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Short QT Syndrome


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Puplications related to Short QT Syndrome

In nine different categories the articles are presented in chronological order with each article followed by a brief summery and occasionally a comment in italic by the creator of this website.

Definition and prevalence of short QT interval

Short QT interval in situations other than SQTS

Clinical cases of SQTS

Genetic and cellular basis for SQTS

Experimental models of Short QT

Treatment of SQTS with an ICD

Pharmacological treatment of patients with SQTS

Review articles of SQTS

Miscellaneous





Definition and prevalence of short QT interval

Schulze-Bahr E, Breithardt G.
Short QT Interval and Short QT Syndrome.
J Cardiovasc Electrophysiol 2005;16:397-398
Summery:The authors present data from several papers showing the lower limit of normal for the QT interval, including Rautaharju's data from 14000 healthy individuals, where the lower limit of normal for the QT interval at 60 bpm was 361 msec.

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
Summery: Among 12,012 healthy Italian subjects (90.7 % male) 30 +/- 10 years old the cut-off QTc for the lowest half centile of QTc values (60 subjects) was 361 msec and the shortest QTc 335 msec. Comments: 36 subjects with QTc ≤ 360 ms were followed for 7.9 +/- 4.5 years and none of them died suddenly.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 in subjects with the shortest QTc is no 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.

Mason JW, Ramseth DJ, Chanter DO, Moon TE, Goodman DB, Mendzelevski B. Electrocardiographic reference ranges derived from 79,743 ambulatory subjects.
J Electrocardiology 2007;40:228-234.
Comment: No particular reference to short QT.

Reinig MG, Engel TR.
The Shortage of Short QT Intervals.
CHEST 2007;132:246-249
Summery:In a hospital based population of 106,432 patients the mean QTc (+/- SD) was 430 +/- 19 msec , not a single ECG was found to have a QTc ≤ 300msec

Anttonen O, Junttila MJ, Rissanen H, Reunanen A, Viitasalo M, Huikuri HV.
Prevalence and Prognostic Significance of Short QT Interval in a Middle-Aged Finnish Population.
Circulation 2007;116:714-720
Summery: 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. Comment: 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 isoelectric 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 QTc were the subjects with the lowest heart rate. Bazett's formula is known for its tendency to over-correct the QT interval during bradycardia.

Viswanathan MN, Page RL.
Short QT. What Does It Matter?
Circulation 2007;116:686-688
Editorial to the previous article.
Comment: An important fact pointed out by the authors is related to the 11 patients with QTc < 320 msec who were followed for approximately 29 years. The 95 % confidence interval around an incidence of 0 sudden death out of 11 with QTc less than 320 ms would include frequencies that might even allow for implantation of a prophylactic ICD.The authors suggest, however, that one should consider SQTS in a patient with QTc < 340 msec when seen in the context of other factors suggestive of an increased risk of serious arrhythmic events (such as syncope or family history of sudden death).

Moriya M, Seto S, Yano K, Ahahoshi M.
Two Cases of Short QT Interval.
PACE 2007;30:1522-1526
Summary: 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 (0.01 %) were found to have QTc < 350 msec, but none of them a family history or symptoms suggesting SQTS.

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
Summary:ECGs were obtained from a hospital population of 12,149 and in 10,984 the RR and QT intervals were measured. The QTc values showed a near normal distribution with mean +/- SD of 408 +/- 25 msec and a range (SD +/- 2 SD) of 458-358 msec. The minimum QTc was 290 msec and only 3 subjects had QTc < 300 msec (Which was their definition of SQTS, but none had clinical symptoms compatible with that diagnosis).

Miyamoto A, Hayashi H, Toshino T, Kawaguchi A, Taniguchi A, Itoh H, Sugimoto Y, Itoh M, Makiyama Y, Xue JQ, Murakami Y, Horie M.
Clinical and electrocardiographic characteristics of patients with short QT interval in a large hospital-based population.
Heart Rhythm 2012;9(1):66-74
Summary: In a hospital-based population of 114,334 QT intervals and HRs were digitally measured, and 427 found to have short QT interval defined statistically (0.15 percentile) as QTcB </= 362 ms in males and </= 369 ms in females. Out of this group 327 patients were followed a mean of 54 months, and during that period 2 patients developed life-threatening events. One patient who also had early repolarization had recurrent VF related to bradycardia and another patient with Brugada type ECG after IV Pilsicainide had recurrent syncope during sleep. Genetic testing of these two patients was negative.

Kobza R.
Identifying risk of cardiac events in short QT syndrome.
Heart rhythm 2012;9(1):75-76 (Editorial to the article above)
Comment: The author rightly points out the possible relationship between early repolarization and short QT, and also between atrial fibrillation and short QT.

Iribarren C, Round AD, Peng JA, Lu M, Klatsky AL, Zaroff JG, Holve TJ, Prasad A, Stang P.Short QT in a Cohort of 1.7 Million Persons: Prevalence, Correlates, and Prognosis.
Ann Noninvasive Electrocardiol 2014;19(5):490-500.
Conclusion: QTcreg ≤ 300 ms was extraordinarily rare and was associated with significant ECG abnormalities and reduced survival.
Comment: Factors independently and significantly associated with validated QTcreg ≤ 300 ms were age over 65 years, Black race, prior history of ventricular dysrhythmias, COPD, ST-T abnormalities, ischemia, bigeminy pattern, and digitalis effect.

Guirrier K, Kwiatkowski D, Czosek RJ, Spar DS, Anderson JB, Knilans TK.
Short QT Interval Prevalence and Clinical Outcomes in a Pediatric Population.
Circ Arrhythm Electrophysiol. 2015;8:1460-1464.
Conclusions: Short QT interval (</+ 340 ms) was a rare finding in this pediatric population, with a prevalence of 0.05%. Male predominance was identified, although the median QT interval was significantly shorter in women. There seem to be no unifying clinical characteristics for this pediatric patient cohort with short QT interval.

Dhutia H, Malhotra A, Parpia S. Gabus V, Finocchiaro G, Mellor G, Merghani A, Millar L, Narain R, Sheikh N, Behr ER, Papadakis M, Sharma S.
The prevalence and significance of a short QT interval in 18,825 low-risk individuals including athletes.
Br J Sports Med
2015;0:1-6 (Online publication Sept 23, 2015).
Conclusion: The prevalence of a short QT-interval depends upon the recommended cut-off values. Even at values </= 320 ms, there was an excellent medium term prognosis among 14 people followed. The authors conclude that a definition of </= 320 ms is realistic to prevent overdiagnosis and excessive investigations.

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Short QT interval in situations other than SQTS

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
Summary: 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 IkACh 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?

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

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
Summary: ECGs of 28 patients with idiopathic VF (17 men and 11 women, age 31 +/- 17 years) 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.
Comment: The findings suggest, but does not prove, that QTc intervals shorter than 360 msec may entail some arrhythmic risk.The study also emphasizes that QTc </= 360 msec (for males) or QTc </= 370 msec (for females) are not exceptional in healthy adults, especially during bradycardia.

Zareba W.

Idiopathic VF and short repolarization: Intriguing new concept.
Heart Rhythm 2004:1(5);592-593
(Editorial comment to the article above by Viskin S et al.).
Summary: It is pointed out that the difference in QTc between controls and patients with idiopathic ventricular fibrillation is very small (14 msec on average) and could be an incidental finding. Problems in using a much larger control group than patient group for comparison is pointed out, and the lack of a difference between the female groups is puzzling.

Morphet JAM.
The short QT syndrome and sudden infant death syndrome.
Can J Cardiol 2007;23(2):105
Summary: Three week-old neonate was admitted with episodes of apnea. The ECG showed QT-interval of 210 msec. During ECG monitoring sinus node dysfunction in terms of sinus bradycardia, sinus arrest and atrial and ventricular standstill was observed.

The case was interpreted as SIDS with SQTS in which sinus node dysfunction was an important aspect of the pathophysiology.

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
Summary: By screening of 82 consecutive probands with clinically robust diagnosis of Brugade Syndrome for ion channel gene mutations, they found 3 probands displaying ST-segment elevation in V1 through V3 and QTc </= 360msec among 7 who had mutations in genes encoding the cardiac L-type calcium channel. Rate adaptation of QT interval was reduced 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 β2b -subunits of the L-type calcium channel.
Comment: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 short QT intervals.

Itoh H, Sakaguchi T, Ashihara T, Ding W-G, Nagaoka I, Oka Y, Nakazawa Y, Yao T, Jo H, Ito M, Nakamura K, Ohe T, Matsuura H, Horie M.
A novel KCNH2 mutation as a modifier for short QT interval.
Int J Cardiol 2008
Comment: This study using voltage clamp experiments describes a novel C-terminal KCNH2 mutation, R1135H, which was able to explain both the marked QT shortening (QTc 329 msec) and the Brugada-type ECG seen in a 34 year-old man.
Later these findings were confirmed by computer stimulation studies by:

Wilders R and Verkerk AO.
Role of the R1135H KCNH2 mutation in Brugada syndrome.

Int J Cardiol 2010;144:149-51.

Bigi MAB, Aslani A, Aslani A.
Short QT Interval: A Novel Predictor of Androgen Abuse in Strength Trained Athletes.
Ann Noninvasive Electrocardiol 2009;14(1):35-39
Summary: The QTc was measured in 90 sedentary men (418 +/- 24 msec), 86 drug-free bodybuilders (422 +/- 25 msec) and in 79 bodybuilders using anabolic androgenic steroids (367 +/- 17 msec). The heart rate was the same in the two groups of bodybuilders.

Holbrook M, Malik M, Shah RR, Valentin J-P.
Drug induced shortening of the QT/QTc interval: An emergence safety issue warranting further modeling and evaluation in drug research and development.
J Pharmacology and Toxicology Methods 2009;59:21-28

Discussions from a session dedicated to the issue of drug-induced QT and/or QTc interval shortening of the ECG held at the 2007 Safety Pharmacology Society meeting in Edinburg.

Shah RR, Bjerregaard P, Gussak I.
Drug-induced QT interval shortening: an emerging component in integrated assessment of cardiac safety of drugs.
J Electrocardiol 2010 (Editorial)

Bjerregaard P, Nallapaneni H, Gussak I.
Short QT interval in clinical practice.
J Electrocardiol 2010;43:390-395

Summary : Review of clinical settings with short QT interval, including SQTS, idiopathic VF, Brugada syndrome, early repolarization, hypercalcemia, chronic fatigue syndrome and hyperthermia.

Bohora S, Namboodiri N, Tharakan J, Kumura A, Nayyar S.
Dilated Cardiomyopathy with Short QT Interval: Is It a New Clinical Entity?

PACE 2009;32:688-690

Summary: 27 year-old male presents with an eight-year history of dyspnea on exertion. ECG shows Atrial fibrillation with narrow QRS and QT 260 msec (QTc always < 320 msec). Echocardiography showed severe dilated cardiomyopathy (LVEF 36%).

Evaluation of his brother and only younger sibling also showed dilated cardiomopathy (LVEF 48%) with atrial fibrillation with narrow QRS and QT 312 msec (average QTc 302 msec). No other family members with known heart disease. Genetic testing not performed.

