Short QT syndrome
Template:Good article Template:Infobox medical condition (new) Short QT syndrome (SQT) is a very rare genetic disease of the electrical system of the heart, and is associated with an increased risk of abnormal heart rhythms and sudden cardiac death.<ref name="Bjerregaard_2018" /> The syndrome gets its name from a characteristic feature seen on an electrocardiogram (ECG) – a shortening of the QT interval. It is caused by mutations in genes encoding ion channels that shorten the cardiac action potential, and appears to be inherited in an autosomal dominant pattern.<ref name="Bjerregaard_2018" /> The condition is diagnosed using a 12-lead ECG.<ref name="Bjerregaard_2013" /> Short QT syndrome can be treated using an implantable cardioverter-defibrillator or medications including quinidine.<ref name="Schimpf_2005" /> Short QT syndrome was first described in 2000,<ref name="Gussak_2000" /> and the first genetic mutation associated with the condition was identified in 2004.<ref name="Brugada_2004" />
Signs and symptoms
Those affected by short QT syndrome (SQT) have an increased risk of developing abnormal heart rhythms.<ref name="Schimpf_2005">Template:Cite journal</ref> These abnormal heart rhythms often occur at a young age. They may take relatively benign forms such as atrial fibrillation, leading to symptoms of palpitations, breathlessness, or fatigue.<ref name="Schimpf_2005" /> Accordingly, atrial fibrillation presenting in a newborn should raise the suspicion of short QT syndrome.<ref name="Bjerregaard_2018" /> In addition, far more dangerous heart rhythm disturbances such as ventricular fibrillation can also occur in those with short QT syndrome, leading to blackouts or even sudden death.<ref name="Schimpf_2005" /> More than a third of those with short QT present with ventricular arrhythmias or sudden cardiac death, while one in five cases are detected during family screening, and one in five cases are found incidentally after an electrocardiogram (ECG) has been recorded for another reason.<ref name="Bjerregaard_2018" />
If someone with short QT syndrome is examined while their heart is beating in an abnormal rhythm such as atrial fibrillation, this can be detected by feeling their pulse.<ref>Template:Cite web</ref> No abnormal signs will usually be found when examining someone with short QT syndrome while their heart is beating in its normal or sinus rhythm.
Cause
Short QT syndrome is a genetic disorder caused by mutations in genes responsible for producing certain ion channels within heart cells. It appears to be inherited in an autosomal dominant pattern.<ref name="Bjerregaard_2018" /> Some genetic variants cause an increased flow of potassium out of the cell, while others reduce the flow of calcium into the cell.<ref name="Bjerregaard_2018" /> The common effect of all these variants is to shorten the cardiac action potential, reflected on the surface ECG as a shortening of the QT interval. A list of genes in which variants have been associated with short QT syndrome can be found in the table below.
| Type | OMIM | Gene | Channel | Notes |
|---|---|---|---|---|
| SQT1 | Template:OMIM | KCNH2 | Kv11.1 | Also known as hERG, encodes the potassium channel Kv11.1 responsible for the delayed rectifier potassium current IKr<ref name="Bjerregaard_2018">Template:Cite journal</ref> |
| SQT2 | Template:OMIM | KCNQ1 | Kv7.1 | Encodes the potassium channel responsible for the delayed rectifier potassium current IKs<ref name="Bjerregaard_2018" /> |
| SQT3 | Template:OMIM | KCNJ2 | Kir2.1 | Encodes the potassium channel Kir2.1 responsible for the inward rectifying potassium current IK1<ref name="Bjerregaard_2018" /> |
| SQT4 | Template:OMIM | CACNA1C | Cav1.2 | Encodes the alpha subunit of the L-type calcium channel carrying ICa(L)<ref name="Bjerregaard_2018" /> |
| SQT5 | Template:OMIM | CACNA2D1 | ICa(L) | Encodes the alpha2/delta subunit of the L-type calcium channel carrying ICa(L)<ref name="Bjerregaard_2018" /> |
| SQT6 | Template:OMIM | SLC4A3 | Anion exchanger 3 | Encodes a bicarbonate / chloride exchanger<ref name="Bjerregaard_2018" /> |
Mechanism
The overall effect of each of the genetic variants associated with short QT syndrome is to shorten the cardiac action potential, which in turn increases the risk of developing abnormal heart rhythms including atrial fibrillation and ventricular fibrillation.<ref name="Bjerregaard_2013" /> During the normal rhythm of the heart, or sinus rhythm, smooth waves of electrical activity pass regularly through the cardiac muscle. In contrast, during atrial or ventricular fibrillation, waves of electrical activation spiral through the cardiac muscle chaotically in a mass of disorganised, broken wavelets. The consequence of fibrillation is that the chambers of the heart affected by the disorganised electrical activation lose their pumping ability – fibrillation of the cardiac atria in atrial fibrillation leads to an irregular pulse, and fibrillation of the cardiac ventricles in ventricular fibrillation renders the heart unable to pump blood at all.<ref name="Antzelevich_2013"">Template:Cite book</ref>
