TU alternans, long QTU, and torsade de pointes: clinical and experimental observations

T or U wave alternans in association with long QTU and torsade de pointes (TdP) is uncommon and its mechanism(s) is unknown. We studied three patients with TU alternans, long QTU, and TdP: patient 1 was a newborn with congenital long QTU; patient 2 had marked hypokalemia and hypomagnesemia; and patient 3 was receiving procainamide. In the three patients, TU alternans was tachycardia dependent and preceded the onset of TdP. In the patient on procainamide, TU alternans and TdP occurred at long cardiac cycles. In this patient, endocardial monophasic action potential (MAP) recordings showed that TU alternans was associated with alternation of the duration of the plateau. A deflection consistent with early afterdepolarization (EAD) arose at a constant time interval from phase 0 but alternated from high and low levels of phase 3. The first ectopic beat of TdP arose on the descending limb of the EAD. TU alternans was investigated by MAP recordings in six normal dogs, following the administration of anthopleurin-A (AP-A), a drug shown to delay sodium inactivation and to induce bradycardia dependent long QTU, EADs, and TdP. In two dogs TU alternans was associated with 2:1 recordings of EAD and nearly constant plateau duration. In three dogs, TU alternans was associated with EAD that occurred in consecutive beats at constant time intervals from phase 0, but alternated from high and low phase 3 because of alternation of the duration of the plateau. In one dog, alternation of EAD and plateau duration occurred. In 36 separate episodes of TdP that were analyzed in the six dogs, 32 were bradycardia dependent but four developed on abrupt shortening of the cardiac cycle associated with alternation of action potential duration. Our results suggest: (1) TU alternans may be due to 2:1 propagation of an EAD or to alternation of the recovery kinetics of a repolarization current; (2) The constant occurrence of EAD in relation to phase 0 in spite of alternation of plateau duration suggests an ionic mechanism synchronized to depolarization; (3) Tachycardia dependent TdP in clinical and experimental examples of long QTU seems to be characteristically associated with TU alternans. Dispersion of repolarization may underlie the increased ventricular electrical instability in these cases.