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REFERENCES TO ARTICLES ABOUT SHORT QT SYNDROME

1999

1.   Gussak I, Liebl N, Nouri S, Bjerregaard P, Zimmerman F, Chaitman BR.

Deceleration-Dependent Shortening of the QT Interval: A New Electrocardiographic Phenomenon?

      Clin Cardiol 1999;22:124-126 

Case report describing a 4 year old African-American girl with complications related to premature birth, developmental delay and recurrent episodes of cardiac arrest with brady-arrhythmias. An episode documented electrocardiographically showed QT-interval shortening during severe bradycardia.

Activation of the Ik_ACh channel due to high vagal discharge was proposed as a possible mechanism responsible for both slowing of the heart rate and shortening of the QT interval.

The question was raised whether deceleration-dependent shortening of the QT interval has arrhythmogenic potential?

2000

2.      Gussak I, Chaitman BR, Kopecky SL, Nerbonne JM.

Rapid Ventricular Repolarization in Rodents: Electrocardiographic Manifestations, Molecular Mechanisms, and Clinical Insights.

J Electrocardiol 2000;33(2):159-170

2002

4.      Gussak I, Brugada P, Brugada J, Antzelevich C, Osbakken M, Bjerregaard, P.

ECG Phenomenon of Idiopathic and Paradoxical Short QT Intervals.

Cardiac Electrophysiology Review 2002;6:49-53

Discussion of clinical scenarios where a short QT interval may occur followed by a description of possible electrophysiologic consequences of a short QT interval.

2003

5.      Gussak I, Antzelevitch C, Goodman D, Bjerregaard P.

Short QT Interval: ECG Phenomenon and Clinical Syndrome.

In: Gussak I, Antzelevitch C, Hammill SC, Shen W-K, Bjerregaard P, editors: Cardiac Repolarization – Bridging Basic and Clinical Science. 2003;497-505

A description of current perspective of a short QT interval followed by a description of possible electrophysiological mechanisms and the arrhythmogenic potential.

6.      Gaita F, Giustetto C, Bianchi F, Riccardi R, Grossi S, Richiardi E.

Short QT: A New Electrocardiographic Pattern Related to Familial Sudden Death.

JACC 2003;4(Supplement A): 818-3 (Abstract)

Presentation at the ACC meeting in Chicago, March 2003 of three living members of an Italian family with SCD for four generations. The subjects presented with a history of palpitations, syncope or aborted SCD and ECG’s with very short QT intervals (mean value of 240 ms and mean corrected QT of 290 ms). Organic heart disease was ruled out and during EP-study easily inducible VF with very short refractory periods in both atria and ventricles. Flecainide was shown to increase the refractory periods and make VF no longer inducible.

This was the first presentation of a family with both a high incidence of SCD and a high incidence of Short QT in the ECG, and also the first documentation of cardiac arrest in a child (at the age of 8 months) with a short QT-interval.

7.      Gaita F, Giustetto C, Bianchi F, Wolpert C, Schrimpf R, Riccardi R, Grossi S, Richiardi E, Borggrefe M.

Short QT Syndrome. A Familial Cause of Sudden Death.

Circulation 2003;108:965-970

In this paper the Italian family described at the ACC meeting is combined with the description of a German family with very similar story.

A total of six patients from both families were submitted to serial ECG testing, echocardiography, cardiac MRI, exercise testing, Holter monitoring and signal-averaged ECG recording. Four underwent in addition an electrophysiological evaluation including programmed ventricular stimulation.

None of the patient showed any evidence of structural heart disease. Baseline ECG showed in all patient a QT interval </= 280 ms and the EP-study showed very short refractory period both in the atria and the ventricles with induction of VF by PES in 3 of the 4 patients (in 2 patients even by catheter manipulation during placement of the catheters prior to the procedure). Three patients received an ICD.

This paper had clearly demonstrated the malignant nature of idiopathic, extremely short QT interval.

8.  Schrimpf R, Wolpert C, Bianchi F, Giustetto C, Gaita F, Bauersfeld U, Borggrefe M.

Congenital Short QT Syndrome and Implantable Cardioverter Defibrillator Treatment: Inherent Risk for Inappropriate Shock Delivery.

J Cardiovasc Electrophysiol 2003;14:1273-1277

This paper describes the experience of ICD implantation in 5 patients from the Italian and German families. Due to T-wave oversensing  inappropriate shocks were delivered in 3 patients shortly after implantation. Programming lower sensitivities and decay delays prevented further inappropriate discharges.