There are several possible mechanisms by which short action potentials might promote fibrillation. The link between these mechanisms is how the duration of the action potential influences how frequently a heart muscle cell can be excited. A shorter action potential generally allow a heart muscle cell to be excited more frequently – the refractory period is shorter.<ref name="Antzelevich_2013"" />
The first mechanism, referred to as the dispersion of repolarisation, occurs because the action potential shortening seen in this condition occurs to a greater extent in some layers of the heart wall than in others.<ref name="Enriquez_2016">Template:Cite journal</ref> This means that at certain points in the cardiac cycle, some layers of the heart wall will have fully repolarised, and are therefore ready to contract again, while other regions are only partially repolarised and therefore are still within their refractory period and not yet able to be re-excited. If a triggering impulse arrives at this critical point in the cardiac cycle, the wavefront of electrical activation will conduct in some regions but block in others, potentially leading to wavebreak and re-entrant arrhythmias.<ref>Template:Cite journal</ref>
The second mechanism relates to the increased number of fibrillatory wavelets that can simultaneously exist if the action potential decreases, in a concept known as the arrhythmia wavelength.<ref name="Antzelevich_2013"" /> During fibrillation, the chaotic wavelets rotate, or re-enter, within the muscle of the heart, continually extinguishing and reforming. The volume of tissue in which each wavelet can complete a re-entrant circuit is dependent on the refractory period of the tissue and the speed at which the waves of depolarisation traverse move – the conduction velocity.<ref name="Antzelevich_2013"" /> The product of the conduction velocity and refractory period is known as the wavelength. In tissue with a lower wavelength a wavelet can re-enter within a smaller volume of tissue. A shorter refractory period therefore allows more wavelets to exist within a given volume of tissue, reducing the chance of all wavelets simultaneously extinguishing and terminating the arrhythmia.<ref name="Antzelevich_2013"" />
Diagnosis
Short QT syndrome is diagnosed primarily using an electrocardiogram (ECG), but may also take into account the clinical history, family history, and possibly genetic testing. Whilst a diagnostic scoring system has been proposed that incorporate all of these factors (the Gollob score<ref name="Gollob_2011">Template:Cite journal</ref>), it is uncertain whether this score is useful for diagnosis or risk stratification,<ref name="Rudic_2014">Template:Cite journal</ref> and the Gollob score has not been universally accepted by international consensus guidelines.<ref name="Priori_2013" /><ref name="Priori_2015" /> There continues to be uncertainty regarding the precise QT interval cutoff that is should be used for diagnosis.<ref name="Priori_2015">Template:Cite journal</ref>
12-lead ECG
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The mainstay of diagnosis of short QT syndrome is the 12-lead ECG. The precise QT duration used to diagnose the condition remains controversial with consensus guidelines giving cutoffs varying from 330 ms,<ref name="Priori_2013" /> 340 ms or even 360 ms when other clinical, familial, or genetic factors are present.<ref name="Priori_2013" /><ref name="Priori_2015" /> The QT interval normally varies with heart rate, but this variation occurs to a lesser extent in those with short QT syndrome.<ref name="Bjerregaard_2018" /> It is therefore recommended that the QT interval is assessed at heart rates close to 60 beats per minute.<ref name="Bjerregaard_2018" /> Other features that may be seen on the ECG in short QT syndrome include tall, peaked T-waves and PR segment depression.<ref name="Rudic_2014" />
Other features supporting diagnosis
Other features that support a diagnosis of short QT syndrome include: a history of ventricular fibrillation or ventricular tachycardia despite an apparently structurally normal heart; a family history of confirmed short QT syndrome; a family history of sudden cardiac death aged <40 years; and identification of a genetic mutation consistent with short QT syndrome.<ref name="Priori_2015" /><ref name="Priori_2013" />
Invasive electrophysiological studies, in which wires are passed into the heart to stimulate and record the heart's electrical impulses, are not currently recommended for diagnosing short QT syndrome or predicting the risk of sudden cardiac death.<ref name="Priori_2013" /><ref name="Priori_2015" />
Treatment
The treatment for short QT syndrome is aimed at preventing abnormal heart rhythms and reducing the risk of sudden cardiac death. It has been difficult to experimentally test potential treatments as the condition is very rare, so the evidence for treatment effectiveness comes largely from consensus opinion.<ref name="Bjerregaard_2018" /> In addition to treating the person identified as having the condition, screening of family members may be recommended.
