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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]
Synonyms and keywords: SQTS; short QT; short QTc; QT interval shortening
Overview
Short QT syndrome is a rare autosomal dominant inhereted disease of the electrical conduction system of the heart due to gain-of-function mutations in genes encoding for cardiac potassium channels KCNH2, KCNQ1 and KCNJ2. The QT interval is short (≤ 360 ms) and does not significantly change with heart rate, and there are tall and peaked T waves in the right precordium. The heart is structurally normal. Short QT syndrome is associated with an increased risk of atrial fibrillation, syncope and sudden death.
Historical Perspective
The syndrome was first described by Dr. Prebe Bjerregaard MD, DMSc in 1999[1][2].
Description of the First Family with Short QT Syndrome
EKGs of the first patient's family members were analyzed. The QT interval of her 21 year old brother was 240 msec, the QT interval of her 84 year old maternal grandfather was 240 msec, and the QT interval of her 51 year old mother was 230 msec. The EKG of here father was normal[1][3].
He brother was asymptomatic, and on August 13, 2003 was found to have inducible ventricular fibrillation on programmed electrical stimulation. This was treated with implantation of an implantable cardioverter defibrillator. Subsequently he complained of occasional palpitations and paroxysmal atrial fibrillation with a rapid ventricular response was noted on interrogation of the ICD.
Her mother is a 51 year old healthy white female with a history of 3 episodes of sustained palpitations and paroxysmal atrial fibrillation. She has remained asymptomatic on propafenone since April, 2003. Programmed electrical stimulation on September 29, 2003 induced both atrial and ventricular fibrillation and an AICD was implanted.
Her maternal grandfather was an 84 year old white male who had chronic atrial fibrillation, coronary artery disease and hypertension who died following an embolic stroke.
Classification
- Short QT syndrome type 1 (SQT1): This variant is due to a gain-of-function mutation of the rapid component of the delayed rectifier potassium current HERG (KCNH2) channel(IKr)[4]. The variant is a result of missense mutations which increase IKr. It is associated with sudden death and sudden infant death syndrome.
- Short QT syndrome type 2 (SQT2): Caused by a mutation in the KCNQ1 gene[5]. In the first patient, a g919c substitution in the KCNQ1 gene encoding for the K+ channel KvLQT1 was identified. The mutation led to a gain of function in in the KvLQT1 (I(Ks)) channel. This variant is associated with ventricular fibrillation.
- Short QT syndrome type 3 (SQT3): This variant results from a G514A substitution in the KCNJ2 gene ( a change from aspartic acid to asparagine at position 172 (D172N))[6]. This causes a defect in the gene coding for the inwardly rectifying Kir2.1 (I(K1)) channel. The ECG shows asymmetrical T waves. These patients have an increased risk for re-entry arrhythmias.
- Short QT syndrome type 3 (SQT4): A loss of function mutation in the CACNA1C gene alters the encoding for the α1- and β2b-subunits of the L-type calcium channel. The phenotype is similar to Brugada syndrome combined with a short QT interval. There is an increased risk of sudden cardiac death.
- Short QT syndrome type 3 (SQT5): A loss of function mutation in the CACNB2B gene alters the encoding for the α1- and β2b-subunits of the L-type calcium channel. The phenotype is similar to Brugada syndrome combined with a short QT interval. There is an increased risk of sudden cardiac death.
Pathophysiology
Short QT syndrome types 1-3 are due to increased activity of outward potassium currents in phase 2 and 3 of the cardiac action potential. This causes a shortening of the plateau phase of the action potential (phase 2), causing a shortening of the overall action potential, leading to an overall shortening of refractory periods and the QT interval. In the families afflicted by short QT syndrome, two different missense mutations have been described in the human ether-a-go-go gene (HERG). These mutations result in expression of the same amino acid change in the cardiac IKr ion channel. This mutated IKr has increased activity compared to the normal ion channel, and would theoretically explain the above hypothesis. Short QT syndrome types 4 and 5 are due to abnormalities in the calcium channel.