9.   Passman R.

 Inappropriate Inplantable Cardioverter Defibrillator Therapy in the Short QT Syndrome: Old Problem in a New Disease.

J Cardiovasc Electrophysiol 2003;14:1278-1279

This is an editorial comment to the previous paper

2004

10.  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.

Sudden Death Associated With Short-QT Syndrome Linked to Mutations in HERG.

Circulation 2004,109:30-35

In this paper genetic testing was performed in the two families previously described by Gaita et al. in 2003 and in a family from the US not previously published, consisting of a 51 y.o. father with aborted SCD and a 20 y.o. son with short QT. In the German and the Italian family they identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac I_Kr channel HERG (KCNH2). The mutations dramatically increase I_Kr , leading to heterogeneous abbreviation of cardiac action potential duration and refractoriness.

This was the first description of a genetic abnormality responsible for some cases of SQTS

11.     Zipes DP.

The Year in Electrophysiology.

JACC 2004;43:1306-1314

A description of the advances in cardiac electrophysiology during 2003 included a brief (10 lines) description of SQTS.

12.     Gaita F, Giustetto C, Bianchi F, Schrimpf R, Haissaguerre M, Calo L, Brugada R, Antzelevitch C, Borggrefe M, Wolpert C.

Short QT Syndrome: Pharmacological Treatment.

JACC 2004;43:1494-1499

Six members from the previously published German and Italian families 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. Quinidine was recommended as the drug of choice for medical therapy while flecainide because of the increase in the effective refractory period could be the second choice.

13.     Bellocq C, van Ginneken ACG, Bezzina CR, Alders M, Escande D, Mannens MMAM, Baro I, Wilde AAM.

Mutation in the KCNQ1 Gene Leading to the Short QT-Interval Syndrome.

      Circulation 2004;109:2394-2397

This paper describes a 70 year old male with aborted SCD and a short QT interval. Analysis of candidate genes identified a g919c substitution in KCNQ1 (V307L mutation) encoding the K⁺ channel KvLQT1.

This was the second description of a genetic defect leading to SQTS

14.  Bjerregaard P, Gussak I.

Atrial Fibrillation in the Setting of Familial Short QT Syndrome.

      Heart Rhythm 2004;1(1S):522

This was a poster presentation of the four members of the first family with SQTS providing a more detailed description including the result of Holter monitoring, programmed electrical stimulation and treatment of atrial fibrillation with propafenone.

Of special interest was the beneficial effect of propafenone in treatment of atrial fibrillation without any effect on the QT interval.

15.  Bellocq C, van Ginnekan A, Bezzina CR, Alders M, Escanda D, Mannens M. Wilde AA.

Mutation in the KCNQ1 Gene Leading to the Short-QT-Interval Syndrome.

Circulation 2004;110(17); III-230

An oral presentation at the AHA meeting in October 2004 describing what had already been published in May 2004 (see ref. # 13).

16.  Wolpert C, Schimpf R, Gaita F, Bianchi F, Riccardi R, Borggrefe M.

Potential Treatment of Congenital Short QT Syndrome: Response to Oral Quinidine.

Circulation 2004;110(17): III-231

Presentation at AHA meeting of the same data as in ref. # 12

17. Filipecki A, Trusz M, Lubinski A.

 Prevalence of Very Short QT Intervals in Patients with Idiopathic Ventricular Fibrillation and Implanted ICD,

Circulation 2004;110(17);III-501

Oral presentation at AHA meeting of patients with possible SQTS among young individuals, who had undergone ICD implantation. No ECG’s were presented and the validity of the data has later been questioned.

18. Viskin S, Zeltser D, Ish-Shalom M, Katz A, Glikson M, Justo D, Tekes-Manova D, Belhassen B.

 Is idiopathic ventricular fibrillation a short QT syndrome? Comparison of QT intervals of patients with idiopathic ventricular fibrillation and healthy controls.

 Heart Rhythm 2004;1(5):587-591

ECGs of 28 patients with idiopathic VF (17 men and 11 women, age 31 +/- 17years) were compared to those of 270 age- and gender- matched healthy controls.

The QTc of males with idiopathic VF was shorter than the QTc of healthy males (371 +/- 22 ms vs 385 +/- 19 ms, P = 0.034), and 35% of the male patients had QTc < 360 msec (range 326 – 350 msec) compared to only 10 % of male controls (345-360 msec). No such differences were found among women.

The findings suggest that QTc intervals shorter than 360 msec may entail some arrhythmic risk.

19.  Zareba W.

 Idiopathic VF and short repolarization: Intriguing new concept.