Efremidis M, Letsas KP, Weber R, Gavrielatos G, Filippatos GS, Sideris A, Kardaras F. Recurrent syncope associated with a distinct ECG pattern consisting of short QT interval, early repolarization and atrioventricular block.
Clin Res Cardiol 2009;98:807-810

Summary : 17-year-old individual with recurrent syncope and ECG showing prominent J-waves, ST-elevation and short QT interval of 320 msec (QTc 283 msec). Early repolarization disappeared during stress test. Positive late potentials. Holter monitoring showed several episodes of abrupt advanced AV block with longest RR of 4.2 sec's (apparently during sinus bradycardia). Procainamide challenge did not induce Brugada sign. Quinidine normalized the QT interval.EP study showed AH 110 msec, HV 49 msec. AERP 190 msec, VERP 200 msec. No atrial or ventricular arrhythmias and no AV block induced during EP study . Genetic testing negative. Because of the combination of a short QT interval and positive late potentials the patient was found to be at a high risk for ventricular tachy-arrhythmias and received an ICD.

Watanabe H, Makiyama T, Koyama T, Kannankeril PJ, Seto S, Okamura K, Oda H, Itoh H, Okada M, Tanabe N, Yagihara N, Kamakura S, Horie M, Aizawa Y, Shimizu W. High prevalence of early repolarization in short QT syndrome.
Heart Rhythm 2010;7:647-652

Summary : This study consisted of 3 cohorts: 1) 37 SQTS patients (12 new patients with QTc </= 330 msec plus an arrhythmic event and/or genetic mutation, and 25 patients with SQTS from the literature), 2) 44 control cohort with QTc ≤ 330 msec and no symptoms, and 3) 185 control cohort with normal QTc and no sign or symptoms of heart disease. The prevalence of early repolarization was 65% in cohort 1, 30% in cohort 2 and only 10% in cohort 3. In a multivariable model early repolarization was associated with arrhythmic events in the SQTS cohort whereas neither QT nor QTc duration were associated with arrhythmic events. Conclusion: There is a high prevalence of early repolarization in patients with SQTS. Early repolarization may be useful in identifying risk of cardiac events in patients with SQTS. Comment : Approximately 75% in all 3 groups were males.

Panicker GK, Manohar D, Karnad DR, Salvi V, Kothari S, Lokhandwala Y.
Early repolarisation and short QT interval in healthy subjects.
Heart Rhythm 2012;9:1265-1271

Summary: Out of 1886 healthy subjects early repolarization (ER) was found in 514 or 27 %. 35% of males had ER compared to only 2% of females. Highest prevalence was seen in 18- to 29-y-o. The ER group had slightly shorter QTcF (11 +/- 22 ms) than the non-ER group. Only 4 subjects has QTcF < 350 ms and none < 340 ms..

Conclusion : Although ER may be common in subjects with short QT , the converse does not appear to be true.

Schimpf R, Veltman C, Papavassiliu T, Rudic B, Göksu T, Kuschyk J, Wolpert C. Antzelevitch C, Ebner A, Borggrefe M, Brandt C.
Drug-induced QT-interval shortening following antiepileptic treatment with oral rufinamide.
Heart Rhythm 2012;9(5):776-781.
Conclusion: QTc shortening following oral rufinamide administration in a small patient group (19 patients) was not associated with significant clinical adverse effects. These observations notwithstanding, the ability of rufinamide to significantly shorten the QT interval portends a potential arrhythmogenic risk that may best be guarded against by periodic electrocardiographic recordings.

Babaoğlu K, Binnetoğlu K, Altun G, Tuzcu V.
A 13-year-old boy with a short QT interval.
Anadolu Kardiyol Derg 2012;12(3):

Summary : 13 y.o. child with recurrent chest pain, but otherwise asymptomatic. His ECG typical for Short QT syndrome with QT of 280 msec at 62 bpm and tall peaked T-waves in lateral precordial leads. His mother had a QT interval of 320 msec (HR?). His maternal uncle died suddenly at 28 years of age of possible myocardial infarction. An electrophysiologic study showed AERP of 230 ms and VERP of 170 msec, and no inducible arrhythmias. Genetic testing not performed. Comment: Only long term follow-up will be able to tell whether this patient has SQTS. Because of the very short QT interval and relatively short VERP close follow up is warranted. Reports from electrophysiological testing of patients with clinical SQTS has shown inducibility by PES in only 73% and a sensitivity of predicting cardiac arrest of only 37%. A negative PES study in this patient is, therefore, not that reassuring.

Chinushi M, Sato A, Iijima K, Suzuki K, Hiroshi F, Izumi D, Watanabe H, Kanae H, Aizawa Y.
Exercise-Related QT Interval Shortening with a Peaked T Wave in a Healthy Boy with a Family History of Sudden Cardiac Death.

PACE 2012;35:e239-e242

Summary : 15 y.o. asymptomatic boy underwent extensive electrophysiologic examination due to sudden unexplained death in two older siblings, who had normal QT intervals ( 284 ms at 112 beats/min and 378 msec at 55 bpm respectively). The boy had a normal ECG with QT interval of 320 msec at 73 beats per minute (QTc(B) of 388 msec. During a stress test the QT interval shortened to 200 msec while peaking of the T waves were noticed. During an EP study polymorph non-sustained VT episodes were induced and a peculiar hump became apparent on the T wave of the first post-pacing beat. VERPs less than 170 msec were found in both the atria and the ventricles. A genetic test revealed only a single nucleotide polymorphism (C5457T) in the SCN5A gene. The authers suggest that the patient might be in the intermediate range of probability of SQTS.

Comment : A borderline short QT at rest and significant shortening of the QT with an increase in heart rate does not support a diagnosis of SQTS.

Jørgensen IN, Skakkebæk A, Andersen NH, Pedersen LN, Hougaard DM, Bojesen A, Trolle C, Gravholt CH.

Short QTc Interval in Males with Klinefelter Syndrome - Influence of CAG Repeat Length, Body Composition, and Testosteron Replacement Therapy.

PACE 2015;38:472-482

This is a case control study of 62 males with KS and 62 healthy males matched on age.

Comment : CAG (trinucleotide consisting of cytosine, adenine and guanine) repeat length at the androgen receptor situated on the X chromosome is an indicator of testosterone sensitivity, which has previously been linked to other aspects of Klinefelter Syndrome. Summary: QTc intervals were found to be shorter in males with KS, with further shortening of the QTc interval by testosterone. The results suggest that genes on the X chromosome could be involved in regulation of the QTc interval and that testosterone treatment may aggravate this mechanism.

Roussel J, Labarthe F, Thireau J, Ferro F, Farah C, Roy J, Horiuchi M, Tardieu M, Lefort B, Benoist JF, Lacampagne A, Richard S, Fauconnier J, Babuty D, Le Guennec JY.

Carnitine deficiency induces a short QT syndrome.

Heart Rhythm 2016;13:165-174.
Comment: Observational study of 3 patients affected by primary systemic carnitine deficiency and an associated short QT syndrome. Ventricular fibrillation during early adulthood was the initial symptom in 1 case.

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Clinical cases of SQTS

Gussak I, Brugada P, Brugada J, Wright RS, Kopecky SL, Chaitman BR, Bjerregaard P.
Idiopathic Short QT Interval: A New Clinical Syndrome.

Cardiology 2000;94:99-102

The first report of a family with a very short QT interval consisting of a 51 year old white female and her two children, a 17 year old daughter and a 21 year old son, discovered when the daughter presented with atrial fibrillation and a QT interval of 250 msec at a heart rate of 75 bpm. (Later it was discovered that the maternal grandfather also had very short QT interval and atrial fibrillation)

Added to the story of a 37 year old Spanish female with sudden cardiac death and an ECG with a QT interval of 266 msec at a heart rate of 52 bpm led to the suggestion of a link between the very short QT interval and the proclivity to atrial and ventricular tachy-arrhythmias from a very short refractory period in both the atria and ventricles.

The authors made the suggestion "If additional supporting clinical data becomes available, we believe that - in parallel with 'Long QT Syndrome' - the combination of short QT interval and electrical instability could appropriately be named the 'Short QT Interval Syndrome'."

Total # of cases: 4

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 periods in both atria and ventricles. Flecainide was shown to increase the refractory periods and make VF no longer inducible.
Comment: 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.
3 new cases (
Total # 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
Summary: In this paper the Italian family described at the ACC meeting in 2003 is combined with a description of a German family with very similar story. Among the 16 member Italian family there were 6 sudden cardiac death with one having documented short QT. Two additional members of the family had short QT. Two of the 3 patients with short QT also had left axis deviation suggesting left anterior hemiblock. Among the 23 member German family there were 3 sudden cardiac death with one having documented short QT. Three additional members of that family had short QT. Six out of the 7 patients with short QT 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 patients showed any evidence of structural heart disease. Baseline ECG showed in all patients 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.
Comment: This paper had clearly demonstrated the malignant nature of idiopathic, very short QT interval.
4 new cases (Total # 11)

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
Summary : 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 his 20 y.o. son who both had a QTc < 300 msec. In the German family they identified a missense mutation (c1764g) in KCNH2 and in the Italian family a different missense mutation (a1764a) in the same residue. Both mutations, however, substituted the amino acid, asparagine (N) at codon 588 in KCNH2 protein for the positively charged lysine (K) (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). 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 as the end result. 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. Comment: This was the first description of a genetic abnormality responsible for some cases of SQTS - later referred to as SQT1.

2 new cases (Total # 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.
Summary:This paper describes a 70-year old male with aborted VF episode and a short QT interval of 290 msec in several ECGs during a 3-year follow-up period. Analysis of candidate genes identified a g919c substitution in KCNQ1 (V307L (valine to leucine) mutation) encoding the K+ channel KvLQT1, which, in association with the ß-subunit KCNE1 (mink, IsK), forms the slow component of the cardiac rectifier K+ current (IKs). Patch-clamp data and computational studies showed that the mutation caused the channel to activate faster and at more negative potentials favoring the association of a short QT interval with mutation in KCNQ1. Comment: This was the second description of a genetic defect leading to SQTS - later called SQT2
1 new case (total # 14)

Bjerregaard P, Gussak I.
Atrial Fibrillation in the Setting of Familial Short QT Interval
Heart Rhythm 2004;1(1S):522
Comment: Grandfather to the very first patient with Short QT Syndrome here described for the first time.
1 new case (total # 15)

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. (IRCCS Fondazione Maugeri, Pavia, Italy)
A Novel Form of Short QT Syndrome (SQT3) Is Caused by a Mutation in the KCNJ2 Gene.
Circ Res . 2005;96:800-807
Summary: An asymptomatic 5-year-old girl presented with an ECG during routine clinical evaluation with a QTc of 315 ms and noticeably narrow, peaked and asymmetrical T waves. Her father had a QTc of 320 ms and a history of presyncopal events and palpitations since the age of 15. He underwent electrophysiologic investigation showing VERP of 160 msec and induction of VF by 3 extrastimuli. He refused an ICD. 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 (IK1). The authors hypothesized that the tall and asymmetrical T-waves with an exceedingly rapid terminal phase not seen in SQT1 or SQT2 patients may be related to a sudden acceleration of the final phase of action potential repolarization in the D172N mutation. None of the patients had any documented spontaneous tachy-arrhythmias. Whole-cell patch-clamp studies of the heterologously expressed human D172N channel demonstrated larger outward IK1 than the wild-type at potentials between 75mV and -45 mV, with the peak current being shifted in the former with respect to the later (WT, -75mV; D172N and -65 mV). Coexpression of WT and mutant channels to mimic heterozygous condition of the proband yilded an outward current that was intermediate between WT and D172N. This was the first case of what was later called SQT3.
2 new cases (total # 17)

Riera ARP, Ferreira C, Dubner SJ, Schapachnik E, Soares JD, Francis J. (ABC Foundation, Santo André, Saõ Paulo, Brazil)
Brief Review of the Recently Described Short QT Syndrome and Other Cardiac Channelopathies.
A.N.E . 2005;10(3):371-377
Summary: 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.
1 new case (total # 18)

