Short QT syndrome

INTRODUCTION — Short QT Syndrome (SQTS) is a rare inherited channelopathy (a disorder that affects the movement of ions through channels within the cell membrane) associated with marked shortened QT intervals and sudden cardiac death (SCD) in individuals with a structurally normal heart. In contrast to long QT syndrome, another channelopathy, ion channel defects associated with SQTS lead to abnormal abbreviation of repolarization, predisposing affected individuals to a risk of atrial and ventricular arrhythmias.

Since its first report in 2000, significant progress has been made in defining the genetic and cellular basis of SQTS as well as in therapeutic approaches to treating this syndrome. SQTS is a genetically heterogeneous disease associated with eight different genes encoding various cardiac ion channels, a carnitine transporter, and a chloride-bicarbonate anion exchanger. Data regarding genotype-phenotype correlation and genotype-specific treatment are promising but limited, primarily due to the lack of clinical cases.

The clinical presentation, diagnostic approach, and treatment modalities for SQTS will be discussed here. SCD and other channelopathies are discussed separately. (See "Overview of sudden cardiac arrest and sudden cardiac death" and "Congenital long QT syndrome: Epidemiology and clinical manifestations".)

HISTORICAL BACKGROUND AND INITIAL REPORT — In 1993, it was first proposed that shorter than normal QT intervals (<400 milliseconds) are associated with a 2.4-fold increased risk for SCD [1]. An abnormally short QT interval observed before and after runs of VT/VF has been reported anecdotally [2,3]. Interestingly, certain species of kangaroo, known to have a high incidence of SCD, display an abnormally short QT interval as a normal feature on their electrocardiogram (ECG) [4,5].

SQTS was first described as a clinical entity in a report of four patients with extremely short QT intervals in association with paroxysmal atrial fibrillation and SCD [6,7]. In 2003, another study further described SQTS in two unrelated European families (six patients total) with a strong family history of sudden death in association with short QT interval on ECG [8]. Since then, over 200 cases of SQTS have been reported, and the existence of this novel channelopathy has been validated.

DEFINITION — Abbreviation of the QT interval, the time elapsed between ventricular depolarization and repolarization, on the surface ECG is caused by a decrease in the action potential duration (APD) of ventricular myocytes (figure 1). The upper limit of the normal QT interval is now fairly well defined, but the lower limit of the normal QT interval and the value below which it could be considered arrhythmogenic remain unclear [9,10]. The ECGs of the first few patients with SQTS showed extremely short QT and QTc intervals of less than 300 milliseconds. Since then, patients with SQTS with QT interval longer than 300 milliseconds have been reported; however, in most cases the QT and QTc interval have been less than 360 milliseconds. Yet the diagnosis of SQTS is complicated due to the overlapping QT range of affected individuals and apparently healthy individuals.

To define the lower limit of the QT interval, many experts refer to a comprehensive study that investigated the distribution of normal QT interval in 14,379 healthy individuals [11]. The study established the formula (Rautaharju's formula) by which the QT interval can be predicted as:

QT predicted (QTp) = 656/(1+ heart rate/100)

The prevalence of QT interval shorter than 88 percent of QTp (QT/QTp <88 percent, which is equivalent to two standard deviations below the mean) was 0.03 percent. Based on this observation, it was suggested that QT intervals less than 88 percent of QTp (two standard deviations below mean predicted value) at a particular heart rate may be considered as short QT intervals. For example, at a heart rate of 60 beats per minute (bpm), per Rautaharju's formula, QTp would be 410 milliseconds. Eighty-eight percent of QTp (410 milliseconds) would be 360 milliseconds. QT interval values less than 80 percent of QTp may be considered extremely short (which is equivalent to 330 milliseconds at a heart rate of 60 beats per minute) [12-15].

Clinical experience clearly indicates that the vast majority of patients with QTc values in the 330 to 360 range are not at risk, although a select few may be. (See 'Differential diagnosis' below.)

PREVALENCE OF A SHORT QT INTERVAL — In contrast to the epidemiologic data available for many other ECG parameters, including long QT intervals, the precise prevalence of a short QT interval in the general population is unknown but appears to be 2 percent or less when using a cutoff of 360 milliseconds. This is largely the case due to the long-standing failure to identify any risk associated with shorter-than-normal QT intervals as well as the varying definitions of what constitutes a shorter-than-normal QT interval.

