Short QT Syndrome Patients

Pharmacological treatment of patients with Short QT Syndrome

Short QT Syndrome: Pharmacological Treatment. Gaita F, Giustetto C, Bianchi F, Schrimpf R, Haissaguerre M, Calo L, Brugada R, Antzelevitch C, Borggrefe M, Wolpert CJACC 2004;43:1494-1499

Six members from the previously published German and Italian families (7) were tested with Flecainide, Sotalol, Ibutilide and Hydroquinidine. 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 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 suggest that the (N588K) mutation in theKCNH2 channel in patients with SQT1 may have caused loss of some of the physiologic regulatory mechanisms, and the ion channel is no longer sensitive to a drug that normally has a specific action on it (See also ref. # 10). 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.

Further Insights into the Effect of Quinidine in Short QT Syndrome Caused by a Mutation in HERG Wolpert C, Schimpf R, Giustetto C, Antzelevitch C, Cordeiro J, Dumaine R, Brugada R, Hong K, Bauersfeld U, Gaita F, Borggrefe. J Cardiovasc Electrophysiol 2005;16:54-58

Clinical observations (exercise testing and ECG analysis) of the effect of Quinidine in 3 patients with SQTS caused by a mutation in HERG combined with in vitro patch clamp experiments on transfected human embryonic kidney cells. The linear relationship between QTpV3 and increasing heart rate seen in normal persons does not exists in patients with SQTS and the slope of QTpV3 in these patients is much less steep than in a control group. Quinidine appears able to bring the HR/QTpV3 relationship close to normal.

Reduction of Dispersion of Repolarization and Prolongation of Postrepolarization Refractoriness Explain the Antiarrhthmic Effects of Quinidine in a Model of Short QT Syndrome Milberg P, Tegelkamp R Osada N, Schimpf R, Wolpert C, Breithardt G, Borggrefe M, Eckardt L J Cardiovasc Electrophysiol 2007;18:658-664

A model of Short QT Syndrome was created in 48 Langendorff perfused rabbit hearts by administering an IK-ATP channel opener (Pinacidil) in increasing concentrations. By MAP recording and programmed electrical stimulation technique the effect of Sotalol, Flecainide and Quinidine on dispersion of repolarization, MAP duration, refractoriness, postrepolarization refractoriness and inducibility of VF was assessed. Only Quinidine reduced the inducibility of VF and it was associated with significantly greater prolongation of MAP duration, refractoriness and postrepolarization refractoriness compared with Sotalol and Flecainide. Quinidine was also the only one of the 3 drus which reduced dispertion of refractoriness

The biggest limitation of the study is the fact that the ATP sensitive channel used in this study has not been connected with SQTS in humans.

Quinidine in Short QT Syndrome: An Old Drug for a New Disease Kaufman E. J Cardiovasc Electrophysiol 2007;18:665-666

Editorial comment to previous article.

Sudden Death Associated With Short-QT Syndrome Linked to Mutations in HERG Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick GD, Wolpert C, Burachnikov E, Matsuo K, Wu YS, Guerchicoff A, Bianchi F, Giustetto C, Schrimpf R, Brugada P, Antzelevich C.. Circulation 2004,109:30-35

SOTALOL therapy in SQTS evaluated.

Disopyramide is an effective inhibitor of mutant HERG K+ channels involved in variant 1 short QT syndrome McPate MJ, Duncan RS, Witchel HJ, Hancox JC. J of Molecular and Cellular Cardiology 2006;41:563-566

Using whole-cell patch clamp recordings from Chinese Hamster Ovary cells expressing HERG with a N588K mutation (like SQT1) it was demonstrated, that the HERG-blocking potency of disopyramide was reduced only 1.5 fold. Since other studies have shown that Quinidine’s blocking effect of N588K-HERG channels was reduced 5.8 fold and Sotalol’s 20 fold, the study provides a rational basis for its evaluation as a treatment for STQ1.