Heart Rhythm 2004:1(5);592-593

Editorial comment to ref. # 18

20.    Antzelevitch C, Francis J.

 Congenital short QT Syndrome.

Indian Pacing and Electrophysiology Journal 2004;4(2):46-49.

Editorial with a brief description of the genetic background and channelopathies which may lead to a short QT interval.

21.    Extramiana F, Antzelevitch C.

Amplified Transmural Dispersion of Repolarization as the Basis for Arrhythmogenesis in a Canine Ventricular-Wedge Model of Short-QT Syndrome.

Circulation 2004;110:3661-3666

The authors demonstrates that shortening of the QT interval in a canine wedge preparation by Pinacidil (a specific activator of the I_K-ATP channel) is associated with an increased trasmural dispersion of repolarization and inducibility of VF by programmed stimulation.

2005

22.  Bjerregaard P, Gussak I.

Short QT Syndrome: mechanisms, diagnosis and treatment.

 Nat Clin Pract Cardiovasc Med. 2005;2:84-87

The first review article of Short QT Syndrome

23.  Wolpert C, Schimpf R, Giustetto C, Antzelevitch C, Cordeiro J, Dumaine R, Brugada R, Hong K, Bauersfeld U, Gaita F, Borggrefe.

 Further Insights into the Effect of Quinidine in Short QT Syndrome Caused by a Mutation in HERG.

J Cardiovasc Electrophysiol 2005;16:54-58

Clinical observations in 3 patients with SQTS combined with in vitro patch clamp experiments on transfected human embryonic kidney cells.

24.  Hong K, Bjerregaard P, Gussak I, Brugada R.

Short QT Syndrome and Atrial Fibrillation Caused by Mutation in KCNH2.

J Cardiovasc Electrophysiol 2005;16:394-396

Presentation of genetic testing of the first family with SQTS (see ref. # 3).  The analysis identified a missense  mutation (C to G substitution at nucleotide 1764) which resulted in the amino acid change (N588K) in KCNH2.

25.  Schulze-Bahr E, Breithardt G.

Short QT Interval and Short QT Syndromes.

J Cardiovasc Electrophysiol 2005;16:397-398

Editorial comment discussing how to define a short QT interval.

26.    Schimpf R, Bauersfeld U, Gaita F, Wolpert C.

Short QT syndrome: Successful prevention of sudden cardiac death in an adolescent by implantable cardioverter-defibrillator treatment for primary prophylaxis.

Heart Rhythm 2005;2:416-417

Case report of a previously asymptomatic 16 y.o. male who received an ICD due to a family history of SQTS and his own QT 248 msec and QTc 252 msec. Six month later the ICD saved his life, when he developed ventricular fibrillation during sleep. He is a member of the first German family described in ref. # 7.

This is the first description of a patient with SQTS rescued by an ICD shock.

27.  Priori SG, Pandit SV, Rivolta I, Berenfeld O, Ronchetti E, Dhamoon A, Napolitano C, Anumonwo J, Raffaele di Bartella M, Gudapakkam S, Bosi G, Stramba-Badiale M, Jalife J.

 A Novel Form of Short QT Syndrome (SQT3) Is Caused by a Mutation in the KCNJ2 Gene.

Circ Res. 2005;96:800-807

An asymptomatic 5-year-old girl presented an ECG during routine clinical evaluation with QTc of 315 ms and noticeably narrow and peaked T waves. Her father had a QTc of 320 ms and a history of presyncopal events and palpitations since the age of 15. Genetic analysis led to the identification in both affected individuals of a single base pair substitution (G514A) in KCNJ2, resulting in an amino acid change from aspartic acid to asparagine at position 172 in the Kir2.1 potasseum channel.

28.  Schulze-Bahr E.

Short QT Syndrome or Anderson Syndrome. Yin and Yang of Kir2.1 Channel Dysfunction.

Circ Res. 2005;96:703-704

Editorial comment to # 27

29. Giustetto C, Wolpert C, Anttonen OM, Sbragia P, Leone G, Schimpf R, Borggrefe M, Leclercq JF, Haissaguerre M, Gaita F.

Clinical Presentation of the Patients with Short QT Syndrome.

Heart Rhythm 2005;2(5):S61

Abstract at the Heart Rhythm Society meeting May, 2005

30. Schimpf R, Giustetto C, Bjerregaard P, Gaita F, Gussak I, Borggrefe M, Wolpert C.

 Clinical Follow-up of Patients with Short QT Syndrome.

