Short QT syndrome: The current evidences of diagnosis and management

Abstract There are many cardiac arrhythmias and sudden cardiac death (SCD) related to channelopathies or ion channel disorders. Short QT syndrome (SQTS) is an inherited cardiac channelopathy principally caused by defective functioning of both potassium–calcium ion channel that lead to abnormal shortening of QT interval, and an increased risk of ventricular and atrial arrhythmias. Tall T waves in all lead electrocardiogram (ECG), peaked T waves, and narrow‐based T waves that are reminiscent of the typical “desert tent” T waves of hyperkalemia are frequently associated with SQTS. Diagnosis is based on patient's family history, evaluation of symptoms (palpitations and cardiac arrest), and 12‐lead ECG. It can be time challenging because of the wide range of QT interval in healthy subjects. Implantable cardioverter defibrillator (ICD) is the first‐line therapy in SQTS. Quinidine has the potential to be an effective pharmacological therapy for SQTS patients, especially in young children who are not feasible in ICD implantation, because of the ability to prolong QT interval.


| G ENE TI C FAC TOR S IN SQTS
Same with other congenital arrhythmogenic abnormalities, SQTS is associated with a number of mutations that cause changes in the function of ion channels, which are responsible for regulating currents in generating cardiac action potentials. Some mutations can cause hyperfunction of delayed rectifier potassium current (I Kr ) ( Figure 1). The mutation results in increasing of transmural repolarization dispersion and shortening of the repolarization period, which explains the main features of this syndrome: short atrial-ventricular effective refractory periods and short QT intervals, which will increase susceptibility to ventricular and atrial fibrillation (AF). SQTS is a heterogeneous disease seen both from a phenotype and genotype perspective. Six SQTS subtypes have been discovered so far according to nine mutations in six different genes that encode different cardiac ion channels (Table 1) 9 The researchers explained alternative molecular mechanisms in patients with short QT intervals and ventricular fibrillation (VF). Increasing of KCNQ1 mutation will increase the flow of IKs. However, only a few sporadic cases of this variant have been documented. One year later, the third variant of this syndrome (SQTS 3) was described by Priori et al, in two patients. 10 The presence of genetic changes in the KCNJ2 gene causes a significant increase in the I K1 outflow, which leads to the repolarization final phase acceleration. In 2007, Antzelevitch et al, described two new variants with the same canal dysfunction: loss of mutation function in the CACNA1C and CACNB2 genes encoding α1 and β2b subunits on L-type calcium channels associated with SCD related with familial heart disease, where SQTS is combined with the phenotype of Brugada syndrome. 11 The two mutations have been referred to, respectively, as SQTS 4 (two patients) and SQTS 5 (seven patients). Templin et al, described another mutation in the CACNA2D1 gene that causes a decrease in the flow of Ca-type L channels (SQTS 6). However, gene mutations are not found in all SQTS patients and the factors that related the appearance of these mutations have not been identified with certainty. This heterogeneity and the small number of cases are challenges for future research.

| CLINI C AL PRE S ENTATI ON S
The clinical presentations of SQTS are quite diverse. In the case series by Giustetto C et al, the most common symptom is cardiac arrest (34%). It is also the most frequent first clinical presentation appeared (28%). 12 Unlike LQTS, there are no special triggers for SQTS. Although SQTS usually occurs in adults, the average age is 30 years, and the age range of clinical presentation can range from a few months to the sixth decade. Events can occur while resting, during exercise, or after listening to loud sounds. Viskin et al, reported that men with idiopathic VF showed a shorter QT interval than healthy men. 13 Other symptoms that are often documented are palpitations and syncope. In 24% of cases, syncope is the first presenting symptom. 12 Self-terminating VF is considered as the most likely cause of syncope. Palpitations and AF appear in >80% of cases F I G U R E 1 Dysfunction of the heart ion channel in SQTS 22 964 | DEWI anD DHaRMaDJaTI even though the patient is still young (children and adolescents). AF is one of the main symptoms of SQTS; therefore, vigilant management is advisable in young patients with lone AF.

