Quinidine to Treat Short QT Syndrome:
A Real Alternative to ICD?
C. GIUSTETTO
Short QT syndrome (SQTS) is a recently described familial arrhythmogenic disorder related to an accelerated repolarisation time. Patients with short QT syndrome present with a wide spectrum of clinical manifestations, ranging from mild symptoms such as palpitations and dizziness to syncope and sud- den death [1]. Sudden death sometimes occurs in children in the first months of life and is often the first clinical presentation. Palpitations with documentation of atrial fibrillation occur even at a young age [2]. ECG shows QT intervals of less than 320 ms and QTc not exceeding 340 ms [3].
Physical examination, blood laboratory exams, echocardiogram, and stress test are normal. Mutations causing a gain of function in the rapidly activat- ing delayed rectifier potassium current (IKr) [4], in the slowly activating delayed rectifier potassium current (IKs) [5], and in the cardiac inward recti- fier current (IKl) [6], have been described.
Due to the high incidence of sudden cardiac death and the absence of known pharmacological therapy, the placement of an implantable car- dioverter–defibrillator (ICD) is presently the first-choice therapy [1, 7]. ICD implantation, however, is not feasible in every patient. For this reason we administered various anti-arrhythmic drugs to patients with short QT syn- drome to evaluate whether they could prolong the QT interval into the nor- mal range and, thus, potentially prevent symptoms and arrhythmia recur- rences [8]. As the mutations found in our first families increase the activity of IKr, the first drugs we administered were the class III anti-arrhythmic agents sotalol and ibutilide, which are selective IKrblockers. However, these drugs did not prolong the QT interval. The mutation must cause the loss of
Department of Cardiology, Cardinal Massaia Hospital, Asti, Italy
some of the physiological regulatory mechanisms, and IKrbecome insensitive to drugs that normally have a specific action on it [4]. Quinidine, however, produced a marked prolongation of the QT interval, which then entered the normal range, and of ventricular effective refractory periods, preventing induction of ventricular fibrillation. Furthermore, quinidine treatment pro- duced the appearance of an obvious ST segment and of broader T waves [8].
The basis of the greater effectiveness of quinidine is not fully understood, but a greater affinity of quinidine for the open state of the Ikrchannel and its ability to block IKsmight explain the prolongation of the QT interval.
So far we have treated 21 patients, 10 of whom received an ICD, while 11 did not (2 because they were very young and 9 refused the implant). The 11 patients who did not receive an ICD were started on hydroquinidine, as were another 5 patients who did receive an ICD, who had symptomatic episodes of atrial fibrillation. In the patients who received hydroquinidine, QT interval lengthened from 271 ± 13 ms to 347 ± 33 ms (P < 0.005), and QTc changed from 297 ± 15 ms to 397 ± 25 ms (P < 0.0005). One of the char- acteristics of the short QT syndrome is the lack of dependence of QT interval on heart rate. In 3 patients who repeated a stress test during quinidine treat- ment, it was observed that the drug restored the heart rate dependence of the QT interval towards the normal range [9]. The HERG mutation (encoding for IKr) was found in 6 out of the 11 patients; no known mutation was found in the other 5. A repeat electrophysiological study was carried out with hydro- quinidine therapy in the 9 adult patients: ventricular effective refractary period (ERP) lengthened to more than 200 ms in all of them and ventricular fibrillation was no longer inducible. The mean follow-up is 17 ± 13 months.
None of the patients on hydroquinidine died, nor did any have documented or symptomatic atrial fibrillation recurrences. Two patients stopped drug therapy due to enteric side effects.
Quinidine may also be useful in the prevention of inappropriate shocks due to oversensing of the high voltage T waves in patients with ICDs [7].
However, a longer follow-up is needed to decide in favour of the effectiveness of a drug in a life-long disease.
References
1. Gaita F, Giustetto C, Bianchi F et al (2003) Short QT syndrome. A familial cause of sudden death. Circulation 108:965–970
2. Gussak I, Brugada P, Brugada J et al (2000) Idiopathic short QT interval: a new cli- nical syndrome? Cardiology 94:99–102
3. Giustetto C, Wolpert C, Anttonen O et al (2005) Clinical presentation of the patients with short QT syndrome. Heart Rhythm 2:S61
4. Brugada P, Hong K, Dumaine R et al (2004) Sudden death associated with short QT
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syndrome linked to mutations in HERG. Circulation 109:30–35
5. Bellocq C, van Ginneken A, Bezzina C (2004) Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 109:2394–2397
6. Priori SG, Pandit SV, Rivolta I et al (2005) A novel form of short QT syndrome (SQTS3) is caused by a mutation in the KCNJ2 gene. Circ Res 96:800–807
7. Schimpf R, Wolpert C, Bianchi F et al (2003) Congenital short QT syndrome and implantable cardioverter defibrillator. Inherent risk for inappropriate shock deli- very. J Cardiovasc Electrophysiol 14:1273–1277
8. Gaita F, Giustetto C, Bianchi F et al (2004) Short QT syndrome: pharmacological treatment. J Am Coll Cardiol 43:1294–1299
9. Wolpert C, Schimpf R, Giustetto C et al (2005) Further insights into the effect of quinidine in Short QT syndrome caused by a mutation in HERG. J Cardiovasc Electrophysiol 16:1–5
335 Quinidine to Treat Short QT Syndrome: A Real Alternative to ICD?