Heart Rhythm 2005;2(5):S68

Abstract at the Heart Rhythm Society meeting May, 2005

31.  De Ferrari GM, Crotti L, Lundquist AL, Pedrazzini M, Insolia R, Ferrandi C, Vicentini A, Vaccari D, Schwartz PJ, George Jr. AL.

 Long QT Syndrome With Cardiac Arrest And Transient Short QT Due To A Novel KCNH2  Mutation Causing Both Loss and Gain Of Function.

Heart Rhythm 2005;2(5):S145

Abstract at the Heart Rhythm Society meeting May, 2005 showing evidence of both short and long QT interval (mixed phenotype) in a patient with a KCNH2 mutation. (Awaiting peer review publication)

32.  Anttonen OM, Silvola J, Kokkonen L, Brugada R, Junttila J, Hong K, Huikuri HV,

 A Novel Inherited Syndrome of Short QT Interval, Malignant Ventricular Arrhythmias and Familial Clustering of Otosclerosis.

Heart Rhythm 2005;2(5):S172

Abstract at the Heart Rhythm Society meeting May, 2007 describing a Finish family with both Short QT Syndrome and Familial Otosclerosis. Result of genetic testing not available.

33.  Riera ARP, Ferreira C, Dubner SJ, Schapachnik E, Soares JD, Francis J.

 Brief Review of the Recently Described Short QT Syndrome and Other Cardiac Channelopathies.

A.N.E. 2005;10(3):371-377

A review of cardiac channelopathies including a description of a 27-year-old male with paroxysmal atrial fibrillation, right bundle branch block and QT and QTc intervals of 302 ms and 315 ms, respectively, at a heart rate of 67 beats/min.

34.    Wolpert C, Schimpf R, Veltman C, Giustetto C, Gaita F, Borggrefe M.

Clinical characteristics and treatment of short QT syndrome.

Expert Rev. Cardiovasc. Ther. 2005;3(4):

Review article.

35.    Maury P, Hollington L, Duparc A, Brugada R.

Short QT syndrome: Should we push the frontier forward?

Heart Rhythm 2005;2:1135-1137

Description of a 15-year old boy resuscitated from VF. QT intervals varied between 245 and 320 ms with QTc’s at HR < 85 bpm between 315 and 375 ms. Repeat ECG’s in his two brothers displayed QT intervals </= 300 ms in one sibling and of 320 ms in the other in whom ventricular arrhythmia was induced. QT intervals of the mother were variable, but always at the lower limit value (300-320 ms, QTc 365 ms), whereas the father had a normal ECG.

A plea was made not to limit the definition of short QT syndrome only to patients with the very short QT intervals in order to prevent under-diagnosis of some cases of this syndrome.

36.  Bjerregaard P, Gussak I.

 Short QT Syndrome.

A.N.E. 2005;10(4):436-440

Review article.

37.  Borggrefe M, Wolpert C, Antzelevitch C, Veltmann C, Giustetto C, Gaita F, Schimpf R.

Short QT syndrome. Genotype-phenotype correlations.

J Electrocardiol 2005;38:75-80

Review article

38.  Kirilmaz A, Ulusoy RE, Kardesoglu E, Ozmen N, Demiralp E.

Short QT interval syndrome: a case report.

J Electrocardiol 2005;38:371-374

The first patient with SQTS in Turkey

39.  Gussak I, Bjerregaard P.

Short QT syndrome – 5 years of progress.

J Electrocardiol 2005;38:375-377

Editorial describing the progress in our knowledge of SQTS five years after the discovery of the syndrome.

40.     Hong K, Piper DR, Diaz-Valdecantos A, Brugada J, Oliva A, Burashnikov E, Santos-de-Soto J, Grueso-Montero J, Diaz-Enfante E, Brugada P, Sachse F, Sanguinetti MC, Brugada R,

 De novo KCNQ1 mutation responsible for atrial fibrillation and Short QT Syndrome in utero.

Cardiovasc Res 2005;68:433-440

The first description of a newborn with atrial fibrillation in the setting of SQTS diagnosed in utero and linked to a De Novo KCNQ1 mutation.

41.     Bjerregaard P, Jahangir A, Gussak I.

Targeted therapy for short QT syndrome.

Expert Opin. Ther. Targets 2006;10(3):393-400

Review comparing LQTS with SQTS. Also potential targets for therapy in SQTS patients is reviewed for KCNH2, KCNQ1 and KCNJ2 mutation patients separately.