Genetics
In the families afflicted by short QT syndrome, mutations have been described in three genes, KvLQT1, the human ether-a-go-go gene (HERG), and KCNJ2. Mutations in the KCNH2, KCNJ2, and KCNQ1 genes cause short QT syndrome. These genes provide instructions for making proteins that act as channels across the cell membrane. These channels transport positively charged atoms (ions) of potassium into and out of cells. In cardiac muscle, these ion channels play critical roles in maintaining the heart's normal rhythm. Mutations in the KCNH2, KCNJ2, or KCNQ1 gene increase the activity of the channels, which changes the flow of potassium ions between cells. This disruption in ion transport alters the way the heart beats, leading to the abnormal heart rhythm characteristic of short QT syndrome. Short QT syndrome appears to have an autosomal dominant pattern of inheritance.
Due to the autosomal dominant inheritance pattern, individuals may have family members with a history of unexplained or sudden death at a young age (even in infancy), palpitations, or atrial fibrillation. The penetrance of symptoms is high in affected family members.
Causes
The causes of shortening of the QT interval can be divided into primary causes (Short QT syndrome types 1-5) and secondary causes such as drugs and electrolyte disturbances.
Common Causes
Causes in Alphabetical Order
- Acidosis
- Altered autonomic tone
- Digoxin
- Hypercalcaemia
- Hyperkalemia
- Hyperthermia
- Lanatoside C
- Rufinamide
- Short QT syndrome type 1
- Short QT syndrome type 2
- Short QT syndrome type 3
- Short QT syndrome type 4
- Short QT syndrome type 5
Differentiating Short QT Syndrome from other Disorders
In contrast to Long QT Syndrome (LQTS), there is often no specific trigger (such as a loud noise or exercise) for an episode of arrhythmia.
Epidemiology and Demographics
Since the syndrome was first described in 2000, < 30 cases have been identified.
Age
The median age of presentation is 30 years, but ranges from just weeks to the sixth decade of life.
Natural History, Complications, Prognosis
Short QT syndrome is associated with an increased risk of atrial fibrillation, syncope and sudden death due to ventricular fibrillation.
Screening
A young patient with lone atrial fibrillation should be assessed for short QT syndrome.
Diagnosis
Secondary causes of a short QT interval such as drugs and electrolyte disturbances should be ruled out before embarking on an evaluation as to whether the patient has one of the short QT syndrome variants.
Diagnostic Criteria
Recent diagnostic criteria have been published out of the Arrhythmia Research Laboratory at the University of Ottawa Heart Institute from Drs. Michael H Gollob and Jason D Roberts.[7]
The Short QT Syndrome diagnostic criteria is based on a point system as follows:
- QTc in milliseconds
- <370 = 1 point
- <350 = 2 points
- <330 = 3 points
- J point - T peak interval in milliseconds
- <120 = 1 point
- Clinical History
- Sudden cardiac arrest = 2 points
- Polymorphic VT or VF = 2 points
- Unexplained syncope = 1 point
- Atrial fibrillation = 1 point
- Family History
- 1st or 2nd degree relative with SQTS = 2 points
- 1st or 2nd degree relative with sudden death = 1 point
- Sudden infant death syndrome = 1 point
- Genotype
- Genotype positive = 2 points
- Mutation of undetermined significance in a culprit gene = 1 point
The points are summed and interpreted as follows:
- > or equal to 4 points: High-probability of SQTS
- 3 Points: Intermediate probability of SQTS
- 2 points or less: Low probability of SQTS
Symptoms
Sudden Death
Sudden death may be the first presentation of the disease.
- The most common symptom of short QT syndrome is cardiac arrest (34%)[8].
- The first symptom of short QT syndrome is most often cardiac arrest (28%)[8]
Syncope
- Syncope is the first symptom in 24% of patients and is most likely due to self-terminating ventricular fibrillation.
Palpitations
- Palpitations are present in 31% of patients.
Atrial Fibrillation
- Atrial fibrillation is present in up to 80% of patients with short QT syndrome.
Triggers
In contrast to Long QT Syndrome (LQTS), there is often no specific trigger (such as a loud noise or exercise) for an episode of arrhythmia.
Screening
Short QT syndrome should be excluded in patients without structural heart disease presenting with sudden cardiac death.