Maury P, Hollington L, Duparc A, Brugada R. (University Hospital Rangueil, Toulouse, France) Short QT syndrome: Should we push the frontier forward? Heart Rhythm 2005;2:1135-1137
Summary: 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.
Comment: 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.
3 new cases (total # 21)

Kirilmaz A, Ulusoy RE, Kardesoglu E, Ozmen N, Demiralp E. (Gulhane Military Medical Academy Haydarpasa Training Hospital, Istanbul, Turkey)
Short QT interval syndrome: a case report.
J Electrocardiol 2005;38:371-374
Summary: The first patient with SQTS in Turkey. A 20-year-old male presented with atrial fibrillation at an average HR of 54 bpm. And a QT interval of 308-340 msec. The patient was unable to point a specific time indicating the beginning of atrial fibrillation. On standard Bruce protocol stress test he achieved a maximal HR of 90 bpm in stage 4. EP study showed normal HV of 42 msec. VF was inducible by triplets from the RV where the effective refractory period was 130 msec at 400 msec drive cycle length. The patient remained in atrial fibrillation following defibrillation.
Comment : This case is very similar to the one later described by Hong K. et al. in Cardiovascular Research 2005;68:433-440 (See below), and more recently by Villafane J. et al. in Cardiology 2014;128:236-240
1 new case (total # 22)

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. (Masonic Medical Research Laboratory, Utica, NY)
De novo KCNQ1 mutation responsible for atrial fibrillation and Short QT Syndrome in utero.
Cardiovasc Res 2005;68:433-440
Summary: 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. The HR was 60 bpm and an EP study showed normal HV interval suggesting AV nodal block. DC cardioversion was unsuccessful. Genetic testing showed a missense mutation, 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. The mutation causes IKs channels to remain constitutively open leading to shortening of the action potential and tendency to atrial fibrillation.
Comment: The unsuccessful attempt of cardioversion and slow HR suggest both sinus nodal and AV nodal disease.
1 new case (total # 23)

Giustetto C, Di Monte 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. Eur Heart Journal 2006;27:2440-2447

Summary: Multicenter European study of 29 patients with SQTS including 3 children with aborted SCD. Four families consisting of a total of 12 patients and 4 sporadic cases is presented for the first time

16 new cases (total # 39)

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

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

Resuscitation 2007;71(1):115-121.
Comment: A 30 year old resuscitated woman with short QT is described together with an example of the classic ECG characteristics. A short-coupled variant of torsade de pointes was revealed on Holter recordings.

3 new cases (total # 42)

Sawicki S, Stadnicki W, Kuśnierz J, Kochmański M.
Zespół skróconego odstępu QT (Short QT Syndrome - a case report)
Kardiol Pol 2008;66(3):307312 (Article in Polish).
Comment: Two patients (23 y.o. male and his 42 y.o. mother) with short QT < 320 ms, non-inducible during EP study, but with non-sustained polymorph VT during Holterminitoring. Genetic testing not performed. The male received an ICD.

2 new cases (total # 44)

Fichet J, Genee O, Pierre B.
Fatal QT Interval.
Am J Emergency Med 2008;26:739.e5-739.e6.
Comment: 21 y.o. previously healthy women resuscitated from ventricular fibrillation cardiac arrest. ECG two hours later shows SR with QT of 280 ms and QTc 315 ms in addition to prominent peaked T waves. Following hospital admission the patient again developed VF with unsuccessful resuscitation attempt.

1 new case (total # 45)

Bjerregaard P, Collier JL, Gussak I.
Upper limits 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):AB43-4 (Oral presentation at Heart Rhythm 2008).
Comments: Eight previously unpublished individuals from 3 USA families were added to 45 previously published patients in order to provide a review of the World-Wide (10 countries) short QT population eight years after it was first described. Family # 1 consisted of 4 members with SQTS: 13 y.o. male with QT 300 ms at 65 bpm, 15 y.o. female with QT 310 ms at 73 bpm, 38 y.o. female with QT 335 ms at 59 bpm and 56 y.o. female with QT 324 ms at 68 bpm. Family # 2 consisted of 3 members with SQTS: 21 y.o. male with QT 299 ms at 70 bpm, 25 y.o. female with QT 330 ms at 81 bpm and ECG with RBBB+LPH, 60 y.o. male with QT 340 at 54 bpm. Family # 3 consisting of a newborn female with QT 220 ms at 105 bpm in the setting of atrial fibrillation. It was suggested that the previous upper limits for QT or QTc for short QT syndrome had been too low, and it was recommended that anyone with QT or QTc below 345 ms and their family be ruled out for SQTS.

8 new cases (total # 53)

Villafane J, Young ML, Maury P, Wolpert C, Anttonen, Hamilton R, Kannereril PJ, Fischbach PS.
Short QT Syndrome in a Pediatric Patient.

Pediatr Cardiol 2009
Comment: This article was based upon data collected from 10 male pediatric patients (ages 7 to 19 years old) from 8 families, from North American and European Centers, with SQTS. All, except for one patient, have been published previously.

1 new case (total # 54)

Liu G, Guo JH, Zhang P, LI XB, Sun YX.
Clinical characteristics and treatment of a Chinese family with congenial short QT Syndrome.
Zhinghua Xin Xue Guan Bing Za Zhi 2009;37(3):248-252 (Article in Chinese). Summary: 45 y.o. male presented with occasional dizziness and a family history including four members who had died suddenly at young ages. In addition to the proband himself, his two daughters and one son was diagnosed with SQTS. QTc intervals were ≤ 320 ms and T-waves were high and peaked. No genetic testing.

4 new cases (total # 58)

Watanabe H, Makiyama T, Koyama T, Kannankeril PJ, Seto S, Okamura K, Oda H, Itoh H, Okada M, Tanabe N, Yagihara N, Kamakura S, Horie M, Aizawa Y, Shimizu W. High prevalence of early repolarization in short QT syndrome.
Heart Rhythm 2010;7:647-652
(Described in more detail in the section about short QT interval in situations other than SQTS)

12 new cases (total # 70)

Redpath CJ, Green MS, Birnie DH, Gollob MH.
Rapid genetic testing facilitating the diagnosis of short QT syndrome.
Can J Cardiol 2009;25(4):e133-e135

1 new case (total # 71)

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

Summary: A total of 53 patients from the European Short QT Registry followed up for 64 +/- 27 months. Twenty patients had not been reported earlier.

20 new cases (total # 91)

Ruan Y, Cerrone M, Novelli V, Liu N, Blaufox AD, Sicca F, Moro F, Pessia M, Napolitano C, Priori SG.

Novel Mechanism of KCNJ2-Related Short QT Syndrome .

AHA Scientific Sessions 2011, Abstract 13462

3 new cases (total # 94)

Chinushi M, Sato A, Izumi D, Furushima H.

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.

J Cardiovasc Electrophysiol 2012;23:877-880

2 new cases (total # 96)

Hattori T, Makiyama T, Akao M, Ehara E, Ohno S, Iguchi M, Nishio Y, Sasaki K, Itoh H, Yokode M, Kita T, Horie M, Kimura T.
A novel gain of function KCNJ2 mutation associated with short-QT syndrome impairs inward rectification of Kir2.1 currents.
Cardiovasc Res 2012;93(4):666-673
Summary : An 8-year-old girl with a markedly short QT interval (QT/QTc = 172/194 ms) who suffered from paroxysmal AF was studied. Mutational analysis identified a novel heterozygous KCNJ2 mutation, M301K. Functional assays displayed no Kir2.1 currents when M301K channels were expressed alone. However, co-expression of wild-type (WT) with M301K resulted in larger outward currents than the WT at more than -30 mV. These results suggest a gain-of-function type modulation due to decreased inward rectification. In addition to paroxysmal AF the girl had been suffering from multiple disorders, such as severe mental retardation, abnormal proliferation of oesophageal blood vessels, epilepsy, and Kawasaki disease. Her family did not undergo genetic evaluation, but ECGs from her father, elder brother and a younger sister showed a normal QT in all of them.
1 new case (total # 97)

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

Summary: 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). His mother also presented with SQTS by ECG (QT interval not provided). No mutations were found in KCNH2 or KCNQ1 genes.

2 new cases (total # 99)

Villafañe J, Atallah J, Gollob MH, Maury P, Wolpert C, Gebauer R, Watanabe H, Horie M, Anttonen O, Kannankeril P, Faulkner B, Bleiz J, Makiyama T, Shimizu W, Hamilton RM, Young M-L.

Long-Term Follow-Up of a Pediatric Cohort With Short QT Syndrome.

JACC 2013;61:1183-1191

1 new case (total # 100)

Deo M, Ruan Y, Pandit SV, Shah K, Berenfeld O, Blaufox A, Cerrone M, Noujaim SF, Denegri M, Jalife J, Priori SG.
KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia.
PNAS 2013;110(11):4291-4296
Summary: A new mutation (E299V) in KCNJ2 was found in an 11-y-old boy with recurrent atrial fibrillation and mild LV dysfunction. The patients ECG showed extremely abbreviated QT interval of 200 ms at 60 bpm with merging of the QRS and peaked T waves. Holter recording showed paroxysmal AF with an average HR of 98 bpm and confirmed the presence of a short QT interval that failed to adapt to HR.

Maltret A, Wiener-Vacher S, Denis C, Fabrice E, Morisseau-Durand MP, Fressart V, Bonnet D, Chabbert C.
Type 2 short QT syndrome and vestibular dysfunction: Mirror of the Jervell and Lange-Nielsen syndrome.
Int J Cardiol 2014;171(2):291-293
Summary: Baby girl born preterm at 32 weeks by cesarean section that was prompted by fetal bradycardia. The postnatal ECG showed sinus bradycardia at 69 bpm with QT interval of 260 ms. ECG monitoring repeatedly showed sinus bradycardia and junctional rhythms. Genetic analysis showed a V141M mutation in KCNQ1 similar to the findings in a newborn by Hong K, et al. in Cardiovasc Res 2005;68:433-40. The patient later had symptoms of imbalance and spontaneous left nystagmus suggesting a profound alteration of the canalar function.
Comment : The bradycardia suggest a sick sinus node as also demonstrated in the patient described by Hong K, at al.

Villafane J, Fischbach P, Gebauer R.
Short QT Syndrome Manifesting with Neonatal Atrial Fibrillation and Bradycardia. Cardiology 2014;128:236-240
Summary: Based upon four children identified in the literature and two patients followed by the authors, a subclass of patients with SQTS characterized by atrial fibrillation with slow heart rate presenting in early childhood is described.

Sadeghian S, Bozorgi A, Safkhani Z. Short QT syndrome and idiopathic ventricular tachycardia in a 28-year-old young man: a potential disease-specific link? EUROPACE 2014;16(11):1645
Summary:28 y.o. male presented with monomorph VT (RBBB, superior axis). One week earlier an ECG in sinus rhythm had shown a short QT less than 300 ms similar to post VT. No information about family history or genetic testing.

Portugal G, Oliveira MM, Cunha PS, Ferreira F, Lousinha A, Fiarresga A, da Silva MN, Ferreira C.
Short QT Syndrome presenting as syncope: How short is too short?
Rev Port Cardiol 2014;33(10)649.e1-649.e6
Summary: 52 y.o male with frequent episodes of sustained polymorph VT leading to syncope within a span of less than24 hours. No such episodes earlier or during 14 months follow-up after ICD implantation. His father had died suddenly at the age of 38 years old. QT interval was 280 msec with a QTc of 329 msec. Genetic testing negative. First reported case of SQTS in Portugal.