42.     Cordeiro JM, Brugada R, Wu YS, Hong K, Dumaine R.

Modulation of I_Kr inactivation by mutation N588K in KCNH2: A link to arrhythmogenesis in short QT syndrome.

Cardiovascular Research 2005;67:498-509

The authors measured the characteristics of HERG current generated by wild-type KCNH2 and the N588K mutant channel expressed in mammalian TSA201 cells. They found that the ventricular action potentials were preferentially reduced in SQTS, while the Purkinje fiber action potentials remained unchanged. This would lead to a shortening of the refractory period in the ventricles, but not in the Purkinje fibers. They suggested that the longer action potentials in the Purkinje fibers might re-excite the repolarized endocardial layer of the ventricles and thereby create tachyarrhythmias. This may also explain the wider than usual separation between T and U waves seen in SQTS patients.

43.  McPate MJ, Duncan RS, Milnes JT, Witchel HJ, Hancox JC.

The N588K-HERG K⁺ channel mutation in the ‘short QT syndrome’: Mechanism of gain-in-function determined at 37 ^oC.

Biochemical and Biophysical Research Communications 2005;334:441-449

These authors examined at physiologic temperature the importance of the S5-P linker for HERG channel function. They demonstrated that N588K-HERG contributes increased repolarising current earlier in the ventricles action potential due to a ~+60 mV shift in voltage dependence of I_HERG inactivation. This explains the accelerated repolarisation and short QT interval in some SQTS patients.

44.  Antzelevitch C.

Cardiac repolarization. The long and short of it.

Europace 2005;7:53-59

Review of the importance of electrical heterogeneity of transmural ventricular repolarization in the heart for the occurrence of tachy-arrhythmias in LQTS, SQTS, Brugada syndrome and catecholaminergic polymorph ventricular tachycardia.

45.   Brugada R, Hong K, Cordeiro JM, Dumaine R.

Short QT Syndrome.

CMAJ 2005;173(11):1349-1354

Canadian review article of SQTS

46. Paulussen AD, Raes A, Jongbloed RJ, Gilissen RA, Wilde AA, Snyders DJ, Smeets HJ, Aerssens J.

HERG mutation predicts short QT based on channel kinetics but causes long QT by heterotetrameric trafficking deficiency.

Cardiovasc Res 2005;67(3):467-475

47. Weiss DL, Seemann G, Sachse FB, Doessel O.

Modelling of short QT syndrome in a heterogeneous model of the human ventricular wall.

Europace 2005;7:S105-S117

These authors have been able to create a computer model of human cardiomyocytes that incorporates modifications in I_Kr as seen in some SQTS patients. They found a heterogeneous abbreviation of the action potential duration leading to a decreased dispersion of repolarization in heterogeneous tissue. Repolarisation was homogenized and the final repolarisation was shifted to epicardial sites.

2006

48. Tanabe Y, Hatada K, Naito N, Aizawa Y, Chinushi M, Nawa H, Aizawa Y.

Over-expression of Kv1.5 in rat cardiomyocytes extremely shortens the duration of the action potential and causes rapid excitation.

Biochemical and Biophysical Research Communications 2006;345:1116-1121

Tanabe at als. Have been able to create a model based upon fetal rat cardiomyocytes with over-expression of Kv1.5 leading to shortening of the action potential. They have suggested that this model can be used to study the arrhythmogenic substrate in SQTS.

49.  Cerrone M, Noujaim S, Jalife J.

The short QT syndrome as a paradigm to understand the role of potassium channels in ventricular fibrillation.

J Int Med 2006;259:24-38

                 Review article.

                  Molecular and genetic features of  SQTS is addressed.

                  New knowledge on   the mechanism of wavebreak, which is the hallmark of              reentry initiation, is summarized.  The authors state, that it is likely that the mechanisms that lead to electrical instability and eventually results in VF in patients carrying mutations in HERG or KvLQT1 would be different from those resulting from gain-of-function substitutions in Kir2.1 . 

50.  Itoh H, Horie M, Ito M, Imoto K.

Arrhythmogenesis in the short QT syndrome associated with combined HERG channel gating defects: a simulation study.

Circ J 2006;70(4):502-508

Conclusion: Although gain of function of the KCNH2 (HERG) channel shortens APD in the Short QT Syndrome, arrhythmogenesis may be associated not only with gain of function, but also with accelerated deactivation of KCNH2.

51.  Schulze-Bahr E.

Short QT Syndromes.