Rapid communication of what was later presented as:

Pharmacology of the short QT syndrome N588K-hERG K+ channel mutation: differential impact on selected class I and class III antiarrhythmic drugs. McPate MJ, Duncan RS, Hancox JC, Witchel HJ. British Journal of Pharmacology 2008;155:957-966

In vivo Effects of Mutant HERG K+ Channel Inhibition by Disopyramide in Patients with a Short QT-1 Syndrome: A Pilot Study Schimpf R. Veltmann C, Giustetto C, Gaita F, Borggrefe M, Wolpert C. J Cardiovasc Electrophysiol 2007;18:1157-1160

Two female patients with an ICD in the setting of SQTS and N588K-HERG mutation underwent ECG recording, before and after treatment with disopyramide 400 mg/day. One of the patients underwent in addition stress-testing and programmed electrical stimulation. Disopyramide increased the QT interval from QTc 329 ms/QTc 315 ms, respectively, off drugs to QTc 358 ms/QTc 333 ms in both patients and restored the heart rate dependence of the QT interval toward normal. The VERP increased under disopyramide by 40 msec.

Nifekalant and Disopyramide in a Patient with Short QT Syndrome: Evaluation of Pharmacological Effects and Electrophysiological Properties Mizobuchi M, Enjoji Y, Yamamoto R, Ono T, Funatsu A, Kambayashi D, Kobayashi T, Nakamura S. PACE 2008:31;1229-1232

A 24 y.o. male with family history of SCD presented with syncopal episode at rest and diagnosed with SQTS based upon a QT interval of 313 msec and QTc interval of 308 msec. Both AF and VF were easily induced during programmed electrical stimuation. No genetic mutation was identified. Pharmacological challenge tests revealed that disopyramide and a selective IKr blocker, nifekalant, normalized the QT interval and atrial and ventricular ERP.

Short QT Syndrome: A case report and review of literature.Lu LX, Zhou W, Zhang X, Cao Q, Yu K, Zhu C. Resuscitation 2007;71(1):115-121

A patient with an episode of VF cardiac arrest, recurrent syncope and documented episodes of polymorph VT in the setting of SQTS of unknown genotype, where amiodarone was able to prevent episodes of polymorph VT despite the persistence of a short QT interval. During a 12-months follow-up period on amiodarone the patient did not have any further syncope or palpitations.

Targeted therapy for short QT syndrome Bjerregaard P, Jahangir A, Gussak I. (Saint Louis University Hospital & Mayo Clinic)Expert Opin. Ther. Targets 2006;10(3):393-400

Review comparing LQTS with SQTS. Potential targets for therapy in SQTS patients are reviewed for KCNH2, KCNQ1 and KCNJ2 mutation patients separately

Chloroquine Blocks a Mutant Kir2.1 Channel Responsible for Short QT Syndrome and Normalizes Repolarization Properties in silico.Lopez-Izquierdo A, Ponce-Balbuena D, Ferrer T, Sachse FB, Tristani-Firouzi M, Sánchez-Chapula JA. (University of Utah, Salt Lake City) Cell Physiol Biochem 2009;24:153-160

SQT3 and CHLOROQUINE in silico evaluation.

Action potential clamp and chloroquine sensitivity of mutant Kir2.1 channels responsible for variant 3 short QT syndrome. Harchi AE, McPate MJ, Zhang YH, Zhang H, Hancoc JC. J Moll Cell Cardiol 2009;47(5):743-747

The first AP clamp information on effects of Kir2.1 mutation (SQT3) at physiological temperature showed marked augmentation of outward Kir2.1 current through D172N channels, associated with right-ward voltage shofts of peak repolarization current during both ventricular abd atrial commands. Peak outward current was inhibited by chloroquine with an IC50 of 2.45 µM for wild-type Kir2.1 and of 3.30 µM for D172N-Kir2.1 establishing chloroquine as an effective inhibitor of SQT3 mutant Kir2.1 channels.

.Action Potential Clamp and Mefloquine Sensitivity of Recombinant ‘IKS’ channels incorporating the V307L-KCNQ1 Mutation. Harchi AE, McPate MJ, Zhang YH, Zhang H, Hancox JCJ Physiol Pharmacol 2010;61(2):123-131

Perforated-patch voltage-clamp recordings (Chinese Hamster Ovary cells) at 370C of whole-cell current carried by co-expressed KCNQ1 and KCNE1 showed a marked (-36 mV) shift in half-maximal activation for V307L compared to WT KCNQ1; a significant slowing of current deactivation was also observed.Under AP clamp peak repolarising current was significantly augmented for V307L-KCNQ1 compared to WT for both ventricular and atrial AP commands, consistent with an ability of the V307L mutation to increase repolarising Iks in both regions. The quinoline agent mefloquine showed effective inhibition of recombinant ‘Iks’ channels incorporating this SQT2 KCNQ1 mutation.