Suzuki H, Hoshina S, Ozawa J, Sato A, Minamino T, Aizawa Y, Saitoh A,
Short QT syndrome in a boy diagnosed on screening for heart disease.
Pediatr Int 2014;56(5):774-776
Summary: A QTc of 260 msec detected in a 10-year-old boy during school screening for heart disease. The patient had been asymptomatic except for two episodes of febrile convulsions at the age of 3 years. Family history significant for similar ECG finding in the mother and hx of SCD of maternal grandmother at the age of 45 years. Genetic testing in the boy and his mother showed in both of them a N588K mutation in the KCNH2 gene. During a treadmill exercise stress test heart rate increased, while the QT interval remained unchanged throughout the test.

Moreno C, Oliveras A, de la Cruz A, Bartolucci C, Muñoz C, Salar E, Gimeno JR, Severi S, Comes N, Felipe A, González T, Lambiase P, Valenzuela C.
A new KCNQ1 mutation at the S5 segment that impairs its association with KCNE1 is responsible for short QT syndrome.
Cardiovascular Research 2015;107:613-623
Summary: The index case is a 37-year-old man who died unexpectedly. Post mortem examination was negative. Later his 23-year-old healthy son underwent cardiac evaluation. ECG showed a QT of 330 ms at 70 bpm, QTc of 356 ms. Echocardiography, 24-hour Holter and exercise stress test negative. A blood sample from the son and his sister underwent genetic testing. Analysis of the KCNQ1 gene in the index case son, but not in his sister revealed a novel heterozygous mutation, a single base substitution at nucleotide 127910 (T127910A) in the exon 6 of the KCNQ1 gene, resulting in an amino acid change from phenylalanine to isoleucine at 279 in Kv7.1 (F279I) within the S5 transmembrane segment, which was not reported before. Functional analysis of F279I Kv7.1 in the presence of KCNE1 revealed a negative shift in the activation curve and an acceleration of the activation kinetics leading to a gain of function of IKs.

Ergül Y,Özyilmaz I, Onan SH, Güzeltaş A.
Short QT syndrome in a 14-year-old patient: The first pediatric case from Turkey.
Anatol J Cardiol 2015;15:586-591
Summary: 14-year-old male presented with syncope. His elder brother had died suddenly while taking a bath, and his father had died during sleep. QT-interval was 310 ms with a QTc interval of 320 ms. PES induced both atrial fibrillation and ventricular fibrillation with AERP of 150 ms and VERP of 160 ms. Result of genetic testing not available. Treated with Sotalol and an ICD.

Right D, Silvetti MS, Drago F.
Sinus bradycardia, junctional rhythm, and low-rate atrial fibrillation in Short QT syndrome during 20 years of follow-up: three faces of the same genetic problem.
Cardiol Young 2015;
Summary: Asymptomatic girl with sinus bradycardia and short QT at birth, junctional bradycardia in infancy requiring pacemaker, atrial fibrillation in adolescence, and V141M mutation in the KCNQ1 gene. Atrial fibrillation recurred and became unresponsive to electrical or anti-arrhythmic therapy. During 29 years of follow-up, a progressive evolution from sinus node dysfunction to low rate atrial fibrillation was observed. (Comment: Similar cases described initially by Hong K et al in 2005 and latest by Villafane J et al in 2013.)

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Genetic and cellular basis for SQTS

KCNH2

N588K-KCNH2

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 his 20 y.o. son who both had a  QTc < 300 msec. In theGerman 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 IKr channel HERG (KCNH2). No mutation was found in the American 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. Comment: This was the first description of a genetic abnormality responsible for some cases of SQTS - later referred to as  SQT1 . Standard whole-cell patch-clamp technique was used to measure currents in transfected human embryonic kidney cells (TSA201). KCNH2 channels (N588K) were coexpressed with and without the ancillary β-subunit KCNE2 (MiRP1).The N588K missense mutation was shown to abolish rectification of the HERG-current and reduce the affinity of the channel for drugs with class III antiarrhythmic action.

Zhang H, Hancox JC.
In silico study of action potential and QT interval shortening due to loss of inactivation of the cardiac rapid delayed rectifier potassium current.
Biochem Biophys Res Commun 2004;322(2):693-699
Here, computer simulations were used to investigate the effects of the selective loss of voltage-dependent inactivation of IKr upon ventricular action potentials and on the QT interval in the electrocardiogram. Comment: the results from this study substantiate the notion that selective loss of  IKr  inactivation produces a gain in IKr function that causes QT interval shortening.

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
This is a description of the genetic analysis of the first family with SQTS (Gussak I et al.2000), who turned out to have a c to a substitution at nucleotide 1764 resulting in the amino acid change (N588K in KCNH2 similar to the previously described Italian family. The family had no history of sudden cardiac death, but all members had a history of paroxysmal atrial fibrillation.

Cordeiro JM, Brugada R, Wu YS, Hong K, Dumaine R. (Masonic Medical Research Laboratory, Utica, NY)
Modulation of IKr 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 (as in SQT1) expressed in mammalian TSA201 cells. They found that the ventricular action potentials were shortened except for the Purkinje fiber action potentials, which 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 cells of the ventricles and cause VT by phase 2 re-entry. Might that also explain the wider than usual separation between T and U waves (final repolarization of Purkinje fibers?) seen in SQTS patients?

McPate MJ, Duncan RS, Milnes JT, Witchel HJ, Hancox JC. (School of Medical Sciences, University of Bristol, UK).
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
This study was undertaken in order to determine how the N588K mutation alters HERG channel current kinetics at mammalian physiological temperature. Chinese Hamster ovary cells we used. They demonstrated that N588K-HERG contributes increased repolarizing current earlier in the ventricles action potential due to a ~+60 mV positive-shift in voltage dependence of IHERG inactivation that results in increased current earlier during the ventricular AP. This helps explain the mechanism of gain-in-function, accelerated repolarisation and short QT interval in SQT1 patients.

Itoh H, Horie M, Ito M, Imoto K.(Shiga University, Otsu, Japan)
Arrhythmogenesis in the Short-QT Syndrome Associated with Combined HERG Channel Gating Defects. A Simulation Study.
Circ J 2006;70:502-508
The authors used a computer model including a N588K-KCNH2 mutant Markov model integrated into the Luo-Rudy theoretical model of the cardiac ventricular AP. They were unable to confirm previous suggestions of transmural dispertion of depolarization (TDR), and simulation studies suggested that arrhythmogenesis was associated not only with gain of function, but also with accelerated deactivation of the N588K-HERG channel (loss-of-function). At a BCL of 2000 msec EADs occurred in M cells, but not in epicardial or endocardial cells.

Grunnet M, Diness TG, Hansen RS, Olesen S-P. (The Danish National Research Foundation Center for Cardiac Arrhythmia, University of Copenhagen, Denmark)
Biophysical Characterization of the Short QT Mutation hERG-N588K reveals a Mixed Gain-and Loss-of-function.
Cell Physiol Biochem 2008;22:611-624
Patch-clamp experiments were conducted after heterologous expression in both Xanopus laevis oocytes and mammalian cells and at both room temperature and at 37 oC. Also the impact of the β-subunits KCNE2 was investigated.

The present study describes a profound biophysical characterization of hERG-N588K revealing both loss-of-function and gain-of-function. The most prominent loss-of-function property was reduced tail currents, but also slower activation and faster deactivation kinetics . It must therefore be expected that the hERG-N588K mutant will have reduced ability to conduct current at the end of repolarization. Furthermore this mutant will also have a diminished open probability in the diastolic interval. The gain-of-function stems from severely compromised ability to inactivate. The authors therefore stress that in patients carrying hERG-N588K the loss-of-function of repolarization current and diastolic hERG current may be at least as pro-arrhythmic as the gain-of-function of plateau current. Potential pro-arrhythmia from loss-of-function: 1) Due to the fast deactivation the number of channels able to counteract depolarization events in the post-repolarization period is significantly reduced and thereby the ability of the myocytes to counteract triggered activity, and 2) reduction in the repolarising reserve can lead to triangulation and early afterdepolarization.

McPate MJ, Zhang H, Adeniran I, Cordeiro JM, Witchel HJ, Hancox JC.
Comparative Effects of the Short QT N588K Mutation at 37oC on HERG K+ Channel Current during Ventricular, Purkinje Fibre and Atrial Action Potentials: An Action Potential Clamp Study.
J of Physiol Pharmacol 2009;60(1):23-41


McPate MJ, Zhang H, Cordeiro JM, Dempsey CE, Witchel HJ, Hancox JC.
HERG1a/1b heteromeric currents exhibit amplified attenuation of inactivation in variant 1 short QT syndrome
Biochem Biophys Res Commun 2009;386(1):111-117
All information on the likely consequences for IKr  kinetics of N588K hERG mutation comes from studies of the hERG1a isoform. Recent evidence suggests, however, that native cardiac IKr may not be comprised of hERG1a alone, but rather of hERG1a heteromerically expressed with an alternative transcript, hERG1b, an isoform with a truncated N-terminus. The present study was conducted to determine the effects of the N588K hERG SQT1 mutation on co-expressed hERG1a/1b channels. The data showed that the inactivation-attenuation effects of the N588K mutation were markedly greater when co-expressed hERG1a and 1b were studied than when hERG1a alone was studied. The study also confirmed the differential effect the N588K hERG mutation has on current during ventricular and Purkinje APs as initially suggested by data from the study by Cordeiro JM et al. and McPate MJ et al.This is the first study to have investigated hERG1a/1b heteromeric channels in the context of the short QT syndrome. Similar studies have never been done for LQTS.

Suzuki H, Hoshina S, Ozawa J, Sato A, Minamino T, Aizawa Y, Saitoh A,
Short QT syndrome in a boy diagnosed on screening for heart disease .
Pediatr Int 2014;56(5):774-776
Summary : A QTc of 260 msec detected in a 10-year-old boy during school screening for heart disease. The patient had been asymptomatic except for two episodes of febrile convulsions at the age of 3 years. Family history significant for similar ECG finding in the mother, and a hx of SCD of maternal grandmother at the age of 45 years. Genetic testing in the boy and his mother showed in both of them a N588K mutation in the KCNH2 gene. During a treadmill exercise stress test heart rate increased, while the QT interval remained unchanged throughout the test.

R1135H-KCNH2

Itoh H, Sakaguchi T, Ashihara T, Ding W-G, Nagaoka I, Oka Y, Nakazawa Y, Yao T, Jo H, Ito M, Nakamura K, Ohe T, Matsuura H, Horie M.
A novel KCNH2 mutation as a modifier for short QT interval.
Int J Cardiol 2008
This study using voltage clamp experiments describes a novel C-terminal KCNH2 mutation, R1135H, which was found to explain both a marked QT shortening (QTc 329 msec) and the Brugada-type ECG in a 34 year-old man.
Later computer simulation studies (Wilders R, Verkerk AO. Role of the R1135H KCNH2 mutation in Brugada syndrome. Int J Cardiol 2010;144:149-51) confirmed the findings.

T618I-KCNH2

Sun Y, Quan X-Q, Fromme S, Cox RH, Zhang P, Zhang L, Guo D, Guo J, Patel C, Kowey PR, Yan G-X.
A novel mutation in the KCNH2 gene associated with short QT syndrome.
J Molecular and Cellular Cardiology 2011;50:433-441
In 4 members of a Chinese family with markedly short QT interval and a strong family history of sudden cardiac death, a C1853T mutation in the KCNH2 gene encoding for the HERG channel resulting in an amino change T618I was identified. Whole cell voltage clamp studies of the T618I mutation in HEK-cells demonstrated a 6-fold increase in maximum steady state current (146.1 +/- 16.7 vs 23.8 +/- 5.5 pA/pF) that occurred at 20 mV more positive potential compared to the wild type. The voltage dependence of inactivation was significantly shifted in the positive voltage direction (WT -78.6 +/- 6.8 vs T618I - 29.3 +/- 1.7 mV). Kinetic analysis revealed slower inactivation rates of T618I, but faster rates of recovery from inactivation.