Herz 2006;31(2):118-122

Review article in German

52.  Gallagher MM, Magliano G, Yap YG, Padula M, Morgia V, Postorino C, Liberato FD, Leo R, Borzi M, Romeo F.

Distribution and Prognostic Significance of QT Intervals in the Lowest Half Centile in 12,012 Apparently Healthy Persons.

Am J Cardiol 2006;98:933-935

Among 12,012 healthy subjects (90.7 % male) 30 +/- 10 years old there were 60 with a QTc < 361 msec and the shortest QTc was 335 msec. 36 of these 60 subjects were followed for 7.9 +/- 4.5 years and none of them died suddenly.

A QTc </= 360 msec was seen in only 0.4 %

The absence of any QTc < 335 msec confirms the impression that Short QT Syndrome is a distinct clinical entity involving QT intervals substantially shorter than those found in a normal population.

53.  Giustetto C, DiMonte F, Wolpert C, Borggrefe M, Schimpf R,  Sbragia P, Leone G, Maury P, Anttonen O, Haissaguerre M, Gaita F.

Short QT syndrome: clinical findings and diagnostic-therapeutic implications.

European Heart Journal 2006;27:2449-2447

54.   McPate MJ, Duncan RS, Witchel HJ, Hancox JC.

 Disopyramide is an effective inhibitor of mutant HERG K⁺ channels involved in variant 1 short QT syndrome.

J of Molecular and Cellular Cardiology 2006-

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.

55.   Lu LX, Zhou W, Zhang X, Cao Q, Yu K, Zhu C.

Short QT Syndrome: A case report and review of literature.

Resuscitation 2006;71:115-121

The first description from China of a family with SQTS. Includes some very interesting ECG rhythm-strips from Holter monitoring showing self-terminating polymorph ventricular tachycardia initiated by a very premature PVC.

Amiodarone combined with a beta-blocker was effective in treating the episodes of polymorph ventricular tachycardia.

56.   Rhodes TE, Crotti L, Arnestad M, Insolia R, Pedrazzini M, Ferrandi C, Rognum T, Schwartz PJ, George AL.

Gain of Function KCNQ1 Mutation Associated With Sudden Infant Death Syndrome

Heart Rhythm 2006;3(5):S2

During the examination of 201 Norwegian SIDS cases  for genetic variants in the major LQTS genes, a gain-of-function KCNQ1 mutation was found. This mutation is predicted to enhance cardiac repolarization resulting in a shortened QT interval and an increased risk of atrial and ventricular tachyarrhythmias - features typical of the Short QT Syndrome.

57.   Assadi R, Chang R, Abdipour A, Pai SM, Jutzy KR.

Possible Increased Risk of Cardiac Arrhythmias in Patients With Acquired Short QT Interval

JACC 2007;xxx:8A

Nineteen patients with QTc < 300 msec were compared with 36 patients matched by sex, age and ethnicity and evaluated for cardiac arrhythmias on the day of the short QT.                                     

Twelve cases (63%) showed afib/flutter and 32 % developed cardiac arrest due to VF after short QT was detected.

Corrected for known causes of a short QT interval, patients with a short QT had an increased risk of arrhythmias compared to the controls (p=0.017).

Conclusion: Short QT including the acquired form may be an independent risk factor for cardiac tachy-arrhythmias.

2007

58. Reinig MG, Engel TR

The Shortage of Short QT Intervals

CHEST 2007;132:246-249

In a hospital based population of 106,432 patients, not a single one was found to have a QTc </= 300msec

59. Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B, Gelber P, Bonaros EP, Burashnikov E, Wu Y, Sargent JD, Schickel S, Oberheiden R, Bhatia A, Hsu L-F, Jaissaguerre M, Schrimpf R, Borggrefe M, Wolpert C.

Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short OT Intervals, and Sudden Cardiac Death

   Circulation 2007;115:442-449

Among 82 probands with a clinically robust diagnosis of Brugada syndrome, 6 % (5) presented with a shorter-than-normal  QT interval.

Three of these 5 probands with a QTc </= 360 msec carried a cardiac L-type calcium channel missense mutation (CACNAIC or CACNBSb). A loss of function of any of these channels can contribute to a sudden death syndrome that consists of a shorter-than-normal QT interval and ST-segment elevation (Brugada Syndrome phenotype).

This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada Syndrome phenotype is combined with shorter-than-normal QT intervals.

60. Milberg P, Tegelkamp R Osada N, Schimpf R, Wolpert C, Breithardt G, Borggrefe M, Eckardt L.

Reduction of Dispersion of Repolarization and Prolongation of Postrepolarization Refractoriness Explain the Antiarrhthmic Effects of Quinidine in a Model of Short QT Syndrome

J Cardiovasc Electrophysiol 2007;18:658-664

A model of Short QT Syndrome was created in 48 Langendorff perfused rabbit hearts by administering an I_K-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.