Several large cohorts have attempted to identify the frequency of short QT interval in the general population [16-19]. The precise definition of a short QT has varied slightly in each of the cohorts, but in all of the studies, patients classified as having a short QT interval had a rate-corrected QTc of 369 milliseconds or less. The prevalence was estimated as follows:

●In a Finnish cohort of 10,822 middle-aged (mean 44 years) patients, 0.4 percent had a short QTc interval (<340 milliseconds), and 0.1 percent had a very short QTc interval (<320 milliseconds) [16].

●In a Swiss cohort of 41,767 army conscripts (99.6 percent male, mean age 19 years), 1 percent had a short QTc interval (<347 milliseconds), and 0.02 percent had a very short QTc interval (<320 milliseconds) [17].

●In an American cohort of 46,129 healthy volunteers (53 percent female), 2 percent had a QTc interval ≤360 milliseconds [19].

●In a Japanese cohort of 114,334 patients with ECGs stored in an electronic database, 0.37 percent were found to have short QTc intervals (≤357 milliseconds in males, ≤364 milliseconds in females) [18].

GENETIC BASIS — SQTS is a genetically heterogeneous disease with mutations in eight different genes (three gain of function and five loss of function) that encode different cardiac ion channels, a carnitine transporter, and a chloride-bicarbonate anion exchanger (AE3), having been identified and termed SQT1 to SQT8 based on the chronology of their discovery (table 1). SQT1 and SQT3-8 have been reported in a familial setting, and SQT2 is reported only in a single patient in a sporadic setting. SQTS traits are transmitted in an autosomal dominant fashion. Many of the genes involved in SQTS are the same as those responsible for LQTS; however, the net effect of the pathogenic variants in SQTS is to increase repolarizing forces, an effect opposite to that encountered in LQTS. (See "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Types of congenital LQTS'.)

The largest available case series of SQTS describes the clinical presentation of 29 patients with SQTS [20]. The most common form of SQTS (SQT1) was linked to pathogenic variants in KCNH2, the gene encoding the α-subunit of the rapid delayed rectifier K⁺ channel (I_Kr) (figure 2). Approximately 25 percent of patients had a mutation in KCNH2, and no pathogenic variant was found in the rest of the patients. Mutations in KCNQ1 and KCNJ2 were not detected, and CACNA1c, CACNB2b, and CACNA2D1 were not screened. A genetic cause remains to be identified in the majority of SQTS cases [21].

The N588K pathogenic variant in KCNH2 was first identified in three separate families with shorter than normal QT intervals and a high incidence of ventricular arrhythmias and sudden death [8,22]. Patch clamp analysis of N588K revealed this mutation completely removed inactivation over a physiological range of potentials, resulting in a dramatic increase in I_Kr [23,24]. A second mutation at T618I in KCNH2 has been discovered and linked to SQT1 [25]. The T618I-KCNH2 missense mutation was recently designated as a hotspot, having been identified in 18 members of seven unrelated families [26].

Many patients with SQTS carrying pathogenic variants in the L-type calcium channel genes (CACNA1C, CACNB2 and CACNA2D1) manifest an ST segment elevation on the surface ECG in addition to a shorter than normal QT interval and have a combined Brugada/Short QT syndrome [27,28]. Most patients harboring a calcium channel mutation who display normal QT intervals have been shown to carry secondary genetic variations that are known to prolong the QT interval. QT-prolonging variations (p.D601E-CACNB2b, p.K897T-KNCH2, p.T10M-KCNE2, p.R1047L-KCNH2, p.D76N-KCNE1, p.G643S-KCNQ1) were found in 12 of the 14 BrS probands presenting with a normal QTc [29].

Initially, only pathogenic variants in genes encoding the cardiac potassium and calcium channels were implicated in SQTS. However, a subsequent report provides evidence that a disturbance of long-chain fatty acid metabolism can influence the morphology and the electrical function of the heart, leading to development of SQTS [30]. In this case series, three patients affected by primary systemic carnitine deficiency presented with SQTS associated with ventricular fibrillation. Primary carnitine deficiency is a rare (1:50,000) autosomal recessive disorder caused by defective transport of carnitine into the cell, in which mutations in SLC22A5 have been implicated [31,32]. Administration of oral DL-carnitine or L-carnitine supplements (5 g/day) over a period of months abolished the ECG and arrhythmic manifestations of the syndrome. Additional evidence in support of the relationship between carnitine deficiency and SQTS was obtained by using a mouse model of carnitine deficiency induced by long-term subcutaneous perfusion of MET88 [30]. Previous studies have reported that the absence of long-chain fatty acids leads to an increase in the rapidly activating delayed rectifier potassium channel current (I_Kr) [33], which may participate in the abbreviation of the QT interval in primary carnitine deficiency. This study suggests that long-chain fatty acids can directly regulate I_Kr. The effects of Class III antiarrhythmic agents have not been tested either in humans with primary carnitine deficiency or in the mouse model of the syndrome. (See "Specific fatty acid oxidation disorders", section on 'Carnitine transporter deficiency'.)