Electrocardiogam
The diagnosis of short QT syndrome on the EKG is based upon three criteria:
Duration of the QT Interval
While the QT interval is generally short, the QT interval alone cannot be used to distinguish the patient with short QT syndrome from a normal patient (similar to long QT syndrome).[9] In general though, if the QTc is < 330 msec in a male, and <340 msec in a female, then short QT syndrome can be diagnosed even in the absence of symptoms as these QT intervals are much shorter than in the rest of the population. On the other hand, if the QTc is moderately shortened to < 360 msec in a male or < 370 msec in a female, the short QT syndrome should only be diagnosed in the presence of symptoms or a family history given the overlap of these QT intervals with that of the healthy population.
SQTS 1,2,3
The QTc is < 300-320 msec.[4][5][6]
SQTS 4,5
The QTc is just under 360 msec [10]
Variability of the QT Interval with Heart Rate
The short QT interval does not vary significantly with the heart rate. Normally the QT will become longer at slow heart rates and this does not occur among patients with short QT syndrome. The Bazett formula may overcorrect (i.e. shorten) the QT interval in the patient with bradycardia, and it is therefore important to use treadmill testing to increase the heart rate and confirm the absence of QT interval variation.[11]
Morphology of the T Wave
SQT1
Tall, narrow, peaked, symmetric T waves in the right precordial leads.
SQT3
Asymmetric peaked T waves due to more rapid repolarization at the end of the T wave.
SQT4 and 5
There is Brugada syndrome-like ST segment elevation in leads V1 and V2.
Morphology of the ST Segment
The ST segment is short or even missing. The T wave begins right after the S wave.
Early Repolarization
In a very limited number of patients it has been observed that early repolarization (which is present in 65% of patients with SQTS) and a longer T wave peak to T wave end period is associated with the occurrence of arrhythmic events[12].
Rhythm
70% of patients with short QT have a history of either paroxysmal atrial fibrillation or permanent atrial fibrillation, and atrial fibrillation is the first sign of short QT syndrome in 50% of patients. In young patients with lone atrial fibrillation, the patient should be screened for short QT syndrome.
Electrophysiologic Studies
Among patients with SQTS, the atrial and ventricular refractory periods are shortened (ranging from 120 to 180 ms). Ventricular fibrillation can be induced on programmed stimulation in 90% of patients with short QT syndrome. Despite the high rate of VF inducibility, the risk of sudden death in an individual patient is difficult to predict given the genetic and clinical heterogeneity of short QT syndrome and the limited number of patients with short follow-up to date. The limitations of electrophysiologic testing are highlighted by a study of Giustetto et al in which the sensitivity of electrophysiologic testing in relation to the clinical occurrence of ventricular fibrillation was only 50% (3 of 6 cases)[8]. Importantly, lack of inducibility does not exclude a future episode of ventricular fibrillation[13]. Thus, the role of electrophysiologic testing in risk stratification of the patient with SQTS is not clear at present.
Genetic Testing
Because new genetic variants of SQTS are still being identified, a negative genetic test for existing variants does not exclude the presence of SQTS. A negative genetic test for existing variants could mean that a patient with a short QT interval does not have a heretofore unidentified variant of SQTS.
However, among family members of an affected patient, genetic testing may identify the syndrome in an asymptomatic patient, and may also rule out the presence of the syndrome in asymptomatic patients.
Mutations in the KCNH2, KCNJ2, and KCNQ1 genes cause short QT syndrome. These genes provide instructions for making proteins that act as channels across the cell membrane. These channels transport positively charged atoms (ions) of potassium into and out of cells. In cardiac muscle, these ion channels play critical roles in maintaining the heart's normal rhythm. Mutations in the KCNH2, KCNJ2, or KCNQ1 gene increase the activity of the channels, which changes the flow of potassium ions between cells. This disruption in ion transport alters the way the heart beats, leading to the abnormal heart rhythm characteristic of short QT syndrome. Short QT syndrome appears to have an autosomal dominant pattern of inheritance.
Centers Performing Genetic Testing for Short QT Syndrome
Treatment
Device Based Therapy
An implantable cardioverter-defibrillator (ICD) is indicated in[14]:
- Symptomatic patients
- Patients with a family history of sudden cardiac death
Generally accepted criteria for implantation of an AICD also include:
- Inducibility on electrophysiologic testing
- Positive genetic test, although a negative result does not exclude the presence of a previously unreported mutation or the occurrence of a future arrhythmic event
Complications of AICD Placement
Inappropriate shocks may be delivered due to[15]:
- The occurence of tachycardias such as sinus tachycardia and atrial fibrillation.