61. Kaufman E.

Quinidine in Short QT Syndrome: An Old Drug for a New Disease

J Cardiovasc Electrophysiol 2007;18:665-666

 Editorial comment to previous article.

62. Anttonen O, Junttila MJ, Rissanen H, Reunanen A, Viitasalo M, Huikuri HV.

Prevalence and Prognostic Significance of Short QT Interval an a Middle-Aged Finnish Population

     Circulation 2007;116:714-720

QT intervals were measured from the 12-lead ECGs of 10,822 subjects (5,658 males, mean age 44 +/- 8.4 years) enrolled in a population study and followed for 29 +/- 10 years.

QTc < 360 msec was seen in 2.8 %

QTc < 340 msec was seen in 0.4 %.

QTc < 320 msec was seen in 0.1 %.

During follow up there were no sudden deaths in the 43 subjects with a QTc < 340 msec.

The higher number of subjects with a short QT interval in this study than in the study by Gallagher et al. (# 52) is likely due to the difference in defining the end of the T wave.

In the present study the end of the T wave was defined as a point at which a tangent of the descending limb of the T wave intersects the baseline, whereas Gallagher et al defined it as the point at which the T wave returned to the isolelectric line.

Another point of significance is the limitations in the use of Bazett’s correction formula. In both the study by Gallagher et al. and the present study, subjects with the shortest QT were the subjects with the lowest heart rate. Bazett’s formula is known for its tendency to over-correct the QT interval during bradycardia.

63. Viswanathan MN, Page RL.

Short QT. What Does It Matter?

Circulation 2007;116:686-688

Editorial to the previous article (#62)

64. Moriya M, Seto S, Yano K, Ahahoshi M.

Two Cases of Short QT Interval

PACE 2007;30:1522-1526

Among 19,153 subjects (7,525 men and 11,628 women) from the Hiroshima-Nakasaki Radiation Effects Research Study who had undergone biannual health examinations (including ECG recordings) since 1958, only two were found to have QTc less than 350 msec, but none of them a family history or symptoms suggesting SQTS.

65. Schimpf R, Veltman C, Giustetto C, Gaita F, Borggrefe M, Wolpert C.

In vivo Effects of Mutant HERG K⁺ Channel Inhibition by Disopyramide in Patients with a Short QT-1 Syndrome: A Pilot Study

J Cardiovasc Electrophysiol, 2007;18:1157-1160

The QT interval was recorded in 2 females with N588K-HERG mutation off drugs, on oral quinidine and on oral disopyramide.

The QT/RR relationship was determined during stress-test in one patient, who also underwent noninvasive PES via an ICD to determine drug-induced changes in ventricular ERP.

Disopyramide was found to prolong both the QT interval and the ventricular ERP at the same time as it restored the HR dependency toward normal subjects.

2008

66.  Bjerregaard P, Gussak I.

Short QT Syndrome

Electrical Diseases of the Heart. Genetics, Mechanisms, Treatment, Prevention: Gussak I, Antzelevitch C, Eds. Springer 2008:554-563

Review article of SQTS.

67. Hassel D, Scholz EP, Trano N, Friedrich O, Just S, Meder B, Weiss DL, Zitron E, Marquart S, Vogel B, Karle CA, Seemann G, Fishman M, Katus  HA, Rottbauer W.

Deficient Zebrafish Ether-à-Go-Go-Related Gene Channel Gating Causes Short-QT Syndrome in Zebrafish Reggae Mutants

Circulation 2008;117:866-875 

The authors present a zebrafish with a missense mutation (L499P) in the HERG potassium channel leading to a gain of function due to impaired inactivation gating resulting in a significant decrease of cardiac action potential duration.

The authors demonstrates a propensity to atrial fibrillation but not ventricular fibrillation in their model and also tendency to sinus arrest and to AV conduction disturbances during atrial fibrillation, while the AV conduction seems unimpaired during normal sinus rhythm.

With its molecular and pathophysiological concordance to human SQTS type I, the zebrafish model may prove to be the first valuable animal model to investigate disease mechanisms genetically and to test new pharmacological treatment options.

The authors are using the Bazett formula for heart rate correction of the QT interval in zebrafish with a heart rate of > 120 bpm, which is difficult to justify for several reasons.

