Short QT Syndrome

Drug studies

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Antiarrhythmic therapy in patients with SQTS has mainly been necessary for paroxysmal atrial fibrillation and as prophylaxis against ventricular tachycardia or fibrillation in patients with an ICD in order to reduce the number of shocks to a minimum.

In the study by Carla Giustetto and coworkers (2011) hydroquinidine was initially used in 22 patients, but in 10 it had to be discontinued because of poor compliance in 6, no QT prolongation in 2 and gastrointestinal side-effects in 2. Twelve patients (3 with history of cardiac arrest, 3 with history of syncope and 6 previously asymptomatic) took hydroquinidine for a mean period of 76 +/-30 months without having any arrhythmic events.

The use of quinidine was based upon limited data from previous studies. In 2004 Gaita and coworkers had tested Flecainide, Sotalol, Ibutilide and Hydroquinidine in 6 patients with SQTS. Flecainide, Sotalol and Ibutilide did not produce any significant QT prolongation. Only hydroquinidine prolonged the QT interval from 263 +/- 12 msec to 362 +/- 25 msec with prolongation of the ventricular effective refractory period to > 200 msec and VF was no longer inducible. The slight prolongation of the QT interval following Flecainide was mainly due to QRS prolongation. The lack of QT prolongation following selective IKr-blocking agents like Ibutilide and Flecainide suggested that the (N588K) mutation in the KCNH2 channel in these patients with SQT1 might have caused loss of some of the physiologic regulatory mechanisms, and the ion channel was no longer sensitive to a drug that normally has a specific action on it.

Quinidine was recommended as the drug of choice for medical therapy while Flecainide because of some increase in the effective refractory period could be the second choice. Wolpert and coworkers in 2005 performed exercise testing of quinidine in 3 patients with SQTS caused by a mutation in HERG and showed that the linear relationship between QTpeak and increasing heart rate seen in normal persons did not exists in patients with SQTS and the slope of QTpeak in these patients was much less steep than in a control group. Quinidine was, however able to bring the HR/QT relationship in patients with SQTS close to normal.

In 2011 Pirro and coworkers reported a 5- year old child with SQTS and an N588H-HERG mutation who had been on hydroquinidine since she was 9 days old. She was followed by frequent ECG and plasma concentration of hydroquinidine with a target QTc interval > 360 msec and a plasma concentration between 0.6 and 2.0 microg ml-1. No cardiac symptoms or major side effects were observed during follow-up. Sun and coworkers tested the effect of quinidine and Sotalol on the mutant T618I-HERG channels expressed in HEK 293 cells and found for both drugs a much smaller loss of inhibitory effect than previously shown on N588K-HERG channels suggesting that SQTS patients with the T618I mutation may not be resistant to these drugs.

Disopyramide is another drug considered as therapy for SQTS patients. In 2006 McPate and coworkers used whole-cell patch clamp recordings from Chinese Hamster Ovary cells expressing HERG with a N588K mutation to demonstrate, that the HERG-blocking potency of disopyramide was reduced only 1.5 fold. Since other studies had shown that Quinidine’s blocking effect of N588K-HERG channels was reduced 5.8 fold and Sotalol’s 20 fold, the study provided a rational basis for further evaluation of disopyramide as a treatment for SQTS. There are, however, at this point only a few case reports about the clinical effect of disopyramide in patients with SQTS and the results have been mixed. Other drugs used sporadically with some success includes amiodarone , and propafenone , but as with any of the other drugs, there are just not enough patients with Short QT Syndrome to make drug testing feasible.

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