Short QT syndrome overview
Synonyms and keywords: SQTS; short QT; short QTc; QT interval shortening

# Overview
Short QT syndrome is a rare autosomal dominant inherited disease of the electrical conduction system of the heart. It is defined by short QT intervals  ( 360 ms) that increases an individual propensity to atrial and ventricular tachyarrhythmias. It occurs due to gain-of-function mutations in genes encoding for cardiac potassium channels KCNH2, KCNQ1 and KCNJ2. The shortened QT interval does not significantly change with heart rate, and there are tall and peaked T waves in the right precordium. It 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, who wrote the first clinical report of three members of one family who presented with persistently short QT interval.

# 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).   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. 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)). 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 4 (SQT4):  A loss of function mutation in the CACNA1C gene alters the  encoding for the 1- and 2b-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 5 (SQT5):  A loss of function mutation in the CACNB2B gene alters the  encoding for the 1- and 2b-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 6 (SQT6):  A loss of function mutation in the CACNAD2D1 coding for the Cav2-1 subunit of the L-type calcium channel. 

# 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 due to mutations in potassium channels. 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 and 6 are due to mutations in the calcium channel and consequent reduction  in L-type Ca-channel current.

## 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. It is also interesting to note that while mutations involving potassium channel genes associated with the long QT syndrome are loss-of-function mutations, the mutations that cause short QT syndrome are gain-of-function mutations.
The calcium channels' dysfunction are mostly due to CACNA1C and CACNB2b genes mutation which caused Brugada-like ECG changes with short QT interval. Lastly, a novel mutation of the CACNA2D1 gene was reported in a 17-year-old female who presented with short QT interval and ventricular fibrillation.

# 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
- Hypercalcemia
- Digoxin

## 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
- Short QT syndrome type 6

## Differentiating Short QT Syndrome from other Disorders
Short QT may have secondary causes that must be ruled out, since the short QT syndrome is by definition a primary, congenital disease of the heart. Such causes include: hyperkalemia, hypercalcemia, acidosis, hyperthermia - caused by the use of drugs like digitalis, effect of acetylcholine or catecholamine and activation of Katp or Kach current. Only after ruling out such causes is that the diagnosis of short QT syndrome may be made.

# Epidemiology and Demographics
European studies have estimated a prevalence of 0.02% to 0.1% among adults. A paper from 2015 which tried to assess the prevalence among pediatric population in the U.S. estimated a prevalence of 0.05% at this population. Sudden cardiac arrest has a peak incidence between the second and fourth decades of life, which might indicate an association with testosterone levels in males.

# Natural History, Complications, Prognosis
The disease can have clinical manifestations from the first year of life until as late as 80 years old, and most cases are symptomatic. Its most frequent symptoms include cardiac arrest (which was the first symptom in 28% of the patients), followed by palpitations, and syncope. Patients may also present with atrial fibrillation and ventricular extrasystoles. They remain at high risk for sudden death during their lifetime and may present with a strong family history for this occurence. Sudden cardiac death presents with two high-risk peaks, one in the first year of life, and another one from 20 to 40 years old. Even though familial association is present in the majority of patients, the yields for genetic tests is low.

# Screening
Since the disease is so rare, no screening for the general population is advised. Individuals with short QT interval detected on the ECG must first rule out other causes. Genetic screening is performed if a patient presents with: sudden cardiac arrest, history of polymorphic ventricular tachycardia or ventricular fibrillation without a known cause, history of unexplained syncope, young individuals with atrial fibrillation, family members diagnosed with short QT syndrome, family members who died from sudden cardiac arrest.

# Diagnosis
The first step for diagnosing short QT syndrome is ruling out secondary causes, such as the ones cited above. Once them are ruled out, there are two suggested diagnostic approaches in the medical literature: one proposed by GOLLOB, and another one proposed by PRIORI:
- Scoring type of diagnostic criteria, as proposed by the Arrhythmia Research Laboratory at the University of Ottawa Heart Institute from Drs. Michael H Gollob and Jason D Roberts.
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
- Diagnostic criteria suggested by PRIORI, 2015 for the European Society of Cardiology:
- QTc <340ms or QTc <360ms and one or more of the following:
Confirmed pathogenic mutation;
Family history of SQTS;
Family history of sudden death at 40 years of age;
Survival from a VT/VF episode at the absence of heart diseases.
- Confirmed pathogenic mutation;
- Family history of SQTS;
- Family history of sudden death at 40 years of age;
- Survival from a VT/VF episode at the absence of heart diseases.

## Electrocardiogam

### 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).  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 according to the guidelines above. 
The QTc is usually < 300-320 msec.
The QTc is usually just under 360 msec 

### 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.

### Other ECG findings:
- There is a high prevalence of early depolarization patterns on SQTS.
- QRS complex is followed by T wave without any ST segment.
- Prominent U wave separated by isoelectric T-U segment.
- Longer Tpeak - Tend interval.
- Prolongation of the QT interval at slower heart rates is suppressed, remaining below the lower limit.
- Depressed PQ segment commonly observed in the inferior and anterior leads.
- 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.
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).  Importantly, lack of inducibility does not exclude a future episode of ventricular fibrillation.  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
- Gene Tests: Short QT Syndrome 1
- Gene Tests: Short QT Syndrome 2
- Gene Tests: Short QT Syndrome 3

# Treatment

## Device Based Therapy
An implantable cardioverter-defibrillator (ICD) is indicated in symptomatic patients who have either survived a sudden cardiac arrest and/or have had documented episodes of spontaneous sustained ventricular tachyarrhythmias with or without syncope. There's a problem with ICD in such patients though, because the tall and peaked T wave can be interpreted as a short R-R interval provoking inappropriate shock.
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:
- 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  . Flecainide has not been shown to consistently reduce the inducibility of ventricular fibrillation. Although it does not prolong the QT interval in SQT1 patients, propafenone reduces the risk of recurrent atrial fibrillation in SQT1 patients.
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. It also prolonged the ST interval and T wave durations, restored the heart rate dependent variability in the QT interval and decreased depolarization dispersion in patients with SQT1.
There is a report which states that disopyramide was also effectively used in two patients with SQT-1, increasing their QT interval and ventricular refractory period while also abbreviating the Tpeak-Tend interval.
As atrial fibrillation is also very commonly found on those patients propafenone has also been successfully used to prevent its paroxysms, without having any effect on QT interval.
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.

### Indications for Pharmacologic Therapy
The following are indications for pharmacologic therapy of SQTS:
- 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.