Long-term Follow-up of Patients with Short QT Syndrome. Giustetto C, Schimpf R, Mazzanti A, Scrocco C, Maury P, Anttonen O, Probst V, Blanc J-J, Sbragia P, Dalmasso P, Borggrefe M, Gaita F. J Am Coll Cardiol 2011;58:587-595

Especial evaluation of the potential benefit of Hydroquinidine .

Short QT syndrome in infancy. Therapeutic drug monitoring of hydroquinidine in a newborn infant. Pirro E, De Francia S, Banaudi E, Riggi C, De Martino F, Piccione FM, Giustetto C, Racca S, Agnoletti G, Di Carlo FBr J Clin Pharmacol 2011 (Epub ahead of print)

A novel mutation in the KCNH2 gene associated with short QT Syndrome. Sun Y, Quan X-Q, Fromme S, Cox RH, Zhang P, Zhang L, Guo D, Guo J, Patel C, Kowey PR, Yan G-X. J Molecular and Cellular Cardiology 2011;50:433-441

Shows that both quinidine and sotalol may be therapeutic options for patients with T618I-HERG mutation.

Inhibition of the HERG potassium channel by the tricyclic antidepressant doxepin. Duncan RS, McPate MJ, Ridley JM, Gao Z, James AF, Leishman DJ, Leaney JL, Witchell HJ, Hancox JC. Biochem Pharmacol 2007;74(3):425-437

Doxepin is a tricyclic antidepressant which can be cardiotoxic in overdose with a number of documented cases of QT prolongation. This study found doxepin to be an effective inhibitor of mutant (N588K) HERG channels responsible for SQT1

Disopyramide: Although potentially life-threatening in the setting of long QT, could it be life-saving in short QT syndrome? Dumaine R, Antzelevitch CJ Mol Cell Cardiol 2006;41(3):421-423

Pharmacological approach to the treatment of long and short QT syndromes. Patel C, Antzelevitch CPharmacol Ther 2008;118(1):138-151

Action potential clamp and pharmacology of the variant 1 short QT syndrome T618I hERG K(+) channel. El Harchi A, Melgari D, Zhang YH, Zhang H, Hancox JC. PloS One 2012;7:e52451

Most patients with documented SQT1 have an N588K-hERG gene mutation while the T618I-hERG mutation examined in this study has only been described in one family with SQT1.

This study finds that the T618I mutation produces a more modest effect on repolarising Ikr than reported previously for the N588K variant. The drugs (quinidine, disopyramide, D-sotalol and flecainide) studied appear substantially to retain their ability to inhibit Ikr in the setting of the SQTS-linked T618I mutation.

Nifekalant Enlarged the Transmural Activation-Recovery Interval Difference as Well as the Peak-to End Interval on Surface ECG in a Patient with Short-QT Syndrome Chinushi M, Sato A, Izumi D, Furushima H.. J Cardiovasc Electrophysiol 2012;23:877-880

In a 38 yo female with SQTS type 1 Nifekalant (a pure Ikr blocker) 0.40 mg/kg/h i.v. induced prolongation of the QT/QTc from 260/300 ms to 364/419 ms without any significant change in HR. A significant enlargement of the transmural activation-recovery interval dispertion was, however, observed, which shows that pharmacological therapy-induced QT-interval prolongation on the surface ECG may not always indicate attenuation of arrhythmogenic potential in patients with SQTS.

Differential Effects of the ß-Adrenoceptor Blockers Carvedilol and Metoprolol on SQT1- and SQT2-Mutant Channels Bodi I, Franke G, Pantulu ND, Wu K, Perez-Feliz S, Bode C, Zehender M, Hausen AZ, Brunner M, Odening KE.. J Cardiovasc Electrophysiol 2013;24:1163-1171

This study shows that under the used experimental conditions, metoprolol was found to be significantly more potent than carvedilol in inhibiting both types of mutant potassium channels.

