceptible to developing torsade de pointes due to various comorbidities, electrolyte disturbances, and receipt of numerous drugs. These two case reports illustrate the increased risk for drug-induced cardiotoxicity in the critically ill patient. They also indicate the need for current knowledge derived from basic research and retrospective case reports on drug-induced torsade de pointes to be integrated into the existing body of knowledge. Guidelines can then be developed to help prospectively reduce the frequency of adverse effects in intensive care patients. Research is necessary regarding identification of high-risk patients before drugs are administered, and clarification of the proper role of therapeutic QT monitoring in clinical practice.

Topics: Administration, Oral; Adult; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Electrocardiography; Female; Haloperidol; Heart Conduction System; Humans; Hypertension, Pulmonary; Injections, Intravenous; Long QT Syndrome; Middle Aged; Pneumonia; Tachycardia, Ventricular; Tacrolimus; Torsades de Pointes