Another study has implicated loss-of-function mutations in the chloride bicarbonate anion exchanger (AE3) encoded by SLC4A3 gene in two unrelated three and four-generation families with SQTS [26]. The SLC4A3 c.1109 G >A, p.R370H variant caused reduced surface expression of the anion exchanger and reduced membrane bicarbonate transport. Additional evidence in support of this as a cause of SQTS derives from the demonstration that SLC4A3 knockdown in zebrafish causes increased cardiac pHi, short QTc, and reduced systolic duration, which is rescued by wildtype SLC4A3. Furthermore, experimental data suggested that an increase in pHi and decrease in [Cl⁻]i abbreviate the action potential duration [26]. Cascade screening in the two families identified a total of 23 carriers of the SLC4A3 variant. Mutation carriers displayed a mean QTc of 340±18 ms compared to a mean QTc of 402±24 ms in the 19 non-carrier family members.

In a 2019 study of variants previously catalogued as pathogenic in SQTS according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, only 9 of the 32 variants studied (28 percent) were shown to have a conclusive pathogenic role [34]. All nine definitively pathogenic variants were located in the genes encoding for the three potassium channel genes KCNQ1, KCNH2, or KCNJ2. Variants in genes encoding calcium or sodium channels were associated with electrical alterations concomitant with shortened QT intervals but not necessarily SQTS.

In 2021, a study with a similar evidence-based reappraisal of previously reported genes found that only one gene studied (KCNH2) was definitively linked to short QT pathogenesis [35]. Three other pathogenic variants (KCNQ1, KCNJ2, SLC4A3) had strong to moderate evidence of being causative of SQTS. It is noteworthy that the majority of genetic evidence was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3).

CELLULAR BASIS OF ARRHYTHMOGENESIS — The QT interval is determined by the ventricular action potential duration, which in turn is dependent upon a delicate balance of currents active during the repolarization phase of the action potential (figure 1). An increase in net outward current due to either a reduction in inward depolarizing currents like I_Ca (SQT4- SQT6) or augmentation of outward repolarizing currents such as I_Kr (SQT1), I_Ks (SQT2), I_K1 (SQT3), or a combination thereof, can shift the balance of current favoring early repolarization, thus leading to abbreviation of action potential duration, refractoriness, and QT interval (figure 2).

Available data suggest that abbreviation of the action potential in SQTS is heterogeneous with preferential abbreviation of either epicardial or endocardial cells as compared with subendocardial M cells, resulting in tall, positive T waves on the ECG and an increase in transmural dispersion of repolarization (TDR) [36,37]. Dispersion of repolarization serves as substrate, and abbreviation of wavelength (product of refractory period and conduction velocity) promotes the initiation and maintenance of reentry under conditions of SQTS.

The trigger responsible for generating the premature beat that precipitates polymorphic ventricular tachycardia (VT) in SQTS is not known but may involve a phase 2 reentry or late phase 3 early afterdepolarization mechanism, which may give rise to R-on-T extrasystoles [37,38]. Alternatively, re-excitation of the ventricles from the Purkinje fiber network may initiate the arrhythmia [23,39].

In the experimental setting, shortening of the action potential duration (and thus QT interval) results in a reduction in contractility [40,41]. However, reports have shown that while electrical repolarization in SQTS patient is abbreviated, mechanical contraction is not, suggesting an electromechanical dissociation [42].

