Short QT Syndrome History

The list of authors had grown to seven. Ihor Gussak and I embrace a group of colleagues, who had all been helping us. Joseph Brugada from The University of Barcelona, Spain had provided ECG and medical history of one of the patients, and Pedro Brugada from the Cardiovascular Research and Teaching Institute, Aalst, Belgium along with R. Scott Wright and Stephen L. Kopecky from The Mayo Clinic, Rochester, Minnesota, USA had all participated in discussions about the possible relationship between a short QT and serious heart rhythm disturbances. Finally, Bernard R Chaitman was included as Chief of Cardiology at the hospital from where the syndrome originated.

In the article we showed the ECG’s of the initial family (the proband, her brother and her mother) and of the 37 year old Spanish woman, which had all earlier been turned down by the editor of Circulation. We also incorporated an ECG rhythm strip from a 4-y-o African-American girl during an episode of brady-arrhythmia accompanied by deceleration-dependent shortening of the QT interval. We realized that we were unable to assess whether or not we were dealing with a new clinical syndrome or simply with an ECG phenomenon of idiopathic short QT interval. We also stated, that if additional supporting clinical data became available, we believed that – parallel to the “long QT syndrome” – the combination of short QT interval and electrical instability could appropriately be named the “short QT interval Syndrome”.

The following 3 years we were waiting for another family with similar findings to show up somewhere in the world, and especially to find out about the danger of having such a short QT interval. Our family was doing well except for occasional episodes of atrial fibrillation.

Then it came:

March 2003: The suspicion of a new syndrome which was potentially life-threatening was hightened at the ACC meeting in Chicago, where a paper from Ospedale Mauriziano Umberto I, Torino, Italy describing a family with history of sudden cardiac death and Short QT was persented by Dr. Fiorenzo Gaita. It described 16 members from 5 generations of an Italian family, where there were 6 sudden cardiac death victims including one with short QT. Two additiona members of this family had short QT.

In the paper above from Circulation, August 2003 this Italian family was described in more detailles in connection with the first presentation from The University Hospital Mannheim, University of Heidelberg, Mannheim of 23 members of a German family, where 6 had died suddenly at the ages of 3 months, 6, 39, 39 and 49 years old respectively and one unknown. Four family members had ECGs with short QT interval, including one of the sudden cardiac death victims.

This article also included the first data from electrophysiologic studies of patients with Short QT Syndrome including the very short ERP’s in such patients both in the atria and the ventricles, and also a high incidence of VF (2 out of 4) in these patients during simple catheter positioning in the right ventricle.

Finally the minimal shortening of the QT interval during stress testing was pointed out by the authors, who had implanted ICD’s prophylactically in 3 patients with Short QT Syndrome.

Based upon this excellent and very comprehensive publication by Gaita et al. in Circulation August 2003 of two families with high incidence of sudden cardiac death in the setting of familial short QT interval, there was finally enough clinical data to support our initial findings suggesting a new clinical syndrome: Short QT Syndrome.

September 29,2003: Press release from Saint Louis University Hospital

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

Incidentally the over-sensing of the T wave lead to the observation, that patients with short QT syndrome often have prominent peaked T waves.

It was from the Masonic Medical Research Laboratory, Utica, NY the first report about a mutation linked to Short QT Syndrome came in January 2004.

Genetic testing was performed in members of the previously described two families from Italy and Germany in addition to a family from the US consisting of a 51 y.o. father with aborted SCD and his 20 y.o. son, who both had short QT intervals < 300 msec.

In the German family they identified a missense mutation (c to g substitution at nucleotide 1764) in KCNH2 and in the Italian family a different missense mutation in the same residue     (c to a substitution at nucleotide 1764). Both mutations, however, substituted the asparagine (N) at codon 588 in KCNH2 protein for a positively charged lysine (K) resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac I_Kr channel HERG (KCNH2). No mutation was found in the US family.

The net effect of the mutation is to increase the repolarization currents active during the early phases of the AP, by eliminating current inactivation leading to loss of normal rectification of the current at plateau voltages with abbreviation of the action potential and thus abbreviation of the QT interval.

The N588K missense mutation was also shown to reduce the affinity of the channel for drugs with class III antiarrhythmic action such as Sotalol and Dofetilide. Sotalol did not prolong the QT interval in patients with short QT.

This was the first description of a genetic abnormality responsible for cases of SQTS – later referred to as  SQT1.

Six members from the previously mentioned 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. The slight prolongation of the QT interval following Flecainide was mainly due to QRS prolongation.

The lack of QT prolongation following selective I_Kr-blocking agents like Ibutilide and Flecainide suggest that the (N588K) mutation in the KCNH2 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.

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.

This study was in a very small group of patient with a single mutation, and the results, therefore, not necessarily applicable to future patients with Short QT Syndrome and other mutations, who might respond to these antiarrhythmic drugs differently.

