Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG

Abstract

Introduction: The principal aim of this study was to assess the efficacy of quinidine in suppressing IKr in vitro and in modulating the rate dependence of the QT interval in the "SQT1" form of the short QT syndrome.

Methods and results: Graded-intensity bicycle exercise testing was performed off drug in three patients and during oral quinidine in two patients with short QT syndrome and compared to a control group of healthy normal subjects. The in vitro effects of quinidine on currents in patch clamp technique were investigated. Off drugs QTpV3/heart rate correlation is much weaker in patients with short QT syndrome, and QTpV3 shortens less with heart rate increase compared to normal subjects. In addition to prolonging the QT interval into the normal range, quinidine restored the heart rate dependence of the QT interval toward a range of adaptation reported for normal subjects. Data from heterologous expression of wild-type and mutant HERG genes indicate the mutation causes a 20-fold increase in IC50 of d-sotalol but only a 5.8-fold increase in IC50 of quinidine.

Conclusion: Oral quinidine is effective in suppressing the gain of function in IKr responsible for some cases of short QT syndrome with a mutation in HERG and thus restoring normal rate dependence of the QT interval and rendering ventricular tachycardia/ventricular fibrillation noninducible.

Figure 1

(Top) Twelve-lead surface ECG at baseline (upper panel). The QT and QTc intervals are 240 and 268 msec, respectively. (Bottom) ECG recorded with patient taking quinidine1,000 mg/day. QT and QTc intervals are prolonged to 360 and 402 msec, respectively.

Figure 2

Heart rate-QTpV3 relationship in a healthy female subject from the control group and a short QT patient off drugs and taking 1000 mg of oral quinidine. There is a linear relationship between the QTpV3 and increasing heart rate in the normal proband. There is no linear relationship (R² = 0.56) and a less steeper slope of QTpV3 increase than in the control group. The heart rate/QTpV3 relationship in the same patient with a short QT syndrome on oral quinidine exhibits a restored linear relationship between QTpV3 and heart rate (R² = 0.93). The decrease of QTpV3 with increasing heart rate and the increase of QTpV3 at decreasing heart rate, respectively, are more pronounced than before quinidine.

Figure 3

Wild-type (WT) HERG (A) and N588K (B) currents in TSA201 cells elicited by 800-msec depolarizing pulses to +20 mV from a holding potential of −80 mV. A large, slowly deactivating inward tail current is observed upon repolarization to −80 mV in HERG. Application of quinidine 5 μM inhibited approximately 80% of the current (A). Mutation N588K increased the size of the activation current and significantly accelerated the tail current decay (B). Quinidine 5 μM inhibited about 50% of the N588K current.