ß-Blockers in Congenital Short-QT syndrome as Ion Channel Blockers. Abriel H, Rougier J-SJ Cardiovasc Electrophysiol 2013;00:1-3

Editorial comment to article by Bodi I et al (vide supra): The study by Bodi et al has demonstrated that the pharmacology of ß-blockers, and in particular their antiarrhythmic properties, may not only encompass their well-described ß-adrenergic receptor antagonistic properties, but also their cardiac ion channel-blocking features as well.

Electrical Storm in Short-QT Syndrome Successfully Treated with Isoproterenol Bun S-S, Maury P, Giustetto C, Deharo J-C.. J Cardiovasc Electrophysiol 2012;23(9):1028-1030

28-year old male admitted after episode of aborted cardiac death during sleep, with documented VF. ECG 6 years earlier had shown QT interval of 320 ms at 60 bpm (QTcB 320 msec). On admission the QT interval was 340 msec at 75 bpm (QTcB 383 msec). In the first 36 hours after admission while under neuroprotective hypothermia, the patient had 8 successive episodes of VF. IV amiodarone and lidocaine unsuccessful. Isoproterenol infusion was then introduced (2 microg/min) and proved extremely effective.

In addition to showing the benefit of isoproterenol in treating electrical storm in SQTS, this case clearly demonstrate the importance of having an ECG at a HR of 60 bpm in order not to miss the diagnosis of SQTS. The ECG on admission at a HR of 75 bpm and a QTc of 383 msec would not have raised the suspicion of SQTS.

The lack of effect of sotalol in short QT syndrome patients carrying the T618I mutation in the KCNH2 gene.

Carlo Giustetto, Chiara Scrocco, Daniela Giachino, Claudio Rapezzi, Barbara Mognetti, Fiorenzo Gaita. HeartRhythm Case Report 2015;1(5):373-378

Modelling the effects of chloroquine on KCNJ2-linked short QT syndrome.

Cunjin Luo, Kuanquan Wang, Henggui Zhang. Oncotarget. 2017;8:{63)

The Pharmacogenomics of a Mutation ‘Hotspot’ for the Short QT Syndrome

Dawood Darbar, Mark McCauley. JACC Clin Electrophysiol . 2017;3(7):744-746

Pro-arrhythmogenic Effects of the V141M KCNQ1 Mutation in Short QT Syndrome and its Potential Therapeutic Targets: Insights from Modelling.

Hsiang-Chun Lee, Yoram Rudy, Hongwu Liang, Chin-Chieh Chen, Ching-Hsing Luo, Sheng-Hsiung Sheu, Jianmin Cui.J MED Biol Eng, 2017;37(5):780-789

In Silico assessment of the effects of quinidine, disopyramide and E-4031 on short QT syndrome variant 1 in the human ventricles.

Cunjin Luo, Kuanquan Wang, Henggui Zhang. PloS One. 2017;6(1):7

Effects of amiodarone on short QT syndrome variant 3 in human ventricles: a simulation study

Cunjin Luo, Kuanguan Wang, Henggui Zhang, Biomed Eng Online. 2017;16:69

Therapeutic effects of a taurine-magnesium coordination compound on experimental models of type 2 Short QT Syndrome

Meng-yao An, Kai Sun, Yan Li, Ying-ying Pan, Yong-qiang Yin, Yi Kang, Tao Sun, Hong Wu, Wei-zhen Gao, Jian-shi Lou. Acta Pharmacol Sin. 2018;39(3):382-392

In silico Assessment of Pharmacotherapy for Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome

Dominic G. Whittaker, Jules C. Hancox, Henggut Zhang. Front Physiol. 2018;9:1888

Electrical storm in an acquired short QT syndrome successfully treated with quinidine.

Michael Spartalis, Efthimios Livanis, Eleftherios Spartalis, Alexandros Tsoutsinos. Clin Case Rep. 2019;7(8):1617-1618

Impact of Antiarrhythmic drugs on the outcome os Short QT Syndrome

Ibrahim El-Battrawy, Johanne Besler, Xin Li, Huan Lan, Zhihan Zhao, Volker Liebe, Rainer Schimpf, Sigfrief Lang, Christian Wolpert, Xiaobo Zhou, Ibrahim Akin, Martin Borggrefe.

Front Pharmacol 2019;10:771

Use of topical lidocaine in eliminating mechanically stimulated ventricular fibrillation in a patient with short QT syndrome.

