tacrolimus and Tachycardia--Supraventricular

CONTEXT Tacrolimus is a potent immunosuppressive drug often administered to transplant recipient patients and exhibits a variety of adverse cardiovascular effects. CASE REPORT We report a case of a 53-year-old Asian female who developed various arrhythmic phenomena including atrial premature complexes and supraventricular tachycardia after administration of tacrolimus. CONCLUSION Tacrolimus-associated arrhythmia after kidney transplantation may be life-threatening, and so patients undergoing this procedure should be carefully monitored.

Topics: Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Tachycardia, Supraventricular; Tacrolimus

Atrial tachycardia (AT) downregulates L-type Ca(2+) current (I(CaL)) and causes atrial fibrillation-promoting electric remodeling. This study assessed potential underlying signal transduction. Cultured adult canine atrial cardiomyocytes were paced at 0, 1, or 3 Hz (P0, P1, P3) for up to 24 hours. Cellular tachypacing (P3) mimicked effects of in vivo AT: decreased I(CaL) and transient outward current (I(to)), unchanged I(CaT), I(Kr), and I(Ks), and reduced action potential duration (APD). I(CaL) was unchanged in P3 at 2 and 8 hours but decreased by 55+/-6% at 24 hours. Tachypacing caused Ca(2+)(i) accumulation in P3 cells at 2 to 8 hours, but, by 24 hours, Ca(2+)i returned to baseline. Ca(v)1.2 mRNA expression was not altered at 2 hours but decreased significantly at 8 and 24 hours (32+/-4% and 48+/-4%, respectively) and protein expression was decreased (47+/-8%) at 24 hours only. Suppressing Ca(2+)(i) increases during tachypacing with the I(CaL) blocker nimodipine or the Ca(2+) chelator BAPTA-AM prevented I(CaL) downregulation. Calcineurin activity increased in P3 at 2 and 8 hours, respectively, returning to baseline at 24 hours. Nuclear factor of activated T cells (NFAT) nuclear translocation was enhanced in P3 cells. Ca(2+)-dependent signaling was probed with inhibitors of Ca(2+)/calmodulin (W-7), calcineurin (FK-506), and NFAT (INCA6): each prevented I(CaL) downregulation. Significant APD reductions ( approximately 30%) at 24 hours in P3 cells were prevented by nimodipine, BAPTA-AM, W-7, or FK-506. Thus, rapid atrial cardiomyocyte activation causes Ca(2+) loading, which activates the Ca(2+)-dependent calmodulin-calcineurin-NFAT system to cause transcriptional downregulation of I(CaL), restoring Ca(2+)i to normal at the cost of APD reduction. These studies elucidate for the first time the molecular feedback mechanisms underlying arrhythmogenic AT remodeling.

Topics: Action Potentials; Animals; Calcineurin; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Signaling; Calmodulin; Cardiac Pacing, Artificial; Cells, Cultured; Chelating Agents; Dogs; Egtazic Acid; Heart Atria; Myocytes, Cardiac; NFATC Transcription Factors; Nimodipine; Potassium; RNA, Messenger; Sulfonamides; Tachycardia, Supraventricular; Tacrolimus; Time Factors; Transcription, Genetic

Topics: Female; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Tachycardia, Supraventricular; Tacrolimus