Amiodarone-associated macroscopic T-wave alternans and torsade de pointes unmasking the inherited long QT syndrome

Abstract

The congenital form of the long QT syndrome (LQTS) results from mutations in cardiac ion channels with a high degree of genetic heterogeneity. Ten different genes and >400 mutations with varying penetrance have been identified to date. Drug-induced acquired LQTS with torsade de pointes tachycardia as its most relevant clinical manifestation has been described as a result of previously unsuspected congenital LQTS. Only rarely, macroscopic T-wave alternans (TWA) is documented before the onset of torsade de pointes. A 62-year-old male patient without previously documented QT prolongation or ventricular tachyarrhythmias presented with new-onset atrial fibrillation and a rapid ventricular response ( Figure 1 A ). The patient was started on intravenous therapy with amiodarone. Following 48 h of drug exposure (total dose of 3.0 g amiodarone), sinus rhythm could be re-established. However, the patient developed massive QT c prolongation from baseline value of 401 ms to 592 ms. Moreover, there was prominent TWA visible on the surface ECG ( Figure 1 B ). This TWA preceded the development of torsade de pointes degenerating in ventricular fibrillation ( Figure 1 C ). Amiodarone plasma concentration was 0.87 mg/l at that time (therapeutic range, 0.59–2.5 mg/l). The patient was resuscitated and taken off amiodarone. He recovered completely and at the time of discharge, the QT interval had normalized (QT c , 416 ms). Subsequent genetic testing revealed a previously unpublished mutation at the KCNE2 gene (exon 1, position A269G), leading to a glycine substitution for glutamine within the C-terminus of this potassium channel β-subunit corresponding to the LQTS VI entity. ( A ) Baseline ECG; ( B ) prominent QT prolongation and macroscopic TWA after restoration of sinus rhythm; and ( C ) onset of torsade de pointes tachycardia. This case illustrates that previously unsuspected congenital LQTS may become clinically manifest when additional risk factors (such as therapy with antiarrhythmic drugs) may synergistically challenge reduced repolarization reserve. In a Finnish population, 19% of patients with drug-induced torsade de pointes carried one of the four common Finnish founder mutations of LQTS. Besides the culprit drug, one or more additional risk factors such as female sex, congestive heart failure, or atrial fibrillation were present. Our patient is a particularly exceptional example of how clinically inapparent congenital LQTS may manifest itself during exposure to repolarization prolonging antiarrhythmic drugs. Whereas the QT interval was within normal limits prior to treatment, it prolonged significantly and—most interestingly and only rarely observed—was associated with macroscopic TWA. This highly arrhythmogenic milieu gave then rise to the development of torsade de pointes and ventricular fibrillation. This case highlights that normal baseline electrocardiogram does not exclude a risk for proarrhythmic events during antiarrhythmic therapy.