68. Schimpf R, Antzelevitch C, Haghi D, Giustetto C, Pizzuti A, Gaita F, Veltman C, Wolpert C, Borggrefe M.

Electromechanical coupling in patients with the short QT syndrome: Further insights into the mechanoelectrical hypothesis of the U wave

Heart Rhythm 2008;5:241-245

Combining echocardiography and electrocardiography in 5 patients with SQTS and 5 subjects with normal QT interval, the authors demonstrated a significant dissociation between the ventricular repolarization and the end of mechanical systole in SQTS patients.

Coincidence of the U wave with termination of mechanical systole provided support for a mechanoelectrical hypothesis for the origin of the U wave.

The existence of mechanosensitive ion channels may transduce changes in pressure and stretch during isovolumetric relaxation, where ventricular morphology changes have been shown to take place, leading to electrical changes generating a voltage gradient in the left ventricular myocardium, which is then detected as U waves in the surface ECG.

69. Surawicz B.

U wave emerges from obscurity when the heart pumps like in a kangaroo

Heart Rhythm 2008;5:246-247

Editorial commentary to ref. # 68 pointing out that the U wave is the only component of the ventricular complex on the ECG that cannot be derived from the ventricular action potential, and also that A. Hoffman as early as 1914 had suggested that U waves were related to ventricular relaxation.

70. Patel C, Antzelevitch C.

Cellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the Short QT syndrome.

Heart Rhythm 2008;5:585-590

In an arterially perfused canine LV wedge preparation an experimental model of SQT1 was created using PD-118057, a novel I_Kr  agonist.

Results from measuring transmembrane actionpotentials at rest and during programmed stimulation suggested, that a combination of ERP abbreviation and transmural dispersion of repolarization underlie the development of polymorph VT in STQ1 and that quinidine prevents pVT principally by prolonging ERP.

71. Extramiana F, Maury P, Maison-Blanche P, Duparc A, Delay M, Leenhardt A.

Electrocardiographic Biomarkers of Ventricular Repolarisation in a Single Family of Short QT Syndrome and the Role of the Bazett Correction Formula.

Am J Cardiol 2008;101:855-860

Based upon ECG recordings from 27 members of a family where one had survived an episode of SCD in the setting of SQTS it was concluded, that  the Bazett correction formula is not appropriate for making a diagnosis of SQTS. Based upon their definition of SQTS, three additional members were considered to have SQTS and a high number (16) had shorter than normal QT interval.

72. Bjerregaard P, Collier JL, Gussak I.

Upper Limit of QT/QTc Intervals in the Short QT Syndrome. Review of the World-Wide Short QT Syndrome Population and 3 New USA Families

Heart Rhythm 2008;5(5S):S91

Currently there are 53 patients in the medical literature with SQTS (21 female, 32 male). Two were diagnosed at birth because of bradycardia due to atrial fibrillation with very slow ventricular response.

35 are from Europe, 14 from USA, 3 from China and one from Brazil.

The average QT interval was 282 +/- 63 ms (range: 210-340 ms)

The average QTc interval was 305 +/- 42 ms (range: 248-345 ms)

The QT intervals in patients with tachy-arrhythmic events are statistically significant shorter than in family members with short QT interval but no such arrhythmias.

The longest QT interval reported in a patient with SQTS and a tachy-arrhythmic event is 315 ms.

It is recommended that SQTS be ruled out in anyone with a primary short QT interval.

73.  Sawicki S, Stadnivki W, Kusnierz J, Kochmanski M

Short QT Syndrome – A case report

Kardiol Pol 2008;66(3):307-312

Two patients with SQTS (23 yo male and his 42 yo mother) are presented.

74   Funada A, Hayashi K, Ino H, Fujino N, Uchiyama K, Sakata K, Masuta E, Sakamoto Y, Tsubokawa T, Yamagishi M.

Assessment of QT intervals and Prevalence of Short QT Syndrome in Japan.

Clin Cardiol 2008;31(6):270-274

ECGs were obtained from a hospital population of 12,149. and in 10,984  RR and QT intervals were measured.

The minimum QTc was 290 msec and only 3 subjects had QTc < 300 msec, which was their definition of SQTS.

75    izobuchi M, Enjoji Y, Yamamoto R, Ono T, Funatsu A, Kambayashi D, Kobayashi T, Nakamura S.

Nifekalant and Disopyramide in a Patient with Short QT Syndrome: Evaluation of Pharmacological Effects and Electrophysiological Properties

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 I_Kr blocker, nifekalant, normalized the QT interval and atrial and ventricular ERP.

last updated: 04/02/2009