- Oversensing of the tall, narrow peaked T wave
Pharmacologic Therapy
Short QT Syndrome 1 (SQT1)
The efficacy of pharmacotherapy in preventing ventricular fibrillation has only been studies in patients with SQT1. Given the limited number of patients studied, and the limited duration of follow-up, pharmacotherapy as primary or secondary preventive therapy for patients with SQT1 cannot be recommended at this time. AICD implantation remains the mainstay of therapy in these patients. Pharmacotherapy may play an adjunctive role in reducing the risk of events in patients with an AICD as described below in the indications section.
Patients with Short QT Syndrome 1 (SQT1) have a mutation in KCNH2 (HERG). Class IC and III antiarrhythmic drugs do not produce any significant QT interval prolongation [16][17] . Flecainide has not been shown to consistently reduce the inducibility of ventricular fibrillation.[18] Although it does not prolong the QT interval in SQT1 patients, propafenone reduces the risk of recurrent atrial fibrillation in SQT1 patients.[19]
Quinidine in contrast may be effective in patients with SQT1 in so far as it blocks both potassium channels (IKr, IKs, Ito, IKATP and IK1) and the inward sodium and calcium channels. In four out of four patients, Quinidine prolonged the QT interval from 263 +/- 12 msec to 362 +/-25 msec, most likely due to its effects on prolonging the action potential and by virtue of its action on the IK channels. Although Quinidine was successful in preventing the inducibility of ventricular fibrillation in 4 out of 4 patients, it is unclear if the prolongation of the QT interval by quinidine would reduce the risk of sudden cardiac death.
Although pharmacotherapy can be used to suppress the occurrence of atrial fibrillation in patients with SQT1, AICD implantation is the mainstay of therapy, and pharmacotherapy to prevent sudden death should is only indicated if AICD implantation is not possible.
Among patients with SQT1, Qunidine also:
- Prolongs the ST segment and T wave durations
- Restores the heart rate dependent variability in the QT interval
- Decreases repolarization dispersion
Indications for Pharmacologic Therapy
The following are indications for pharmacologic therapy of SQTS[20]:
- In children as an alternate to AICD implantation
- In patients with a contraindications AICD implantation
- In patients who decline AICD implantation
- In patients with appropriate AICD discharges to reduce the frequency of discharges
- In patients with atrial fibrillation to reduce the frequency of symptomatic episodes
References
- ↑ 1.0 1.1 Gussak I, Brugada P, Brugada J, Wright RS, Kopecky SL, Chaitman BR, Bjerregaard P (2000). "Idiopathic short QT interval: a new clinical syndrome?". Cardiology. 94 (2): 99–102. doi:47299 Check
|doi=value (help). PMID 11173780. Retrieved 2012-09-03. - ↑ http://www.shortqtsyndrome.org/short_qt_history.htm
- ↑ http://www.shortqtsyndrome.org/short_qt_history.htm
- ↑ 4.0 4.1 Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick GD, Wolpert C, Burashnikov E, Matsuo K, Wu YS, Guerchicoff A, Bianchi F, Giustetto C, Schimpf R, Brugada P, Antzelevitch C (2004). "Sudden death associated with short-QT syndrome linked to mutations in HERG". Circulation. 109 (1): 30–5. doi:10.1161/01.CIR.0000109482.92774.3A. PMID 14676148. Retrieved 2012-09-02. Unknown parameter
|month=ignored (help) - ↑ 5.0 5.1 Bellocq C, van Ginneken AC, Bezzina CR, Alders M, Escande D, Mannens MM, Baró I, Wilde AA (2004). "Mutation in the KCNQ1 gene leading to the short QT-interval syndrome". Circulation. 109 (20): 2394–7. doi:10.1161/01.CIR.0000130409.72142.FE. PMID 15159330. Retrieved 2012-09-02. Unknown parameter
|month=ignored (help) - ↑ 6.0 6.1 Priori SG, Pandit SV, Rivolta I, Berenfeld O, Ronchetti E, Dhamoon A, Napolitano C, Anumonwo J, di Barletta MR, Gudapakkam S, Bosi G, Stramba-Badiale M, Jalife J (2005). "A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene". Circulation Research. 96 (7): 800–7. doi:10.1161/01.RES.0000162101.76263.8c. PMID 15761194. Retrieved 2012-09-02. Unknown parameter
|month=ignored (help) - ↑ Gollob M, Redpath C, Roberts J. (2011). "The Short QT syndrome: Proposed Diagnostic Criteria". J Am Coll Cardiol. 57 (7): 802–812. doi:10.1016/j.jacc.2010.09.048. PMID 21310316.
