Sinus Arrest During Tacrolimus Treatment: Was the Qt Interval Prolonged?

I read with great interest the letter by Sawabe et al.(1) documenting a case of sinus arrest accompanied by syncope and sinus tachycardia in a bone marrow recipient during tacrolimus and digitalis treatment. The authors were able to exclude pharmacokinetic interactions between two drugs because the serum digitalis concentration was lower than the therapeutic range; they also ruled out tacrolimus-related cardiomyopathy by an echocardiographic examination. Therefore, it was suggested that tacrolimus alone or in association with digitalis and cardiotoxic antineoplastic drugs induced severe bradycardia and sinus arrest. However, the authors reported the occurrence of sinus tachycardia, considered as an adverse effect of tacrolimus as well. Moreover, they also recorded by an electrocardiogram (ECG) Holter monitoring an escape junctional rhythm. First, it should be pointed that sinus tachycardia has never been indicated as a direct consequence of tacrolimus treatment; however, a clinical report demonstrates the occurrence of a prolonged QT interval and ventricular "torsade de pointes" tachycardia during the administration of this drug (2). The same electrocardiographic abnormalities have also been shown to occur during intravenous treatment with erythromycin, another macrolide antibiotic (3). The mechanism underlying these findings is unclear. Some experimental evidence suggests that tacrolimus prolongs action potential by the changes of outward potassium currents in ventricular myocytes (4,5). Interestingly, identical abnormality occurs in the setting of both congenital and acquired disorders characterized by a prolonged QT interval and ventricular arrhythmias(6-9). A similar circumstance could have occurred in the case reported by Sawabe et al.: Changes in the action potential duration induced by tacrolimus in the sinus node may induce severe bradycardia and sinus arrest. Moreover, a prolonged QT interval may result. It is well recognized that the QT interval on the surface ECG is an indirect measure of cardiac repolarization, and its prolongation may provide a substrate for ventricular arrhythmias(10). Indeed, a long QT interval is a predictor for ventricular arrhythmias, syncopal episodes, and sudden death in a variety of clinical conditions (11). Jackman et al.(12) reviewed the long QT syndromes and codified two groups: adrenergic-dependent, occurring in congenital syndromes, and pause-dependent, due to acquired conditions, such as drug toxicity, electrolyte imbalance, and severe bradyarrhythmias. Thus, the latter process may also take place during severe sinus node dysfunction. The prototype of arrhythmias occurring in the setting of long QT syndromes is torsade de pointes ventricular tachycardia, which is the same arrhythmia described following tacrolimus administration. Formation of early after-potentials is probably the source of this rhythm disturbance, which results in recurrent syncopal episodes (12). This hypothesis may explain the syncopal attacks described in the report by Sawabe et al. Furthermore, it should be noted that patients with a prolonged QT interval are at more risk of arrhythmias if they present an increased interlead variability of QT interval (QT dispersion) (13). This abnormality is considered a marker of uneven cardiac repolarization, and it seems to be involved in the arrhythmia mechanism. Nonuniform timing of repolarization in different regions of myocardium allows impulses to propagate irregularly, and re-entry activity may occur. Although it is difficult to precisely relate all the clinical findings reported by Sawabe et al. to the proposed hypotheses above, tacrolimus might influence automaticity or conductivity of the sinus node by changing potassium outward currents. Consequently, the significant prolongation of action potential in the sinus node may produce severe bradycardia and sinus arrest. This effect may also increase sensibility of sinus node to the action of other cardioactive drugs, such as digitalis. Hence, toxicity might develop despite a normal serum concentration. The sinus tachycardia reported by the authors may represent a component of bradycardia/tachycardia syndrome(14) rather than a direct effect of tacrolimus. This phenomenon is frequently described in the setting of sinus node disease and pause-dependent long QT syndrome. Finally, recurrent syncopal attacks may be due to episodes of ventricular polymorphic tachycardia associated with a prolonged QT interval. If these hypotheses are correct, one would expect the following: (1) the QT interval would be normal before the tacrolimus therapy and prolonged (> 440 msec) during its administration; (2) the occurrence of episodes of polymorphic ventricular tachycardia should be recorded in correspondence with syncopal attacks; and (3) the QT interval length would return to its normal range soon after the discontinuation of tacrolimus and the cessation of syncopal episodes. It would be of interest, therefore, if Sawabe et al.(1) could provide an evaluation of the QT interval length with appropriate correction for heart rate according to Bazett's formula (QTcorrected = QT/√RR interval)(15) during the clinical course of this patient. Moreover, along with QT interval length, QT dispersion could be determined to evaluate whether tacrolimus makes the repolarization process uneven, thereby increasing the risk for arrhythmias. Lastly, Holter 24-hr ECG monitoring may provide interesting evidence regarding the appearance of episodes of torsade de pointes in correspondence with syncopal episodes. Of course, the proposed hypothesis of a direct effect of tacrolimus on both sinus node function and the repolarization period would not exclude possible parallel mechanisms, such as cardiotoxicity of antineoplastic drugs. Sawabe et al.'s report confirms that tacrolimus should be used carefully when administered to organ recipients because it may induce prolongation of action potential and serious rhythm disturbances. Therefore, an assiduous electrocardiographic assessment is advised. Furthermore, special care needs to be taken with those patients who present a prolonged QT interval prior to transplantation, such as heart and liver recipients. Salvatore Calandra Dipartimento di Medicina Interna; Policlinico Universitario; 98100 Messina, Italy