NORD gratefully acknowledges Ana Isabel Moreno-Manuel and José Jalife, MD, PhD, Senior Investigator, Director, Arrhythmia Research Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain for the preparation of this report.
Short QT syndrome (SQTS) is an extremely rare but life-threatening familial disorder characterized by an abnormally short QT interval on the electrocardiogram (ECG), indicating that the heart muscle takes less time than usual to recharge between beats. SQTS increases the risk of an abnormal rate or rhythm of the heartbeat (cardiac arrhythmia), and sudden cardiac death (SCD). SQTS is a “channelopathy” caused by changes (mutations) in genes encoding proteins forming potassium or calcium ion channels (pores) on the cardiac, and even neuronal, cell membranes that are essential for the heart’s electro-mechanical function. The syndrome was first identified in 2000; since then, only about 250 cases have been reported in the scientific literature. Families with SQTS usually have incomplete penetrance, which means that children of an affected parent who inherit the gene mutation may or may not develop the disease. The specific symptoms, onset of symptoms and severity vary from one sibling to another. Accordingly, although SQTS may be diagnosed in children if they show clear cardiac symptoms, or if family history is suspected, it is difficult to establish a specific age of onset. Consequently, the incidence of SQTS in the general population remains unclear. In cases in which the genetic cause is known (20-30% of cases) the mutation is inherited in an autosomal dominant manner. However, the mechanisms that link the gene mutation to the arrhythmias and SCD are unknown, and the treatment depends on the signs and symptoms in each individual patient.
Short QT syndrome (SQTS) receives its specific name because on the electrocardiogram (ECG), its main characteristic is the presence of an abnormally short QT interval. The ECG is widely used by cardiologists to diagnose heart rhythm and conduction problems associated with cardiovascular conditions. Every time the heart beats, electrical currents flow through it, the ECG records the changes in voltage associated with such currents versus time. By placing electrodes at specific locations of the body surface and connecting them to an ECG machine, an expert can identify a wide variety of cardiac alterations, including abnormal heart rate and rhythm. Normally on ECG, each beat is composed by specific voltage waves, labelled P, Q, R, S and T, and organized as complexes, segments, and intervals with known amplitudes and durations. They indicate the local excitation and recovery as the electrical wave moves from the atria to the ventricles of the heart. The P wave represents the excitation (depolarization) of the atria; the QRS complex represents the depolarization of the ventricles and the T wave indicates the recovery (repolarization) from ventricular excitation. The time interval between the onset of the QRS and the end of the T wave is the QT interval. In humans, the QT interval normally lasts between 0.35 and 0.45 seconds, which is optimal to allow the ventricles to contract and pump the blood to the rest of the body. Since the QT interval normally varies depending on the heart rate, a mathematical formula is used to correct the QT interval (QTc) for changes in this parameter. In patients with SQTS, ventricular repolarization occurs too early and consequently, their QT interval will be too brief. Nowadays, a QTc interval less than 0.34 seconds is sufficient to suspect SQTS.
Although the link between a short QT interval and SCD had previously been suspected, Gussak, I. et al. described the SQTS in 2000 in a family with abnormally short QTc and other cardiac complications. Thereafter, SQTS was considered a new clinical entity associated with cardiac arrhythmia and increased risk of SCD but unknown mechanism. The long QT syndrome (LQTS), another channelopathy in which patients have a QTc interval longer than 0.45 seconds, was described several years earlier and its genetic basis was already known to be associated with mutations in genes for sodium, potassium and calcium ion channel proteins. Hence, investigators theorized that perhaps mutations provoking SQTS, while different from LQTS, could occur in the same or related genes. The first time SQTS was linked to a genetic cause was in 2004, when Brugada, R. et al. screened candidate genes encoding ion channels contributing to the repolarization phase of the cellular equivalent of the QT interval, the ventricular action potential. They identified a mutation in KCNH2, the gene coding the membrane potassium channel HERG responsible for positive repolarizing current, in two families with history of short QTc interval, arrhythmias and SCD. However, with time, it has become apparent that SQTS is a genetic disease caused by mutations in several different genes. Much effort has been devoted since then to the study of the causes of SQTS to include these genes in genetic screening panels with the aim of getting an early and appropriate diagnosis.