E50D

Redpath CJ, Green MS, Birnie DH, Gollob MH
Rapid genetic testing facilitating the diagnosis of short QT syndrome.
Can J Cardiol 2009;25(4):e133-e135

Martinez HB, Hu D, Gollob M, Antzelevitch C.
Novel Gain-of-Function N-terminal KCNH2 Mutation Associated with the Short QT Syndrome.
AHA Scientific Sessions 2011, Abstract # 12845.
Summary: 22-year-old man "experienced unheralded syncope for the first time while driving, resulting in a motor vehicle accident". The patient had no documented arrhythmias, but a QT interval of 366 msec at 66 bpm (QTc = 381 ms). Treadmill testing did not result in ventricular arrhythmia, but did reveal a lack of adaptation of the QT interval to increasing heart rate during exercise and a failure to adapt to decreasing heart rate during recovery. Direct DNA sequencing of the KCNQ1 and KCNH2 genes identified a novel mutation of highly conserved residue, Glu50Asp, in KCNH2, which was also present in the patient's mother, who had a normal QT interval. The E50D-KCNH2 mutation was not found in 1300 healthy controls and alignment of the amino acid sequence of HERG showed that residue E50 is highly conserved among species. Functional expression of E50D-KCNH2 in TSA201 cells at 370C showed a 6-fold gain in function of Ikr tail current density, slower deactivation and, a positive shift in the voltage dependence of inactivation (WT: -76.8 vs. E50D: -65.3 mV. This is the first report of a pathogenic mutation in the N-terminal of KCNH2 associated with SQT1. Comment: With a normal ECG (QT interval of 366 ms at 66 bpm, and QTc 381ms) and no family history of short QT (mother with the same mutation also had a normal QT interval) in the setting of unheralded syncope, this case is an outlier compared to other cases of SQTS, even though the functional expression of the mutation is compatible with a shortened QT interval. By the proposed diagnostic criteria for SQTS  published in JACC in 2011 by two of the authors above (Michael H. Gollob and Calum J. Redpath) in co-operation with Jason D. Roberts, a patient with a QTc > 370 ms would not be considered a candidate for further diagnostic work-up for SQTS.

p.Pro872fs-KCNH2

Paulussen AD, Raes A, Jongbloed RJ, Gilissen RA, Wilde AA, Snyders DJ, Smeets HJ, Aerssens J. (University of Maastricht, Maastricht, The Netherlands)
HERG mutation predicts short QT based on channel kinetics but causes long QT by heterotetrameric trafficking deficiency.
Cardiovasc Res 2005;67(3):467-475
In a Dutch family of Caucasian origin diagnosed with long QT syndrome genetic screening revealed a heterozygous frameshift mutation p.Pro872fs located in the C-terminus of the KCNH2 gene. The authors found that the KCNH2 mutation that clinically leads to long QT syndrome causes at a cellular level both a "gain" and a "loss" of HERG-channel function due to a kinetic increase in repolarising power and adecrease in trafficking efficiency of heteromultimeric channels. The finding provides a novel proof of concept for heteromultimeric channels.

KCNQ1


V307L-KCNQ1

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 VF episode and a short QT interval of 290 msec in several ECGs during a 3-year follow-up period. Analysis of candidate genes identified a g919c substitution in KCNQ1 (V307L  (valine to leucine) mutation) encoding the K+ channel KvLQT1, which, in association with the ß-subunit KCNE1 (mink, IsK), forms the slow component of the cardiac rectifier K+ current(IKs). Patch-clamp data and computational studies showed that the mutation caused the channel to activate faster and at more negative potentials favoring the association of a short QT interval with mutation in KCNQ1.
Comment :This was the first description of a genetic defect in the KCNQ1 gene leading to SQTS - later called  SQT2

Zhang H, Kharche S, Holden AV, Hancox JC.
Repolarization and vulnerability to re-entry in the Human heart with short QT syndrome arising from KCNQ1 mutation - A simulation study.
Progress in Biophysics and Molecular Biology 2008;96:112-131
In this study a computer modeling approach was adopted in order to determine whether and how the V307L-KCNQ1 mutation might generate an electrical substrate for arrhythmias in SQT2 patients. The V307L-KCNQ1 mutation is: (i) causally linked to QT interval shortening; (ii) leads to an increased transmural heterogeneity of APD, ERP and membrane potential (δV), that increases tissue's vulnerability to the genesis of re-entry by a premature excitation; (iii) and shortens tissue's ERP that facilitates the maintenance of re-entry.
The findings from this study both substantiate a causal link between the V307L-KCNQ1 mutation and QT interval shortening and provide a comprehensive explanation for increased susceptibility to re-entry and perpetuation of reentrant arrhythmia in SQT2.

Harchi AE, McPate MJ, Zhang YH, Zhang H, Hancox JC.
Action Potential Clamp and Mefloquine Sensitivity of Recombinant 'IKS' channels incorporating the V307L-KCNQ1 Mutation.
J 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.

V141M-KCNQ1


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. (Masonic Medical Research Laboratory, Utica, NY)
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. The HR was 60 bpm and an EP study showed normal HV interval suggesting AV nodal block. DC cardioversion was unsuccessful. Genetic testing showed a missense mutation, 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. Voltage clamp recordings: Oocytes from Xenopus laevis were injected with WT or V141M-KCNQ1 cRNA with or without KCNE1 cRNA and 2-3 days later exposed to two electrode voltage clamp recordings. The V141M mutation did not noticeably alter the gating of KCNQ1 channels expressed alone in oocytes. The WT-KCNQ1/KCNE1 channels exhibited a voltage-dependent threshold of activation near -50 mV and activated very slowly. In sharp contrast , the V141M-KCNQ1/KCNE1 channel current developed instantly at all voltages tested, consistent with the interpretation that these channels were constitutively open. Computer modeling showed decrease in peak voltage and shortening of APD consistent with shortening of the QT interval. The effect of the V141M gain of function mutation was also modeled in a model of rabbit sinoatrial node cells. The results indicate that the enhanced outward Iks causes cessation of spontaneous activity and a stabilization of the resting membrane potential at a level positive to the normal maximum diastolic potential of these cells. Comment: The unsuccessful attempt of cardioversion and slow HR suggest both sinus ndal and AV nodal disease.

Bjerregaard P, Collier JL, Gussak I.
Upper limits 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):AB43-4
Summary: This review contains a US case similar to the one described by Hong K et al.. Only the proband had the V141M-KCNQ1 mutation.

Maltret A, Wiener-Vacher S, Denis C, Fabrice E, Morisseau-Durand MP, Fressart V, Bonnet D, Chabbert C.
Type 2 short QT syndrome and vestibular dysfunction: Mirror of the Jervell and Lange-Nielsen syndrome .
Int J Cardiol 2014;171(2):291-293
Summary: Baby girl born preterm at 32 weeks by cesarean section that was prompted by fetal bradycardia. The postnatal ECG showed sinus bradycardia at 69 bpm with QT interval of 260 ms. ECG monitoring repeatedly showed sinus bradycardia and junctional rhythms. Genetic analysis showed a V141M mutation in KCNQ1 similar to the findings in a newborn by Hong K, et al. in Cardiovasc Res 2005;68:433-40. The patient later had symptoms of imbalance and spontaneous left nystagmus suggesting a profound alteration of the canal function.

I274V-KCNQ1

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 mutation (I274V) was found in theKCNQ1 gene. 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.

The finding was later described in more detail in:


Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C, Vege A, Wang DW, Rhodes TE, George AL, Schwartz PJ.
Prevalence of Long-QT Syndrome Gene Variants in Sudden Infant Death Syndrome
Circulation 2007;115:361-367
Among the patients with Sudden Infant Death Syndrome Arnestadt et al. found one with an I274V-KCNQ1 mutation.

And in :

Rhodes TE, Abraham RA, Welch RC, Vanoye CG, Crotti L, Arnestad M, Insolia R, Pedrazzini M, Ferrandi C, Vege A, Rognum T, Roden DM, Schwartz PJ, George Jr 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 I274V-KCNQ1 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.

F279I-KCNQ1


Moreno C, Oliveras A, de la Cruz A, Bartolucci C, Muñoz C, Salar E, Gimeno JR, Severi S, Comes N, Felipe A, González T, Lambiase P, Valenzuela C.
A new KCNQ1 mutation at the S5 segment that impairs its association with KCNE1 is responsible for short QT syndrome .
Cardiovascular Research 2015;107:613-623
Summary: The index case is a 37-year-old man who died unexpectedly. Post mortem examination was negative. Later his 23-year-old healthy son underwent cardiac evaluation. ECG showed a QTc of 356 ms. Echocardiography, 24-hour Holter and exercise stress test negative. A blood sample from the son and his sister underwent genetic testing. Analysis of the KCNQ1 gene in the index case son, but not in his sister revealed a novel heterozygous mutation, a single base substitution at nucleotide 127910 (T127910A) in the exon 6 of the KCNQ1 gene, resulting I an amino acid change from phenylalanine to isoleucine at 279 in Kv7.1 (F279I) within the S5 transmembrane segment, which was not reported before. Functional analysis of F279I Kv7.1 in the presense of KCNE1 revealed a negative shift in the activation curve and an acceleration of the activation kinetics leading to a gain of function of IKs.

R259H-KCNQ1


Wu Z-J, Huang Y, Fu Y-C, Zhao X-J, Zhu C, Zhang Y.
Characterization of a Chinese KCNQ1 mutation (R259H) that shortens repolarization and causes short QT syndrome 2.
J Geriatr Cardiol 2015;12:394-401
Summary: Genetic screening of SQTS genes was performed in 25 probands and their family members (63 patients). In one of the 25 SQTS probands screened a KCNQ1 mutation R259H was discovered. The mutation was shown to effectively increase the slowly activated delayed rectifier potassium current in phase 3 of the cardiac action potential and therefore the likely cause of QT interval shortening.

KCNJ2


D172N-KCNJ2

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. (IRCCS Fondazione Maugeri, Pavia, Italy)
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 with an ECG during routine clinical evaluation with QTc of 315 ms and noticeably narrow, peaked and asymmetrical T waves. Her father had a QTc of 320 ms and a history of presyncopal events and palpitations since the age of 15. He underwent electrophysiologic investigation showing VERP of 160 msec and induction of VF by 3 extrastimuli. He refused an ICD. 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 (IK1).The authors hypothesized that the tall and asymmetrical T-waves with an exceedingly rapid terminal phase not seen in SQT1 or SQT2 patients may be related to a sudden acceleration of the final phase of action potential repolarization in the D172N mutation. None of the patients had any documented spontaneous tachy-arrhythmias. Whole-cell patch-clamp studies of the heterologously expressed human D172N channel demonstrated larger outward IK1 than the wild-type at potentials between 75mV and -45 mV, with the peak current being shifted in the former with respect to the later (WT, -75mV; D172N and -65 mV). Coexpression of WT and mutant channels to mimic heterozygous condition of the proband yilded an outward current that was intermediate between WT and D172N. This was the first case of what was later called SQT3.

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 the above article.