At the Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, the authors produced and characterized the first transgenic mouse model of I_K1 up-regulation, which lead to multiple abnormalities in excitability, including pronounced shortening of action potentials and effective refractory period with a short QT interval in the ECG.

The authors felt their data strongly supported the notion that a short QT interval is indeed associated with life-threatening arrhythmias in humans. Thus the transgenic mouse model of I_K1 up-regulation might be considered the first experimental model of Short QT Syndrome.

Interestingly enough, in 2005 a group from The University of Pavia, Italy (Silvia G. Priori el al.) found a mutation in the KCNJ2 gene that regulates the Kir2.1 potassium channel (I_K1) in a patient with Short QT Syndrome. Since it was the third mutation found in a patient with Short QT Syndrome, it was named SQT3.

Wolpert C, Schimpf R, Veltman C, Giustetto C, Gaita F, Borggrefe M. (University Hospital Mannheim, Mannheim, Germany) Clinical charactetics and treatment of short QT syndrome. Expert Rev. Cardiovasc. Ther. 2005;3(4):1-7

Case report of a previously asymptomatic 16 y.o. male from the first German family with Short QT Syndrome had received a prophylactic ICD. He had a QT interval of only 248 msec with a QTc of 252 msec. Interestingly, at his initial work-up ventricular tachy-arrhythmias could not be induced during programmed ventricular stimulation. Six month later the ICD saved his life, when he developed ventricular fibrillation during sleep.

The episode occurred during a HR of approximately 60 bpm, initiated by a premature beat with a coupling interval of 180 msec.

In Sevilla, Spain a baby girl was born following interruption of the pregnancy at 38 weeks due to severe bradycardia and irregular rhythm, suggesting atrial fibrillation since the 6^th month of gestation. At birth the baby was stable at a heart rate of 60 bpm. The ECG showed a short QT interval and atrial fibrillation was confirmed by intracardiac electrography.  DC cardioversion was unsuccessful.

By a combined effort at several laboratories headed by the Masonic Medical Research Laboratory in Utica, NY, USA, genetic testing of the baby and her biological parents was performed.

Since KCNQ1 mutations had been shown to lead to familial atrial fibrillation (Chen et al. 2003) and short QT (Bellocq et al.2004) the group decided to analyze the DNA sequence of KCNQ1 in the baby girl.

The genetic testing confirmed the suspicion of a mutation in KCNQ1, with a G to A substitution at nucleotide 421 (g421a). This mutation results in substitution of valine by methionine at position 141 (V141M) adjacent to a previously described S140G mutation for familial AF, and different from theV307L-KCNQ1 mutation previously found in an adult patient with SQTS.

The mutation causes I_Ks channels to remain constitutively open leading to shortening of the action potential and tendency to atrial fibrillation.

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Mark Michael Gallagher and his colleagues at the Department of Cardiological Sciences, St. George’s Hospital Medical School, London, UK used an existing archive of medical information from apparently healthy subjects at the The Medical Forensic Institute of Rome, Italy to investigate the distribution and prognostic importance of shorter QT intervals.

Among 12,012 healthy Italian subjects (90.7 % male) 30 +/- 10 years old the cut-off QTc for the lowest half centile (60 subjects) was 361 msec and the shortest QTc 335 msec.

36 subjects with QTc ≤ 360 ms were followed for 7.9 +/- 4.5 years and none of them died suddenly during that period.

The QT intervals were measured manually and the end of the T wave was the point at which the T wave returned to the isoelectric line. QTc was calculated according to Bazett formula. Since Bazett formula overcorrects at slow heart rates the significantly slower heart seen in subjects with the shortest QTc should not be a surprise.

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

By screening of 82 consecutive probands with clinically robust diagnosis of Brugade Syndrome at genetic laboratories in the US, Germany, France and Italy for ion channel gene mutations, 3 probands displaying ST-segment elevation in V1 through V3 and QTc </= 360msec were found among 7 who had mutations in genes encoding the cardiac L-type calcium channel. In addition in these 3 patients rate adaptation of QT interval was found to be reduced just like in patients with SQTS and Quinidine normalized the QT intervals and prevented stimulation-induced VT.

Genetic and heterologous expression studies revealed loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the α₁ and β_2b –subunits of the L-type calcium channel.

Patch-clamp experiments showed that the two mutations in CACNA1C and the one mutation in CACNB2b all cause a major loss of function in calcium channel activity.

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.

In this study Arnestad et al. presents a patient with Sudden Infant Death Syndrome in whom a I274V-KCNQ1 mutation was found, and in the following study by Rhodes et al the mutation was found to cause a short QT interval phenotype:

Rhodes TE et al. Cardiac Potassium Channel Dysfunction in Sudden Infant Death Syndrome J Moll Cell Cardiol 2008;44(3):571-581

Electrophysiological data from patch clamp recordings (Chinese hamster ovary cells) showed that the I274V-KCNQ1 mutation in the presence of KCNE1 causes gain of function in Iks characterized by increased current density, faster activation, slower deactivation, and accumulation of instantaneous current during repeated stimulation.