- ↑ 8.0 8.1 8.2 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 LF, Haïssaguerre M, Schimpf R, Borggrefe M, Wolpert C (2007). "Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death". Circulation. 115 (4): 442–9. doi:10.1161/CIRCULATIONAHA.106.668392. PMC 1952683. PMID 17224476. Retrieved 2012-09-02. Unknown parameter
|month=ignored (help) - ↑ Viskin S. The QT interval: Too long, too short or just right. Heart Rhythm 2009; 6: 711–715.
- ↑ Antzelevitch C, Pollevick GD, Cordeiro JM et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST- segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007: 115: 442-449.
- ↑ Moreno-Reviriego S, Merino JL.Short QT Syndrome. An article from the E-Journal of the ESC Council for Cardiology Practice. Vol9 N°2, 17 Sep 2010 [1]
- ↑ 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 (2010). "High prevalence of early repolarization in short QT syndrome". Heart Rhythm : the Official Journal of the Heart Rhythm Society. 7 (5): 647–52. doi:10.1016/j.hrthm.2010.01.012. PMID 20206319. Retrieved 2012-09-03. Unknown parameter
|month=ignored (help) - ↑ Schimpf R, Bauersfeld U, Gaita F, Wolpert C (2005). "Short QT syndrome: successful prevention of sudden cardiac death in an adolescent by implantable cardioverter-defibrillator treatment for primary prophylaxis". Heart Rhythm : the Official Journal of the Heart Rhythm Society. 2 (4): 416–7. doi:10.1016/j.hrthm.2004.11.026. PMID 15851347. Retrieved 2012-09-03. Unknown parameter
|month=ignored (help) - ↑ Borggrefe M. FESC, Wolpert C, Veltmann C, Giustetto C, Gaita F, Schimpf R. Short QT Syndrome : A new primary electrical disease, ESC E journal, Vol 3 N°34, 10 May 2005. [2]
- ↑ Schimpf R, Wolpert C, Bianchi F, et al. Congenital Short QT Syndrome and Implantable Cardioverter Defibrillator Treatment: Inherent Risk for Inappropriate Shock Delivery. J Cardiovasc Electrophysiol 2003; 14: 1273-1277.
- ↑ Gaita F, Giustetto C, Bianchi F, Schimpf R, Haissaguerre M, Calo L, Brugada R, Antzelevitch C, Borggrefe M, Wolpert C. (2004). "Short QT syndrome: pharmacological treatment". J Am Coll Cardiol. 43 (8): 1494–1499. doi:10.1016/j.jacc.2004.02.034. PMID 15093889.
- ↑ Wolpert C, Schimpf R, Giustetto C, Antzelevitch C, Cordeiro J, Dumaine R, Brugada R, Hong K, Bauersfeld U, Gaita F, Borggrefe M (2005). "Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG". Journal of Cardiovascular Electrophysiology. 16 (1): 54–8. doi:10.1046/j.1540-8167.2005.04470.x. PMC 1474841. PMID 15673388. Retrieved 2012-09-03. Unknown parameter
|month=ignored (help) - ↑ Gaita F, Giustetto C, Bianchi F, Schimpf R, Haissaguerre M, Calò L, Brugada R, Antzelevitch C, Borggrefe M, Wolpert C (2004). "Short QT syndrome: pharmacological treatment". Journal of the American College of Cardiology. 43 (8): 1494–9. doi:10.1016/j.jacc.2004.02.034. PMID 15093889. Retrieved 2012-09-03. Unknown parameter
|month=ignored (help) - ↑ Bjerregaard P, Gussak I. Atrial fibrillation in the setting of familial short QT interval. Heart Rhythm 2004; 1: S165 (abstract).
- ↑ Moreno-Reviriego S, Merino JL.Short QT Syndrome. An article from the E-Journal of the ESC Council for Cardiology Practice. Vol9 N°2, 17 Sep 2010 [3]