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

Adeniran I, Harchi AE, Hancox JC, Zhang H.
Proarrhythmia in KCNJ2-linked short-QT syndrome: insights from modelling.
Cardiovascular Research 2012;94:66-76

M301K-KCNJ2


Hattori T, Makiyama T, Akao M, Ehara E, Ohno S, Iguchi M, Nishio Y, Sasaki K, Itoh H, Yokode M, Kita T, Horie M, Kimura T.
A novel gain of function KCNJ2 mutation associated with short-QT syndrome impairs inward rectification of Kir2.1 currents .
Cardiovasc Res 2012;93(4):666-673
An 8-year-old girl with a markedly short QT interval (QT/QTc = 172/194 ms) who suffered from paroxysmal AF was studied. Mutational analysis identified a novel heterozygous KCNJ2 mutation, M301K. Functional assays displayed no Kir2.1 currents when M301K channels were expressed alone. However, co-expression of wild-type (WT) with M301K resulted in larger outward currents than the WT at more than -30 mV. These results suggest a gain-of-function type modulation due to decreased inward rectification. In addition to paroxysmal AF the girl had been suffering from multiple disorders, such as severe mental retardation, abnormal proliferation of oesophageal blood vessels, epilepsy, and Kawasaki disease. Her family did not undergo genetic evaluation but ECGs from her father, elder brother and a younger sister showed a normal QT in all of them.

Casini S, Postma AV.
Decreased inward rectification of Kir2.1 channels is a novel mechanism underlying the short QT syndrome .
Cardiovasc Res 2012;93:535-536
Editorial comments to the article by Hattori T et al. pointing out the significant differences in the functional consequences of the previously described D172N mutation and the current M301K mutation both in the KCNJ2 gene. The D172N mutation resulted in the shortening of the terminal phase of the action potential whereas the M301K mutation led to the loss of the action potential plateau phase which probably caused the extremely short QTc observed in the M301K proband. The diminished inward rectification of the M301K may also create problems in other tissues as Kir.2.1 channels are ubiquitously expressed (mental retardation for one).

E299V-KCNJ2


(First presented as Abstract 13462 at AHA Scientific Sessions 2011: Ruan Y, Cerrone M, Novelli V, Liu N, Blaufox AD, Sicca F, Moro F, Pessia M, Napolitano C, Priori SG. Novel Mechanism of KCNJ2-Related Short QT Syndrome.)

Deo M, Ruan Y, Pandit SV, Shah K, Berenfeld O, Blaufox A, Cerrone M, Noujaim SF, Denegri M, Jalife J, Priori SG.
KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia.
PNAS 2013;110(11):4291-4296
A new mutation (E299V) in KCNJ2 was found in an 11-y-old boy with recurrent atrial fibrillation and mild LV dysfunction. The patients ECG showed extremely abbreviated QT interval of 200 ms at 60 bpm with merging of the QRS and peaked T waves. Holter recording showed paroxysmal AF with an average HR of 98 bpm and confirmed the presence of a short QT interval that failed to adapt to HR. Whole-cell patch-clamp experiments showed that E299V presents an abnormally large outward current at potentials above -55 mV due to lack of inward rectification

K346T-KCNJ2


Ruan Y, Cerrone M, Novelli V, Liu N, Blaufox AD, Sicca F, Moro F, Pessia M, Napolitano C, Priori SG.
Novel Mechanism of KCNJ2-Related Short QT Syndrome .
AHA Scientific Sessions 2011, Abstract 13462
Summary: A not previously described KCNJ2 gene mutation was identified in two 8-years old homozygous twins with short QT intervals (QTc 316ms and 310 ms). Whole-cell patch-clamp studies demonstrated that the K346 T mutation presents a larger outward IK1 than WT at potentials between -75 mV and - 55 mV, therefore the biophysical properties overlap with those of the D172N mutation. The same twins were later described in much more detail in:

Ambrosini E, Sicca F, Brignone MS, Adamo MC, Napolitano C, Servettini I, Moro F, Ruan Y, Guglielmi L, Pieroni S, Servillo G, Lanciotti A, Valvo G, Catacuzzeno L, Franciolini F, Molinari P, Marchese M, Grottesi A, Guerrini R, Santorelli FM, Priori S, Pessia M.
Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism-epilepsy phenotype.
Human Molecular Genetics 2014;23(18):4875-4886
Summary: Report on monozygotic twins displaying a short QT interval and autism-epilepsy syndrome. Genetic screening identified a novel KCNJ2 variant in Kir2.1 that (i) enhanced the channel's surface expression and stability at the plasma membrane (ii) reduced protein ubiquitylation and degradation, (iii) altered protein compartmentalization in lipid  rafts by targeting more channels to cholesterol-poor domains and (iv) reduced interactions with caveolin 2. Importantly, the study reveals novel physiological mechanisms concerning wild-type Kir2.1 channel processing by the cell, such as binding to both caveolin 1 and 2, protein degradation through the ubiquitin-proteasome pathway; in addition, it uncovers a potential multifunctional site that controls Kir2.1 surface expression, protein half-life and portioning to lipid rafts. The reported mechanisms emerge as crucial also for proper astrocyte function, suggesting the need for a neuropsychiatric evaluation in patients with SQT3 syndrome and offering new opportunities for disease management.

Genetic mutations in patients with Brugada Syndrome and a  short QT interval


CACNA1C & CACNB2


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
By screening of 82 consecutive probands with clinically robust diagnosis of Brugade Syndrome for ion channel gene mutations, they found 3 probands displaying ST-segment elevation in V1 through V3 and QTc </= 360msec among 7 who had mutations in genes encoding the cardiac L-type calcium channel. Rate adaptation of QT interval was 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 β2b -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.
Comment : 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.


Novelli V, Memmi M, Cerrone M, Bkoise R, Zucca F, Song C, Napolitano C, Priori SG.
Presence of Short QT Identifies Brugada Syndrome Patients With Higher Yield of CACNA1c   Mutations: Implications for Genotyping Strategies.
AHA Scientific Sessions 2011, Orlando Florida
By screening for CACNA1c mutations in 26 BrS patients with QTc < 360 msec, 4 were found to have the mutations (15%) compared to only 2 (1.1%) in 168 BrS patients with QTc > 360 msec. Because of the high cost of genetic screening it is therefore suggested that screening of BrS patients forCACNA1c should be limited to patients with QTc < 360 msec, where the incidence of this mutation is comparable to the incidence of SCN5A mutations in BrS patients in general.

S755T-CACNA2D1


Templin C, Ghadri JR, Rougier JS, Baumer A, Kaplan V, Albesa M, Sticht H, Rauch A, Puleo C, Hu D, Barajas-Martinez H, Antzelevitch C, Lüscher TF, Abriel H, Duru F.
Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6).
Eur Heart J. 2011;32(9):1077-1088
A 17-year old Caucasian female presented following sudden loss of consciousness while sitting during a church service. Initial ECG showed VF. After defibrillation the patient arrived at a hospital where the ECG showed SR with a QT interval of 317 msec (QTc 329 msec) and intermittent incomplete RBBB. Flecainide provocation test with IV Flecainide 2 mg/kg while the ECG showed incomplete RBBB did not produce Brugada-like changes, but slight depression of the J-point with doming of the ST-segment. Programmed ventricular stimulation in the right atrium induced self-terminating atrial tachycardia and atrial fibrillation and the atrial effective refractory period was 180 ms. Stimulation from the RV apex with S1/S2 of 600/260 ms induced VF. No numbers given for the ventricular effective refractory period, but it is mentioned that it was short. DNA screening showed a new variant at a heterozygous state in the CACNA2D1 gene (nucleotide c.2264G>C; amino acid p.Ser755Thr) encoding for the Ca(v)α(2)δ-1 subunit of the L-type calcium channel. In vitro analysis of the S755T variant in the CACNA2D1 gene showed a strongly reduced current compared with the WT.
Comment: The CACNA2D1 gene has recently been linked to Brugada Syndrome and early repolarization syndrome and since it is known that there is a low penetrance for clinical manifestations of the Brugada Syndrome in young females, and a false negative response to Flecainide is common, it is somewhat unsettled whether this patient has SQTS only or a short QT interval combined with some other abnormality.

R689H-SCN5A


Hong K, Hu J, Yu J, Brugada R.
Concomitant Brugada-like and short QT electrocardiogram linked to SCN5A mutation.
European Journal of Human Genetics 2012;20:1189-1192
Asymptomatic 40-year-old male with family history of sudden death of unknown origin was found to have a Brugada-like ECG with a QT interval of 320 ms at 71 bpm. Sequence analysis of the coding region of the SCN5A gene identified an R689H mutation, and patch clamp analysis confirmed it to be a loss-of-function mutation.

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Experimental models of Short QT

Li J, McLerie M, Lopatin AN.
Transgenic upregulation of  IK1 in the mouse heart leads to multiple abnormalities of cardiac excitability.
Am J Physiol Heart Circ Physiol 2004;287:H2790-H2802
The authors produced and characterized the first transgenic mouse model of IK1 upregulation. Two lines of animals were established with one showing a short QT interval.

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 IK-ATP channel) is associated with an increased transmural dispersion of repolarization and inducibility of VF by programmed stimulion.
Comment: This model of short QT syndrome is phenotypically different from the clinical short QT syndrome cases caused by a gain of function of either HERG or KCNQ1. In these two syndromes, the ECG of affected individuals often manifests tall, peaked, symmetrical T waves rather than inverted T waves as seen in the experimental model.

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 IKr 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.

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 where 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 stat, 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 channels

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.

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
The authors 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.

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 MC, Katus HA, Tootbauer W .
Deficient Zebrafish Ether-à-Go-Go-Related Gene Channel Gating Causes Short-QT Syndrome in Zebrafish Reggae Mutants.
Circulation 2008;117:866-875

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
An experimental model of SQT1 was created using PD-118057 (Pinacidil) which is an IK-ATP  agonist. Their results suggest that a combination of ERP abbreviation and TDR amplification underlie the development of pVT in SQT1 and that quinidine prevents pVT principally by prolonging ERP.

Nof E, Burashnikov A, Antzelevitch C.
Celluler basis for atrial fibrillation in an experimental model of QT1: Implications for a pharmacological approach to therapy.
Heart Rhythm 2010;7:251-257

Kijtawornrat A, Panyasing Y, del Rio C, Hamlin RL.
Assessment of ECG interval and restitution parameters in the canine model of short QT syndrome.
J Pharmacological and Toxicological Methods 2010;61:231-237
Shortening of the QT was accomplished by IK-ATP agonists.

Adeniran I, Hancox JC, Zhang H.
In silico investigation of the short QT syndrome, using human ventricle models incorporating electromechanical coupling.
Frontiers in Physiology 2013;4:Article 166 (www.frontiersin.org)
The aim of this study was to utilize electromecanically coupled human ventricle models to explore electromechanical consequences of the SQTS. Previously validated K channel formulations for SQT variants 1 and 3 were incorporated.
Whilst there is little evidence of profoundly impaired cardiac contractile function in SQTS patients, the 3D simulations in this study correlate qualitatively with reported evidence for dissociation between ventricular repolarization and the end of mechanical systole.

Huang CL-H .
Computational analysis of the electromechanical consequences of short QT syndrome.
Frontiers in Physiology 2015;6:Article 44 pages 1-3

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Treatment of SQTS with an ICD

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 initial Italian and German families previously described. Due to T-wave oversensing inappropriate shocks were delivered in 3 out of the 5 patients shortly after implantation. Programming lower sensitivities and decay delays prevented further inappropriate discharges.
Comment: The oversensing of the T wave lead to the observation, that patients with short QT syndrome often have prominent peaked T waves.