A gain-of-function mutation augments outward potassium current in SQT1-3, and a loss-of-function mutation reduces I_Ca in SQT4-6 [22,27,28,43,44]. Carnitine deficiency is thought to increase I_Kr in LQT7 and a combination of an increase in pH and reduction in intracellular Cl^- contributes to action potential duration abbreviation in LQT8. T_peak-T_end/QT ratio, an ECG index of spatial dispersion of repolarization, is significantly augmented in most cases of SQTS, suggesting an increase in TDR at the cellular level [26,45,46]. Interestingly, this ratio is amplified in patients who are symptomatic [47]. The increase in TDR is known to predispose to phase 2 reentry and may be responsible for the closely-coupled premature ventricular extrasystole that precedes the onset of polymorphic VT in patients with SQTS [48,49].

The preclinical models discussed above and others, including transgenic rabbits generated by oocyte-microinjection of beta-myosin-heavy-chain-promoter-KCNH2/HERG-N588K constructs, offer opportunities to improve the diagnosis and treatment of patients with SQTS. They have proven useful in identification of genotype–phenotype associations and have uncovered disease mechanisms and revealed underlying pathophysiology of SQTS. These discoveries have been leveraged in drug development for treatment of patients with SQTS [21,50,51].

CLINICAL PRESENTATION — The clinical presentation of SQTS is variable, and many patients are asymptomatic [7].

Typical presentation — The initial presentation and subsequent clinical course of SQTS varies among different families and even within different members of the same family, as shown in the following case series of 29 patients [20]:

●The first manifestation of the disease was reported at an age as young as one month or as old as 80 years.

●Sixty-two percent of the patients (18 out of 29) were symptomatic. The most frequently reported symptoms were:

•Cardiac arrest – 34 percent (this was the initial symptom in 28 percent)

•Palpitations – 31 percent

•Syncope – 24 percent

•Atrial fibrillation – 17 percent

●38 percent of the patients (11 out of 29) were asymptomatic and were diagnosed based on a strong family history of arrhythmic symptoms including SCD, a common finding in familial forms of SQTS.

The circumstances surrounding the onset of symptoms are highly variable, and episodes of sudden cardiac death (SCD) have been reported at rest, following a loud noise, during exercise, and during routine daily activities. SCD occurred in the first month of life in two patients, suggesting that SQTS may contribute to sudden infant death syndrome (SIDS) [20].

Arrhythmogenic events have been reported at all ages from infants to octogenarians, but the first year of life appears to be the most worrisome, with a 4 percent rate of cardiac arrest [52]. One-third of cases present with SCD as their first event, and up to 80 percent show a personal or family history of SCD [53]. Lethal events occur in both sexes, but a slight male predominance appears to exist which may be due to testosterone modulation of potassium currents as seen in other channelopathies [54-56]. Male patients with SQTS presented more often with syncope as compared with female patients (24 percent versus 7 percent) and other presenting symptoms such as palpitations as well as SCD were not significantly different between the sexes [55].

The following findings were noted in a report of 53 patients from the European Short QT Registry (75 percent males; median age 26 years) who were followed for up to 64±27 months [57]:

●A familial or personal history of cardiac arrest was present in 89 percent

●Sudden death was the clinical presentation in 32 percent

●The average QTc was 314±23 milliseconds

Symptomatic patients were found to have a high risk of recurrent arrhythmic events, with a high risk of sudden death in all age groups [57].

In a Japanese cohort of 65 mutation-positive patients, SQT1 patients first presented at an older age (SQT1: 35±19years; SQT2: 17±25years; SQT3-6: 19±15years). SQT2 exhibited a higher prevalence of bradyarrhythmia (SQT2: 6/8, 75 percent; non-SQT2: 5/57, 9 percent) and atrial fibrillation (SQT2: 5/8, 63 percent; non-SQT2: 12/57, 21 percent) [58].

Echocardiographic insights point to mechanical correlates, suggesting that systolic function may be affected as well, as shown in a study of 15 SQTS patients which identified a significant dispersion of myocardial contraction [59].

DIAGNOSTIC EVALUATION — As with any survivor of sudden cardiac death (SCD), a history and physical examination focusing on potential underlying etiologies of SCD (eg, myocardial ischemia, myocarditis, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, intoxications) should be performed, along with a routine surface ECG. Paroxysmal atrial fibrillation is very common in patients with SQTS; thus, diagnosis of SQTS should be considered in young individuals with lone atrial fibrillation with shorter than normal QT intervals. A history of arrhythmic symptoms, family history of lone atrial fibrillation, or primary or resuscitated ventricular fibrillation (VF) or SCD may provide additional clues. The isolated presence of short QT interval without associated arrhythmogenic complication warrants further interrogation to rule out SQTS.