| D IAG NOS IS
The diagnosis of SQTS is based on the patient's family history, symptoms evaluation, and 12-lead ECG. It is important to ask patients about specific symptoms, such as palpitations and syncope, family history of syncope, sudden death, or AF at a young age. Secondary causes of short QT intervals should also be evaluated, such as hypercalcemia, hyperkalemia, hyperthermia, acidosis, and changing of autonomic tone. If no other causes are found, the patient diagnose as suspected SQTS. Schwartz's score can help classify SQTS probabilities ( Table 2). From Schwartz score, we can conclude low probability of SQTS if total score ≤2, intermediate probability 3, and high probability if total score ≥4.
When evaluating ECGs in patients, three main aspects must be observed; heart rate (HR), morphology of the T wave, and duration of the QT interval ( Figure 2). There is no single QTc value to distinguish the majority of SQTS cases from healthy individuals. In initial publication, patients had a short QT if the QTc value <300-320 ms, whereas in the most recent genotype (SQTS 4 and 5), QTc <360 ms. [6][7][8] In the study by Viskin et al, women with QTc <340 ms and men with QTc <330 ms can be diagnosed with SQTS even when they are asymptomatic because the values are very rare in the healthy population. 14  When assessing QT interval, it is also important to measure HR.

Patients with SQTS usually show a constant QT value and lack of HR
adaptation. There is a failure to prolong QT in bradycardia and abnormal shortening in tachycardia (QT interval pseudonormalization with fast HR). Serial ECG, Holter monitoring, and treadmill test can investigate the proper diagnosis and prevent patients from not recognizing basal heart tachycardia. In addition, this investigation can reduce incorrect diagnoses in SQTS patients with sinus bradycardia because it is known that the Bazett formula is over correct at the QT interval during bradycardia.
SQTS patients have a short or even absent ST segment, with the T wave starting immediately after the S wave. T wave is usually narrower and higher than normal subjects. Morphology of several T waves has been described to distinguish healthy subjects and SQTS. Anttonen et al, reported shorter J point-T peak intervals and shorter T-peak end intervals in SQTS patients. 12 Study by Watanabe et al, observed that early repolarization was more common in SQTS patients (65%); this was associated with the appearance of arrhythmias. 16 The duration from the peak to the end of the T wave is longer in patients with SQTS. T wave morphology can also guide a patient's genotype. SQTS has high, pointed, and symmetrical T waves. Asymmetrical T waves are sometimes obtained because of the final phase of the action potential repolarization acceleration.
The role of electrophysiological study (EPS) in SQTS is still controversial. Some researchers have shown a very short period of effective ventricular and atrial refractory, high rates of induction of ventricular and AF, and susceptibility to mechanical induction of VF. However, in the study of Giustetto et al, the sensitivity of EPSs to detect susceptibility to VF was only 50% (3/6). 12 ESC 2015 guidelines stated that invasive EPS with programed ventricular stimulation (PVS) is not recommended for SCD risk stratification. 15 Therefore, the benefits of examining EPS in the diagnosis and stratification of these patients are still unknown.
The genetic testing contribution is also not clearly defined. Seven genetic mutations have been identified but the correlation between Negative test results do not rule out SQTS because of the possibility of mutations that are not identified. Screening in one family is not only to diagnose asymptomatic congenital symptoms at an early stage but also to identify family members who do not carry certain mutations. Although ICD is an effective management, it also has a number of specific problems. Several reports indicate an increased risk of inappropriate shock due to sinus tachycardia, AF, and most importantly the presence of T waves, tall and narrow, oversensing. Study by Schimpf et al, stated that three of five patients received inappropriate shock due to T wave oversensing shortly after implantation.

| MANAG EMENT
Even though there was no evidence of abnormalities in the predischarge test, the reason might be due to T wave signal increasing and reduction R wave amplitude. 17 Therefore, standard programing after implantation to prevent T wave oversensing is needed.
Pharmacological therapy can be indicated as an alternative to ICD implantation in young patients (children), patients who rejected or contraindicated with ICD implantation, and to prevent symptomatic AF. Pharmacological therapy in SQTS must be given with caution because of its long-term efficacy in preventing the incidence of serious arrhythmias only proven in SQTS 1 patients.

| CON CLUS IONS
SQTS is a cardiac channelopathy disorder. SQTS is a life-threatening condition that is more common in young and healthy-looking populations. The incidental ECG findings of short QT intervals in young patients should not be underestimated, especially when associated with symptoms of arrhythmia, syncope, or the presence of paroxysmal or persistent AF documentation. Based on ESC, the diagnosis of SQTS is based on the QT interval ≤340 ms, but the diagnosis is still needed to be studied further and screening is still needed at this time. ICD is the first-line therapy in SQTS. Until now, quinidine has been widely used as a pharmacological therapy in SQTS, especially in patients who contraindicated or rejected ICD implantation.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest for this article.