To test the hypothesis that I274V may promote a short QT syndrome phenotype, computerized modeling of ventricular action potentials were performed comparing WT-Iks to heterozygous I274V-Iks. At all cycle length the AP was shorter for I274V-Iks supporting the prediction that I274V-KCNQ1 will cause a short QT phenotype, a plausible explanation for sudden death in an infant carrying this mutation.

The first original article dealing with safety issues concerning drug induced shortening of the QT/QTc interval based upon presentations at a session held at the 2007 Safety Pharmacology Society meeting in Edinburgh.

It is concluded that it is currently  not clear how much shortening of QT/QTc is required before it might be considered a safety issue and indeed, whether QT/QTc shortening is a suitable biomarker for cardiac arrhythmias. It is found to be clear, however, that with our current understanding, compounds which shorten QT/QTc will attract close regulatory scrutiny.

From 15 articles describing unique cases of SQTS the authors reviewed 61 SQTS cases as a basis for a scoring system to assist in making the diagnosis of SQTS.

Several possible limitations and errors in this scoring system proposed by Gollop MH et al. were, however, soon pointed out by Veltman C et al and Bjerregaard P in the following letters:

Veltman C, Borggrefe M. A ‘Schwartz score’ for short QT Syndrome. Nat Rev. Cardiol. 2011;8:251-252 The lack of a control group of ‘normal’ individuals with shorter than normal QTc intervals is pointed out and it is stressed that at best the scoring system can do is to estimate the probability of having the disease, not to make the diagnosis. Also the omission of using data from an electrophysiological study or exercise testing in the scoring system is emphasized.

Bjerregaard P. Proposed Diagnostic Criteria for Short QT Syndrome Are Badly Founded. J Am Coll Cardiol 2011;58:549-550. The author points out several errors in the collection of date to the article, and the limitations of using Bazett’s formula to correct the QT interval in patients with possible SQTS. It is the opinion of the author: “that the proposed diagnostic criteria for SQTS are poorly founded and should be used with great caution”.

In this study 53 patients from the European Short QT Registry (75% males; median age: 26 years) were followed for 64 +/- 27 months.

A familial or personal history of cardiac arrest was present in 89%. Sudden death was the clinical presentation in 32%. The average QTc was 314 +/- 23 ms. A mutation of genes related to SQTS was found in 23 % of the probands: most of them had a gain of function mutation in HERG (SQTS1). Twenty-four patients received an ICD, and 12 patients received prophylactic treatment with hydroquinidine.

During follow-up, 2 already symptomatic patients received appropriate ICD shocks, and one had syncope. No arrhythmic events occurred in patients receiving hydroquinidin.

In this study 25 patients 21 years or younger from 15 different centers (84% males: median age: 15 years) were followed up for 5.9 years.

A familial or personal history of cardiac arrest was present in 84%. The mean QTc was 312 ms (range: 194 to 355 ms). A gene mutation associated with SQTS was identified in 5 (24%) of 21 probands. Ten patients received medical treatment, mainly with quinidine. Eleven of 25 index cases underwent ICD implantation.

During follow-up two patients had appropriate ICD shocks, while inappropriate shocks were observed in 64 % of patients

Based upon the fact that cation channel mutations explain < 25 % of SQTS cases and other classes of genes therefore likely to be associated with the development of this disease, Thorsen K et al. in a study of two Danish families with dominantly inherited SQTS specifically looked for involvement of other genes by whole exome sequencing. In their study they identified a novel genetic etiology for SQTS in terms of a mutation in the anion exchanger Solute Carrier Family 4 Member 3 (SLC4A3) gene, which encodes a Cl,HCO₃ –exchanger (AE3). The AE3 transports Cl^- into the cardiomyocyte in exchange for transport of HCO₃^- out of the cell. The mutation leads to a trafficking defect, decreased Cl,HCO₃-exchange over the cell membrane, increased pH_i in combination with a decrease in Cl^-_I and was shown to shorten QT duration in zebrafish embryos. The authors have clearly identified a novel mutation in the cardiac chloride-bicarbonate exchanger AE3 in two independent families with SQTS, and in zebrafish demonstrated the impact of the mutation on duration of systolic contraction and on QTc duration. The authors suggest that the mechanism through which a defect in Cl,HCO₃-exchange leads to shortening QTc likely relates to a combined effect of a decrease in HCO₃^- efflux (i.e. increased pH_i) and a decrease in Cl^- influx, both affecting the repolarization. It is also suggested that these findings in addition to offering insight into mechanisms of arrhythmia in general may provide new treatment possibilities in some patients with SQTS.