Passman R.
Inappropriate Implantable 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. The reviewer makes the observation: "At the time of this writing, there are slightly more patients described with short QT syndrome than there are articles written about them"

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 earlier. The episode occurred during a HR of approximately 60 bpm, initiated by a premature beat with a coupling interval of 180 msec.
Comment: This is the first description of a patient with SQTS rescued by an ICD shock.

Borlani G, Biffi M, Valzania C, Bronzetti G, Martignani C.
Short QT Syndrome and arrhythmogenic cardiac diseases in the young: the challenge of implantable cardioverter-defibrillator therapy for children.
Eur Heart J 2006;27:2382-2384 (Editorial)Sun Y, Zhang P, Li X, Guo J.

Inappropriate ICD Discharge Due to T-Wave Oversensing in a Patient with Short QT Syndrome.
PACE 2010;33:113-116
45 yo male with SQTS (QTc: 298 msec) and high peaked T waves received a St. Jude Epic DR V-239 ICD. Ten days later he received 5 inappropriate shocks for T wave oversensing in sinus rhythm. After programming the threshold start value to 100% and decay delay to 0 msec together with a total ventricular refractory period to 432 msec and R wave sensing at 5 mV the patient had no further shocks during 6 months follow-up.

Olde Nordkamp LR, Postema PG, Knops RE, Van Dijk N, Limpens J, Wilde AA, de Groot JR.
Implantable cardioverter-defibrillator harm in young patients with inherited arrhythmia syndromes: A systematic review and meta-analysis of inappropriate shocks and complications.
Heart Rhythm 2015;September 15.
Summary: MEDLINE and EMBASE review revealed 63 studies comprising 4916 patients with inherited arrhythmia syndromes including SQTS (mean age of 39 +/- 15 years). Inappropriate shocks occurred in 20% (crude annual rate of 4.1%), 22 % experienced ICD related complications (4.4% per year) and there was 0.5% ICD related mortality (0.08% per year).

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Pharmacological treatment of patients with SQTS

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. 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 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. Quinidine was recommended as the drug of choice for medical therapy while Flecainide because of some increase in the effective refractory period could be considered the second choice.

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 (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.

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 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 drugs 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.

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.

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
SOTALOL therapy in SQTS evaluated.

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;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:

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

Schimpf R. Veltmann 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

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.

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

Lu LX, Zhou W, Zhang X, Cao Q, Yu K, Zhu C.
Short QT Syndrome: A case report and review of literature.
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.

Bjerregaard P, Jahangir A, Gussak I. (Saint Louis University Hospital & Mayo Clinic)
Targeted therapy for short QT syndrome .
Expert Opin. Ther. Targets 2006;10(3):393-400
Review comparing LQTS with SQTS. Potential targets for therapy in SQTS patients is reviewed for KCNH2, KCNQ1 and KCNJ2 mutation patients separately

Lopez-Izquierdo A, Ponce-Balbuena D, Ferrer T, Sachse FB, Tristani-Firouzi M, Sánchez-Chapula JA. (University of Utah, Salt Lake City)
Chloroquine Blocks a Mutant Kir2.1 Channel Responsible for Short QT Syndrome and Normalizes Repolarization Properties in silico.
Cell Physiol Biochem 2009;24:153-160
SQT3 and CHLOROQUINE in silico evaluation.

Harchi AE, McPate MJ, Zhang YH, Zhang H, Hancoc JC.
Action potential clamp and chloroquine sensitivity of mutant Kir2.1 channels responsible for variant 3 short QT syndrome.
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 shifts 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.

Harchi AE, McPate MJ, Zhang YH, Zhang H, Hancox JC.
Action Potential Clamp and Mefloquine Sensitivity of Recombinant 'IKS' channels incorporating the V307L-KCNQ1 Mutation.
J 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.

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.
Long-term Follow-up of Patients with Short QT Syndrome.
J Am Coll Cardiol 2011;58:587-595

Especial evaluation of the potential benefit of Hydroquinidine .

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

Sun Y, Quan X-Q, Fromme S, Cox RH, Zhang P, Zhang L, Guo D, Guo J, Patel C, Kowey PR, Yan G-X.
A novel mutation in the KCNH2 gene associated with short QT Syndrome.
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.

Duncan RS, McPate MJ, Ridley JM, Gao Z, James AF, Leishman DJ, Leaney JL, Witchell HJ, Hancox JC.
Inhibition of the HERG potassium channel by the tricyclic antidepressant doxepin.
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

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

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

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

Chinushi M, Sato A, Izumi D, Furushima H.
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.
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.

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

Abriel H, Rougier J-S.
ß-Blockers in Congenital Short-QT syndrome as Ion Channel Blockers.
J 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.

Bun S-S, Maury P, Giustetto C, Deharo J-C.
Electrical Storm in Short-QT Syndrome Successfully Treated with Isoproterenol.
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.
Comment : In addition to showing the benefit of isoproterenol in treating electrical storm in SQTS, this case clearly demonstrate te 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.

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Review articles of SQTS

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.

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. The authors found it noteworthy that substitution of aspartic acid (negative) for asparagine (neutral) in the same position of HERG (N588D) has been linked to the LQT2 syndrome secondary to a loss of function of IKr . This substitution leads to replacement of a neutral amino acid with a negatively charged one, whereas the N588K mutation responsible for some cases of short QT syndrome, secondary to gain of function of IKr , replaces a neutral amino acid(asparagine) with a positively charged one (lysine).

Bjerregaard P, Gussak I.
Short QT Syndrome: mechanisms, diagnosis and treatment.
Nat Clin Pract Cardiovasc Med . 2005;2:84-87
Review article of Short QT Syndrome

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

Bjerregaard P, Gussak I. (Saint Louis University Hospital)
Short QT Syndrome .
A.N.E. 2005;10(4):436-440
Review article.

Borggrefe M, Wolpert C, Antzelevitch C, Veltmann C, Giustetto C, Gaita F, Schimpf R. ( University Hospital Mannheim, Germany)
Short QT syndrome. Genotype-phenotype correlations.
J Electrocardiol 2005;38:75-80
Review article

Schimpf R, Borggrefe M, Wolpert C. (University Hospital, Mannheim, Germany)
Clinical and molecular genetics of the short QT syndrome.
Curr Opin Cardiol 2008;23:192-198
Review article.

Maury P, Extramiana F, Sbragia P, Giustetto C, Schimpf R, Duparc A, Wolpert C, Denjoy I, Delay M, Borggrefe M, Gaita F.
Short QT syndrome. Update on a recent entity.
Archives of Cardiovascilar Disease 2008;101:779-786
Review article

Patel C, Yan G-X, Antzelevitch C.
Short QT Syndrome: From Bench to Bedside.
Circ Arrhythm Electrophysiol 2010;3(4):401-408
Review article.

Møller DV, Hedley PL, Olesen M, Kanters J, Svendsen JH, Christiansen M.
Kort QT-syndrom som arvelig sygdom.
Ugeskr L æ ger 2011;173/6:420-424
Review article in Danish.

Pérez-Riera AR, Paixão-Almeida, Barbosa-Barrosa R, Yanowitz FG, Baranchuk A, Dubner S, Chagas ACP.
Congenital short QT syndrome: Landmarks of the newest arrhythmogenic cardiac channelopathy.
Cardiol J 2013;20, 5:464-471

Al Maluli H, Meshkov AB.
A short story of the short QT syndrome .
Cleveland Clinic Journal of Medicine 2013;80:41-47

Mazzanti A, Kanthan A, Monteforte N, Memmi M, Bloise R, Novelli V, Miceli C, O'Rourke S, Borio G, Zienciuk-Krajka A, Curcio A, Surducan AE, Colombo M, Napolitano C, Priori SG.
Novel Insight Into the Natual History of Short QT Syndrome .
J Am Coll Cardiol 2014;63:1300-1308

Tristani-Firouzi M.
The Long and Short of it.
J Am Coll Cardiol 2014;63:1309-1310

Harrell DT, Ashihara T, Ishikawa T, Tominaga I, Mazzanti A, Takahashi K, Oginosawa Y, Abe H, Maemura K, Sumitomo N, Uno K, Takano M, Priori SG, Makita N.
Genotype-dependent differences in age of manifestation and arrhythmia complications in short QT syndrome.
International Journal of Cardiology 2015;190:393-402

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Miscellaneous

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
This article examines specific ECG and EP features of ventricular repolarization in rats and mice, and the role of depolarization-activated potassium-currents in mediating the unique features of ECG recordings in these rodents. The authors points out that the absence of a distinct isoelectric interval between the QRS complex and the T wave, accompanied by a relatively short QT interval, are common features of ECG recordings in mice and rats, but not in ECGs in guinea pigs.

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;818-3(Supplement A)
Abstract of presentation from Torino, Italy at the ACC meeting in 2003 of  the first family with a short QT interval and high incidence of sudden cardiac death.

Zipes DP.
The Year in Electrophysiology.
JACC 2004;43(7):1305-1314
The first time Short QT Syndrome is mentioned alongside other forms of channelopathies in a yearly review in JACC of advances in cardiac electrophysiology.

Bjerregaard P, Gussak I.
Atrial fibrillation in the setting of familial short QT interval.
Heart Rhythm 2004;S165(522)
Poster presentation of the discovery of short QT syndrome.

Bellocq C, van Ginneken A, Bezzina CR, Alders M, Escande D, Mannens MM, Baro I, Wilde AA.
Mutation in the KCNQ1 Gene Leading to the Short-QT-Interval Syndrome.
Circulation 2004;110(17):1105
Abstract of presentation from Nantes, France and Amsterdam, The Netherlands at the AHA meeting in 2004 of the first patient with a KCNQ1 gene mutation leading to the Short-QT-Interval Syndrome.

Wolpert C, Schimpf R, Gaita F, Bianchi F, Riccardi R.
Potential Treatment of Congenital Short QT Syndrome: Response to Oral Quinidine
Circulation 2004;110(17):1106
Abstract of presentation from Mannheim, Germany and Turin, Italy at the AHA meeting in 2004.

Filipecki A, Trusz-Giuza M, Lubinski A.
Prevalence of Very Short QT Intervals in Patients with Idiopathic Ventricular Fibrillation and Implanted ICD.
Circulation 2004;110(17):2350
Abstract of presentation from Katowice and Gdansk in Poland of a retrospective analysis of ECGs from 42 patients with structurally normal hearts who had survived sudden cardiac death and diagnosed with idiopathic cardiomyopathy.Five patients or 12% were found to have QTc intervals =/< than 300 msec leading the authors to conclude: "the presence of short QT interval is not rare in patients with idiopathic ventricular fibrillation".
Comment: unfortunately no ECGs were shown during the presentation, and the authors made the mistake defining short QT interval based upon QTc corrected by Bazett's formula, and not upon an uncorrected QT interval measured at a heart rate close to 60 bpm. (Unfortunately, the patients heart rates were not mentioned in the abstract). The conclusion from this study was most likely incorrect, and no other study has since found such a high incidence of short QT interval in patients with idiopathic VF.

Giustetto C, Wolpert C, Anttonen OM, Shragia 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):AB31-3
Abstract of presentation from six European centers of the clinical presentation of 27 patients with Short QT Syndrome.

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):AB34-6
Abstract of presentation from Mannheim, Germany, Asti, Italy and Saint Louis, USA of clinical follow-up of  9 patients with Short QT Syndrome.

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):P2-118.
Abstract of poster presentation from Finland of 3 members in a family with Short QT Syndrome. While 3 brothers to one of the members had otosclerosis the question was raised, whether there might be a connection between otosclerosis and a short QT interval. Genetic testings were negative.