The extremely abbreviated QTc interval that characterizes the ECG of SQTS patients is associated with defects in cardiac electrical function including life-threatening arrhythmias that may appear at rest or during exercise with no apparent initiating cause.
The median age of appearance is 30 years, though it ranges widely, from a few months to 60 years of life. Moreover, the clinical presentation of the syndrome is diverse due to its variable expressivity even among members of the same family. Nevertheless, in up to 20% of patients, the first symptoms are usually: cardiac arrest (up to 40%), palpitations (30%) and syncope (25%). Atrial fibrillation has been reported in up to 80% of SQTS patients including children, adolescents and young adults. However, frequently, ventricular fibrillation and SCD can be the first manifestation, a fatal event that may have devastating impact on the families and the community. Moreover, since some of the ionic channels related to SQTS are also present in neurons, there are subtypes of SQTS that include epilepsy and autism as well.
All the above signs of the syndrome are associated with a QTc interval briefer than 0.34 seconds in patients with structurally normal hearts, but the precise link between the electrical abnormality and the fatal event has not been established.
While usually assumed to be inheritable, SQTS cases in which a familiar history is absent may be caused by a spontaneous mutation during embryonic development (known as a de novo mutation). Moreover, not all SQTS patients have an identifiable mutation.
Acquired SQTS may be associated with hypercalcemia, hyperkalaemia, acidosis and with some drugs effects.
Before delving into the mode of inheritance of SQTS, it is important to remember that a gene is a coding sequence present in chromosomes with the necessary information to produce a specific protein. The resulting gene product may play essential roles in the correct function of the body. A mutation may provoke an abnormal loss- or gain-of-function of the encoded protein. Consequently, the dysfunction of the resulting protein will be the initial trigger of the chain of events that result in a syndrome like SQTS.
SQTS is considered to be a genetic disease caused by mutations in multiple genes and follows autosomal dominant inheritance; that is, it occurs when a single copy of a non- or hyper-working gene is inherited from either parent. However, follow-up of patients with SQTS showed that only 20 to 30% may be explained by mutations in genes encoding potassium or calcium channels.
To date, of thirty-two variants described in the literature, only nine mutations in three genes encoding potassium ion channels (KCNQ1, KCNH2 and KCNJ2) have been clearly associated with SQTS. Identified variants in potassium channels are gain-of-function mutations and each of the genes causes a different SQTS subtype: KCNH2 – SQTS1 [OMIM 609620], KCNQ1 – SQTS2 [OMIM 609621], and KCNJ2 – SQTS3 [OMIM 609622]. In these cases, the increased function of the potassium ion channels results in a faster than normal repolarization phase of the cardiac action potential, with the consequent shortening of the QTc interval.
Genetic alterations in genes encoding calcium or sodium channels have not been demonstrated to lead to a clear diagnosis of SQTS. Nevertheless, several mutations in calcium channels responsible for depolarizing currents have been associated with the less prevalent forms of SQTS (SQTS4-6). For example, a genetic alteration with loss-of-function in the L-type calcium channel might yield a SQTS subtype (SQTS4) with an extremely low prevalence. As suggested, the reduced negative ionic current conducted by these mutated channels shortens the action potential and the QTc interval duration. The variants identified for the latter genes are also associated with Brugada syndrome, another channelopathy.
Many SQTS patients likely go undiagnosed or misdiagnosed, and determinations of SQTS incidence and prevalence are difficult due to limited data. Some have estimated the SQTS prevalence at less than 1 in 10,000. Others have suggested that SQTS shows a peak of incidence during the first year of life, age at which many SCD events occur and another peak in late adulthood.