Implantable cardioverter-defibrillator
In those with short QT syndrome who have already experienced a life-threatening abnormal heart rhythm such as ventricular fibrillation, an implantable cardioverter-defibrillator (ICD) may be recommended to reduce the chance of sudden death.<ref name="Schimpf_2005" /> This device is implanted under the skin and can continually monitor the heart rhythm. If the device detects a dangerous heart rhythm disturbance it can deliver a small electric shock with the aim of restoring a rhythm. Implanting an ICD in someone with short QT syndrome who has not yet experienced a life-threatening arrhythmia is more controversial but may be considered.<ref name="Bjerregaard_2018" /><ref name="Priori_2013">Template:Cite journal</ref>
Medication
Medication aimed at correcting the ECG abnormality – the shortened QT interval – has been tried. Quinidine, a class Ia antiarrhythmic agent, has been shown to partially correct the QT interval and make the heart more resilient to artificially-induced abnormal heart rhythms,<ref name="Schimpf_2005" /><ref>Template:Cite journal</ref> although it is still uncertain at present whether this translates to a lower risk of sudden death.<ref name="Bjerregaard_2018" /><ref>Template:Cite journal</ref> Sotalol, another antiarrhythmic, may prolong the QT in some subtypes of short QT syndrome.<ref name="Priori_2013" /> Other medications including beta blockers, flecainide, and amiodarone have been tried, but at present there is little evidence to support their use.<ref name="Bjerregaard_2018" />
Drugs can also be used to treat the less dangerous abnormal heart rhythm that is also associated with short QT – atrial fibrillation. Propafenone, a class 1c antiarrhythmic, may be helpful in those with short QT to prevent atrial fibrillation.<ref name="Enriquez_2016" /> Those who develop atrial fibrillation may also require medication to decrease blood clotting in order to reduce the risk of stroke.<ref>Template:Cite journal</ref>
Epidemiology
Short QT syndrome is a very rare condition with, as of 2018, fewer than 300 cases described in the medical literature.<ref name="Bjerregaard_2018" /> As a genetic syndrome, those affected are born with the condition. Symptoms can occur in newborns, potentially presenting as sudden infant death syndrome.<ref name="Bjerregaard_2013">Template:Cite book</ref> Males and females are equally likely to be affected, and have a similar risk of sudden cardiac death.<ref name="Bjerregaard_2013" />
Prognosis
The rarity of short QT syndrome makes calculating prognosis accurately difficult. The risk of sudden cardiac death has been estimated at 0.8% per year,<ref name="Bjerregaard_2013" /> leading to a cumulative risk of sudden cardiac death of 41% by the age of 40.<ref name="Bjerregaard_2018" /> A previous history of cardiac arrest predicts a higher likelihood of further dangerous arrhythmias.<ref name="Bjerregaard_2018" /> Some have suggested that those with the shortest QT intervals may have a higher risk of arrhythmias, but this view has not been supported by all.<ref name="Bjerregaard_2018" /> The findings from invasive electrophysiological studies do not predict an individual with short QT syndrome's risk of cardiac arrest.<ref name="Bjerregaard_2018" />
History
The first report of short QT syndrome to be published was in 2000, describing a family with short QT intervals on the 12-lead ECG, atrial fibrillation occurring at a young age, and an unrelated patient who had a sudden cardiac death associated with a short QT interval.<ref name="Bjerregaard_2013" /><ref name="Gussak_2000">Template:Cite journal</ref> The association between short QT and sudden cardiac death was described in 2003,<ref>Template:Cite journal</ref> and the first gene associated with the condition was identified in 2004.<ref name="Brugada_2004">Template:Cite journal</ref> Criteria for diagnosing Short QT syndrome were proposed in 2011.<ref name="Gollob_2011" /> Recently the first animal model of short QT syndrome was presented, enabling more in depth analysis of arrhythmia mechanisms.<ref>Template:Cite journal</ref>
See also
- Channelopathy
- Long QT syndrome
- Brugada syndrome
- Catecholaminergic polymorphic ventricular tachycardia