Maria J. Farag. Joseph Atallah. HeartRhythm Case Rep. 2019;5(3):152-154

Functional and pharmacological characterization of an S5 domain hERG mutation associated with Short QT Syndrome.

Andrew Butler, Yihong Zhang, A. Graham Stuart, Christoffer E. Dempsey, Jules C. Hancox. Heliyon. 2019;5(4)

Ionic Mechanisms of Disopyramide Prolonging Action Potential Duration in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a patient with Short QT Syndrome Type 1

Huan Lan, Quang Xu, Ibrahim El-Battrawy, Rujia Zhong, Xin Li, Siegfried Lang, Likas Cyganek, Martin Borggrefe, Xiaobo Zhou, Ibrahim Akin, Front Pharmacol.


A computational method for identifying an optimal combination of existing drugs to repair the action potential of SQT1 ventricular myocytes.

Karoline Horgmo Jaeger, Andrew G, Edwards, Wayne R. Giles, Aslak Tveito. PloS Comput Biol 2021;17{8}

Computational prediction of drug response in Short QT Syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes.

Karoline Horgmo Jaeger, Samuel Wall, AslakTveito. PLoS Comput Biol 2021;17(2)

Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient with Short QT Syndrome Type 1  Mengying Huang, Zhenxing Liao, Xin Li, Zhen Yang, Xuehui Fan, Yingrui L;, Zhihan Zhao, Siegfried Lang, Lukas Cyganek, Xiaobo Zhou, Ibrahim Akin, Martin Borggrefe, Ibrahim El-Battrawy. Front Pharmacol. 2021;12

Therapeutic effects of a taurine-magnesium coordination compound on experimental models of type 2 short QT syndrome Meng-yao An, Kai Sun, Yan Li, Ying-ying Pan, Yong-giang Yin, Yi Kang, Tao Sun, Hong Wu, Wei-chen Gao, Jian-shi Lou Acta Pharmacol Sin 2018;39(3):382-392

Emerging therapeutic targets in the short QT syndrome Jules C Hancox, Dominic G Whittiger, Chunyun, A. Graham Stuart, Henggui Zhang Expert opinion on Therapeutic Targets 2018;22(5):439-451

Pharmacotherapeutic Effects of Quinidine on Short QT Syndrome by Using Purkinje-Ventricle Model: A Simulation Study Cunjin Luo, Dominic G Whittaker, Tong Liu, Kuanquan Wang, Yacong Li, Ying He, Henggui Zhang Annu Int Conf IEEE Eng Med Biol Soc 2019Jul;2019:2856-2859

Impact of Antiarrhythmic Drugs on the Outcome of Short QT Syndrome Ibrahim El-Battrawy, Johanna Besler, Xin Li, Huan Lan, Zhihan Zhao, Volker Liebe, Rainer Schimpf, Christian Wolpert, Xiaobo Zhou, Ibrahim Akun, Martin Borggrefe Front Pharmacol 2019;10:Article 771

Use of topical lidocaine in eliminating mechanically stimulated ventricular fibrillation in a patient with short QT syndrome Maria J Farag, Joseph Atallah  Heart rhythm Case Reports 2019;5:152-154

Computational prediction of drug response in short QT syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes Karoline Horgmo Jæger, Samual Wall, Asiak Tveito PLoS Comput Biol 2021;17(2):  e 1008089

Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Synddrome Type 1 Mengying Huang, Zhenxing Liao, Xin Li, Zhen Yang, Xuehui Fan, Yingrui Li, Zhihan Zhao, Siegfred Lang, Lukas Cyganek, Xiaobo Zhou, Ibrahim Akin, Martin Borggrefe, Ibrahim El-Battrawy Front Pharmacol 2021;12:675003

Antiarrhythmic Effects of Vernakalant in Human-Induced Pluripotent Stem Cell -Derived Cardiomyocytes from a patient with Short QT Syndrome Type 1

Qiang Xu, Xuemei Huang, Yingrui Li,  Xin Li, Rujia Zhong, Xin Li, Lukas Cyganek, Ibrahim El-Battrawy, Ibrahim Akin, Xiaoba Zhou and Huan Lan J Cardiovcascular Development and Disease 2022, 9,112.