Gussak I, Bjerregaard P.
Short QT Syndrome - 5 Years of Progress.
J Electrocardiol 2005;38:375-377
Editorial comment

Gouas L, Nicaud V, Berthet M, Forhan A, Tiret L, Balkau B, Guicheney P and the D.E.S.I.R Study Group.
Association of KCNQ1, KCNE1, KCNH2 and SCN5A polymorphisms with QTc interval length in a healthy population.
European Journal of Human Genetics 2005;13:1213-1222
Genetic analysis in 200 subjects with the longest and the shortest QTc from a cohort of 2008 healthy subjects suggest, that genetic determinants located in KCNQ1, KCNE1, KCNH2 and SCN5A influence QTc length in healthy individuals and may represent risk factors for arrhythmias or cardiac sudden death in patients with cardiovascular disease.

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):P2-35
An 18-year old female with recurrent syncope and long QT (QTc 500 ms). While Holtermonitored during syncope with seizures she revealed the presence of a long episode (105 sec) of Torsades des Pointes VT preceded by ventricular bigeminy with marked repolarization changes. At termination of the VT, a phase of atrial fibrillation with slow ventricular response and an extremely short QT interval (QTc 250 ms). Molecular screening disclosed a novel KCNH2 mutation causing an inframe deletion of a conserved lysine residue in the S6 segment. Heterologous expression of the deletion allele alone did not produce current, while coexpression with WT-HERG resulted in channels exhibiting a substantial shift in the voltage-dependence of activation to more hyperpolarized potentials. This results in significantly larger tail currents at negative potential and in significantly smaller tail currents at positive potential, compared with WT-HERG. This pattern of channel dysfunction, either loss or gain of function in a voltage dependent manner, can account for the peculiar ECG features exhibited by the patient.
Commen t: These results illustrate the potential for phenotype overlap between the long and the short QT syndrome.

Poglajen G, Fister M, Radovancevic B, Vrtovec B.
Short QT Interval and Atrial Fibrillation in Patients without Structural Heart Disease.
JACC 2006;47(9):1905-1907 ( Letter to the editor.)
The authors compared the QTc intervals in 165  consecutive healthy subjects presenting with an episode of AF to the QTc intervals in 165 age-and gender matched subjects without evidence of arrhythmias. Short QTc interval (<400 ms) was an independent predictor of AF occurrence in multivariate analysis with QTc intervals in patients with AF significantly shorter than in the control group. The authors speculate whether pathophysiological mechanisms that lead to shortening of the QT interval (even of mild degree) might also play an important role in genesis of AF in structurally normal hearts.

Napolitano C, Bloise R, Priori SG.
Long QT syndrome and short QT syndrome: how to make correct diagnosis and what about eligibility for sports activity.
J Cardiovasc Med 2006;7(4): 251-256
At the time of this article only 23 cases of SQTS from six different families had been reported. The article, therefore, mainly addresses issues regarding LQTS.

Assadi R. Chang R. Abdipour A, Pai SM, Jutzy  KR.
Possible Increased Risk of Cardiac Arrhythmias in Patients with Acguired Short QT Interval.
JACC 2007;March 6:836-6
Abstract from a presentation at the ACC meeting in 2007.

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 (QT ≤ 320 msec and QTc ≤ 340 msec), three additional members were considered to have SQTS and a high number (16) had shorter than normal QT interval and classified as suspected SQTS (ECG-based QT was ≤ 320 msec and/or QTc Bazett interval was > 340 msec and ≤ 380 msec).
Comment: A big limitation of this study is the lack of genotyping.
(The index case, his brothers and his mother have been described previously by Maury P et al in Heart Rhythm 2005;2:1135-1137)

Schimpf R, Antzelevitch C, Haghi D, Giustetto C, Pizzuti A, Gaita F, Veltmann 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
Echocardiography and electrocardiography was performed in 5 SQTS patients from 2 unrelated families with a history of SCD and 5 age-matched and gender matched control subjects. In SQTS patients the end of the T wave preceded aortic valve closure by 111 +/- 30 ms compared to -12 +/- 11 ms in control subjects. The interval from aortic valve closure to the beginning of the U wave was 8 +/- 4 ms in SQTS patients and 15 +/- 11 ms in controls. Thus the inscription of the U wave in SQTS patients coincided with aortic valve closure and isovolumetric relaxation, supporting the hypothesis that the U wave is related to mechanical stretch. Thus, substantial stretch during the isovolumetric phase may induce local membrane repolarization, generating a voltage gradient in the left ventricular myocardium detected as the U wave in the surface ECG.

Surawicz B.
U Wave Emerges from Obscurity when the Heart Pumps like in a Kangaroo.
Heart Rhythm 2008:5:246-247
Editorial commentary to the previous article.

Gross GJ.
IK1: The Long and the Short QT of it.
Heart Rhythm 2006;3(3):336-338
Editorial commentary to an article about the Anderson-Tawil long-QT syndrome which is linked to 20 or so different mutations in the KCNJ2 gene leading to a loss of function of the Kir2.1 potassium channel (IK1). The opposite with gain of function leading to Short QT Syndrome described by Priori SG et al in 2005 was due to a different mutation.

Couderc J-P, Lopes CM.
Short and long QT syndromes: does QT length really matter?
Journal of Electrocardiology 2010;43:396-399

Xu Y, Zhang Q, Chianvimonvat N .
IK1
 and Cardiac Hypoxia: After the Long and the Short QT Syndromes, what else can go wrong with the Inward Rectifier K+ Currents?
J Mol Cell Cardiol 2007;43:15-17
Editorial commentary to an article by Pia et al: Cardiac IK1  underlies early action potential shortening during hypoxia in the mouse heart.

Anttonen O, Junttila MJ, Maury P, Schimpf R, Wolpert C, Borggrefe M, Giustetto C, Gaita F, Sacher F, Haïssaguerre M, Sbregia P, Brugada R, Huikuri HV.
Differences in twelve-lead electrocardiogram between symptomatic and asymptomatic subjects with short QT interval.
Heart Rhythm 2009;6:267-271 (Creative Concepts.)

Grunnet M, Hansen RS, Olesen S-P.
hERG1 channel activators: A new anti-arrhythmic principle.
Progress in Biophysics and Molecular Biology
2008;98:347-362
Review. The authors explain how anti-arrhythmic drugs, which may shorten the QT interval, works, but at the same agree that a fly in this ointment is the Short QT Syndrome. They are, however, able to point out important conceptual differences between the Short QT Syndrome and the hERG channel activation.

Anttonen O, Junttila J, Giustetto C, Gaita F, Linna E, Karsikas M, Seppänen T, Perkiömäki JS, Mäkikallio TH, Brugada R, Huikuri HV.
T-Wave morphology in short QT syndrome.
Ann Noninvasive Electrocardiol 2009;14(3):202-207
Study in 10 subjects with Short QT Syndrome that suggests that patients with a short QT interval and a history of arrhythmic events have abnormal T-wave loop parameters.

Triedman JK.
Brugada and Short QT Syndromes.
PACE 2009;32:S58-S62
Brief review of two rare forms of channelopathies, that may result in sudden cardiac arrest, with emphasis on therapy and risk stratification.

Veltmann C, Schimpf R, Borggrefe M, Wolpert C.
Risk stratification in electrical cardiomyopathies.
Herz 2009;34(7):518-527
LQTS, SQTS, Brugada Syndrome and CPVT are included in this review article.

Hedley PL, Jørgensen P, Schlamowitz S, Wangari R, Moolman-Smook J, Brink PA, Kanters JK, Corfield VA, Christiansen M.
The Genetic Basis of Long QT and Short QT Syndromes: A Mutation Update.
Hum Mutat 2009;30:1486-1511
A mutation update regarding Long and Short QT Syndromes.

Lazzara R.
How the heart can fibrillate: When diversity is a disadvantage.
Heart Rhythm 2010;7:258-259
In this Editorial Comment to an article by Nof E et al. entitled: Cellular basis for atrial fibrillation in an experimental model of SQTS1: implications for a pharmacologic approach to therapy. Heart Rhythm 2010;7:251-257, the author discusses ways atrial fibrillation is initiated and maintained not only in patients with SQTS.

Taggart NW, Haglund CM, Tester DJ, Ackerman MJ.
Diagnostic Miscues in Congenital Long-QT Syndrome.
Circulation 2007;115:2613-2620
Even though this article is about LQTS and not SQTS there are many similarities between the two syndromes in making the right diagnoses and especially the right interpretation of the QT interval. The authors found that diagnostic concordance was present for less than one third of patients who sought a second opinion regarding the diagnosis of LQTS.

Gollob MH, Redpath CJ, Roberts JD.
The Short QT Syndrome. Proposed Diagnostic Criteria.
J AM Coll Cardiol 2011;57:802-12
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.

Veltman C, Borggrefe M.
A 'Schwartz score' for short QT Syndrome.
Nat Rev. Cardiol . 2011;8:251-252
Several possible limitations of the score system proposed by Gollob et al. are discussed. 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
In this letter to the editor of JACC several errors in the article by Gollob et al is pointed out, and the mistake of using Bazett's formula to correct the QT interval in patients with possible SQTS emphasized. It is the opinion of the author: "that the proposed diagnostic criteria for SQTS are poorly founded and should be used with great caution".

Riera ARP, Paixão-Almeida A, Barbosa-Barros R, Yanowitz FG, Baranchuk A, Dubner S, Chagas ACP.
Congenital Short QT Syndrome: Landmarks of the Newest Arrhythmogenic Cardiac Channelopathy.
Cardiol J 2013;20(5):464-471
Chronological historical review which shows how new scientific discoveries have gradually brought clarity to this new form of channelopathy called SQTS. The authors points out several important limitations in diagnostic criteria for making the diagnosis of SQTS proposed by Gollob MH et al in JACC 2011;57:802-812

Brenyo AJ, Huang DT, Aktas MK.
Congenital Long and Short QT Syndromes.
Cardiology 2012;122:237-247 (Review article

Tülümen E, Giustetto C, Wolpert C, Maury P, Anttonen O, Probst V, Blanc C-C, Sbragia P, Scrocco C, Rudic B, Veltman C, Sun Y, Gaita F, Antzelevitch C, Borggrefe M, Schimpf R.
PQ Segment Depression in Short QT Syndrome Patients: A Novel Marker for Siagnosing Short QT Syndrome .
Heart Rhythm 2014;11(6)1024-1030.
Fifty-two of 64 patients (81%) with SQTS from the European SQTS registry reveal PQ segment depression defined as >/= 0.05 mV depression from the isoelectric line.

Frea S, Giustetto C, Capriolo M, Scrocco C, Fornengo C, Benedetto S, Bianchi F, Pidello S, Morello M, Gaita F.
New echocardiographic insights in short QT syndrome: More Than a channellopathy?
Heart Rhythm 2015;12:2096-2105
This study shows that in SQTS patients left ventricular systolic function may be affected, and it is suggested that tissue Doppler imaging and speckle tracking echocardiography could become part of the evaluation of this rare disease.

Giustetto C, Scrocco C, Schimpf R, Maury P, Mazzanti A, Levetto M, Anttonen O, Dalmasso P, Cerrato N, Gribaudo E, Wolpert C, Giachino D, Antzelevitch C, Borggrefe M, Gaite F.
Usefulness of exercise test in the diagnosis of short QT syndrome .
Europace 2015;17:628-634
This study confirms observations from several case reports that SQTS patients have a reduced adaptation of the QT interval to heart rate. Exercise test could therefore be a useful tool in the diagnosis of SQTS.

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