Our approach to additional testing, which may include exercise stress testing, invasive electrophysiology studies, echocardiography, 24-hour ambulatory monitoring, and cardiac magnetic resonance imaging, is discussed separately. (See "Cardiac evaluation of the survivor of sudden cardiac arrest".)

Electrocardiographic findings — Typical ECG findings associated with SQTS include the following (waveform 1) [6,8,20,60]:

●Abnormally short QT interval, usually <360 milliseconds with a range of 220 to 360 milliseconds

●Absence of ST segment

●Tall and peaked T waves in the precordial leads, which can be positive or negative, symmetrical or asymmetrical

●Poor rate adaptation of QT interval (diminished rate dependence) [61]

●Prolonged T_peak-T_end interval and T_peak-T_end/QT ratio [45,46]

The reduced rate adaptation of the QT interval makes SQTS difficult to diagnose at fast heart rates. Calculation of QTc using Bazett’s correction is invalid and when applied erroneously brings QTc into the normal range. Because of the impaired QT adaptation to heart rate changes in patients with SQTS, we recommend measurement of the QT interval at a heart rate between 50 and 70 beats per minute. ECG patterns that support the diagnosis include PQ segment deviation, tall and symmetrical T waves with a very short or negligible ST segment, early repolarization pattern, and impaired adaptation of the QT interval during exercise [16,42,61-63].

Most patients with SQTS have QTc <340 milliseconds with a range of 210 to 320 milliseconds. However, in patients with SQT4, SQT5, and SQT8, QTc intervals are slightly longer (340 to 360 milliseconds).

Depression of the PQ segment, rarely seen in the ECG of apparently healthy individuals but which is seen in patients with acute pericarditis and inferior myocardial infarction, has been reported in patients with SQTS. Among a cohort of 64 patients with SQTS (75 percent male, mean QTc 321 milliseconds) who were compared with 117 healthy controls with normal QT intervals, PQ depression was seen in at least one lead in 81 percent of patients (compared with 24 percent of controls) [62]. PQ depression was most commonly seen in leads II, V3, aVF, V4, and I (67, 47, 42, 39, and 39 percent of patients with SQTS, respectively). The presence of PQ depression in asymptomatic patients or those with syncope or an arrhythmia should prompt close scrutiny of the QT interval for the possibility of a short QT interval. PQ dispersion in this setting is thought to reflect spatial dispersion of repolarization within the atria.

In cases of SQT4, 5, and 6, short QT intervals may appear together with a Brugada type ST segment elevation in the right precordial leads V1-V3 at baseline or after administration of a potent sodium channel blocker (waveform 1) or other unmasking agent, such as a potassium channel opener (I_KATP activator) [28]. Approximately 65 percent of patients with SQTS have ECG features of early repolarization, characterized by J-point elevation in the inferolateral leads, which may also be associated with an increased likelihood of increased arrhythmic events [63,64]. (See "Brugada syndrome: Epidemiology and pathogenesis", section on 'Brugada pattern versus Brugada syndrome'.)

When the diagnosis of SQTS is suspected, a resting 12-lead ECG should be performed at a heart rate within normal limits, preferably 50 to 70 beats per minute. In patients with SQTS, the QT interval fails to lengthen appropriately with a decrease in the heart rate [61]. As a consequence, QT correction using Bazett's or comparable formulas (calculator 1) will overcorrect at initially fast rates, leading to a false negative diagnosis. Overnight Holter monitoring or long-term ECG monitoring may prove helpful in such cases as this allows for analysis of the QT interval during periods of slower heart rate (ie, sleep) and also allows for patient-specific QT correction for heart rate. (See "ECG tutorial: Basic principles of ECG analysis", section on 'QT interval'.)

While data are relatively sparse, owing to the rarity of the syndrome, the picture that appears to be developing is that SQT1 and 2 probands generally manifest symmetrical tall peaked T waves, whereas SQT3 probands display asymmetrical tall peaked T waves with a more rapidly descending than ascending limb of the T wave [44]. SQT4, 5, 6, 7, and 8 show variable T wave heights but are usually symmetrical. In most cases, a distinct ST segment is short or absent, with the T wave originating from the S wave.

Electrophysiological study — Although electrophysiological study (EPS) has a role in confirming the diagnosis by revealing short ventricular refractory periods, its role in risk stratification remains unclear. As such, EPS is not routinely performed unless the diagnosis of SQTS remains unclear based on the available ECG data. (See "Invasive diagnostic cardiac electrophysiology studies".)