When an ECG is taken at rest, the QTc interval duration is longer in females than in males. In addition, data suggest that men with idiopathic ventricular fibrillation (i.e., ventricular fibrillation of an unknown cause) show a higher prevalence of short QT interval than healthy males. However, though there might be a slight male SQTS predominance, no conclusive data are yet published. In addition, there do not seem to be differences between males and females in the risk of experiencing cardiac disorders due to SQTS. Differences in terms of ethnic groups also have not been reported in the literature.
Around 250 cases and nearly 150 families have been reported in the literature with SQTS. These numbers may not be entirely accurate, as there are difficulties diagnosing these patients. While the disease may be obvious in symptomatic patients, doubts may arise when dealing with asymptomatic patients, especially if they have no family history. In the past, SQTS was diagnosed if the QTc interval was 0.3 seconds or less. Nowadays, SQTS is suspected when the QTc interval duration is 0.34 seconds, a threshold under which a definitive diagnosis is established, even in the absence of symptoms. Furthermore, SQTS is also considered in patients with a QTc interval between 0.34 and 0.36 seconds plus one or more of the following signs: history of documented ventricular tachycardia or ventricular fibrillation in the absence of heart disease or reversible causes, family history of SQTS, family history of unexplained SCD at age ≤ 40 or a confirmed disease-causing mutation.
To find a possible causative mutation, genetic screening must be carried out. However, it is important to note that the role of genetic testing is limited in SQTS as most patients who show symptoms currently have an unknown genetic cause. Nevertheless, according to current SQTS guidelines, genetic testing should be considered, and the candidate genes included in this test are: KCNH2, KCNQ1, KCNJ2, CACNA1C, and CACNB2b. In some cases, CACNA2D1, SCN5A and SLC4A3 genes are also analysed. If a causative mutation is found in a patient with SQTS, family members should be tested immediately to diagnose possible SQTS cases early.
Importantly, since the ECG is a very useful and informative tool, findings such as a short QT interval, abnormal changes in the QT interval with heart rate, peaked and asymmetrical T waves (particularly in precordial leads), short (or absent) ST segments and paroxysmal episodes of atrial or ventricular fibrillation may facilitate the correct diagnosis of SQTS.
There are no standardized protocols for the treatment of SQTS patients. The rarity of the disease and its recent description has prevented the design of clinical trials on appropriate groups of patients. A team of specialists including cardiologists and other healthcare professionals together should determine the plan of treatment of patients and their families.
In general, clinical manifestations, family history and a positive electrophysiological study or genetic test may support the implantation of an implantable cardioverter defibrillator (ICD), since SQTS patients have a high risk of SCD. By delivering an electric shock, the device can be lifesaving by restoring the normal heartbeat if an abnormal rhythm is detected. Moreover, the newer-generation ICDs, also include the ability to act as pacemakers. An ICD is the first-line and most effective therapy in patients with severe arrhythmias, but its implantation is controversial in asymptomatic SQTS patients. In addition, the use of an ICD is not recommended in small children and there are adult patients in whom it is also not a therapeutic option.
In symptomatic patients in whom an ICD is not implanted, pharmacological treatment is mandatory. Recommended drugs are anti-arrhythmics like ibutilide, flecainide, sotalol, amiodarone and propafenone, and beta-adrenergic blockers (beta-blockers) like metoprolol and carvedilol. Beta-blockers reduce adrenergic input to the heart, a mechanism that helps control the heartbeat and prevent symptoms. However, due to the lack of conclusive clinical studies, the treatment is specific to each individual patient.
Nowadays, quinidine and hydroxyquinidine are tested as pharmacological treatments of SQTS patients because they prolong the QTc interval duration, reducing the incidence of life-threatening arrhythmias. Nevertheless, in some countries, quinidine has been removed from the market because of important side-effects.
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