During invasive EPS, patients with SQTS characteristically show extremely short atrial and ventricular effective refractory periods (ERP), regardless of genotype [8,20,28,43,44]. The ventricular ERP measured at the right ventricular apex varies between 140 and 180 milliseconds at a cycle length of 500 to 600 milliseconds and 130 to 180 milliseconds at pacing cycle length of 400 to 430 milliseconds. Atrial ERP measured in the high lateral right atrium varies between 120 and 180 milliseconds at a cycle length of 600 milliseconds. The programmed electrical stimulation with two to three premature stimuli down to refractoriness induced both atrial fibrillation and VF in many patients. The inducibility of VF at EPS in SQTS patients is approximately 60 percent. Moreover, in one case series, VF was inducible at EPS in only three of six patients with clinically documented VF, suggesting that the sensitivity of EPS for the inducibility of VF is low [20].

Genetic testing — In patients where SQTS is suspected as the diagnosis, based on ECG findings and clinical history, genetic testing of the patient should be considered. Given the relative scarcity of this clinical entity, decisions regarding genotyping should be performed in collaboration with an electrophysiologist or other clinician with expertise in the evaluation and diagnosis of patients with suspected SQTS. (See 'Genetic basis' above and 'Diagnosis and diagnostic criteria' below.)

Screening family members — First-degree relatives of those diagnosed with SQTS should undergo clinical screening with an ECG and genetic testing. Mutation-specific genetic testing is recommended for all family members and relatives suspected of SQTS following the identification of the SQTS-causative mutation in an index case [65]. Family members who test positive for the familial mutation should consult a cardiologist with expertise in SQTS to discuss further management. Conversely, a negative genetic test for the familial mutation obviates the need for repeated follow-up.

DIAGNOSIS AND DIAGNOSTIC CRITERIA — While ECG findings in SQTS can be suggestive of the diagnosis, the solitary presence of a shorter than normal QT interval is not always diagnostic. Clinical history, family history of sudden death, and genotype results can all contribute to the diagnostic certainty. While there is ongoing debate on the optimal diagnostic strategy for SQTS, the authors and editors of this topic agree with and recommend following the proposed diagnostic criteria for SQTS.

The 2013 HRS/EHRA/APHRS Expert Consensus Statement and the 2015 ESC Guidelines indicate that a QTc of 330 or 340 milliseconds alone may be diagnostic of SQTS, but that SQTS should be considered in the presence of a QTc of <360 milliseconds when accompanied by a confirmed pathogenic mutation, family history of SQTS, family history of sudden death at age <40 years, or survival from a VT/VF episode in the absence of heart disease [66,67].

Based on a comprehensive review of 61 reported cases of SQTS, proposed diagnostic criteria were developed to facilitate the evaluation of individuals suspected to have SQTS [10]. A scoring system was developed based on ECG characteristics, clinical presentation, family history, and genetic findings (table 2). The most controversial aspect of the differential diagnosis of SQTS involves the QT interval cutoff, as shown by the increasing number of points assigned to shorter QT intervals in the proposed diagnostic criteria.

DIFFERENTIAL DIAGNOSIS — Before arriving at a diagnosis of SQTS, other potential causes for QT shortening should be excluded.

Normal variant — The sole presence of a shorter-than-normal QT interval does not appear to be diagnostic for SQTS and, in fact, may represent a normal variant in many people. Up to 2 percent of the population has QT intervals ≤360 milliseconds, highlighting the importance of utilizing the diagnostic criteria for the diagnosis of SQTS. (See 'Prevalence of a short QT interval' above and 'Diagnosis and diagnostic criteria' above.)

Acquired causes of short QT interval — Secondary causes of short QT interval are reviewed in (table 3). Briefly, these include:

●Metabolic and electrolyte abnormalities such as hyperkalemia, acidosis, and hypercalcemia.

●Hyperthermia.

●Drug effects from digitalis, acetylcholine, or catecholamines.

●Myocardial ischemia.

●Vagal tone.

●Combination of genetic and secondary causes, including hyperkalemia, hypercalcemia, acidosis, myocardial ischemia, and increased vagal tone (QTc prolongation is similar in having potential genetic and secondary causes).

Deceleration-dependent shortening of the QT interval — A rare but interesting paradoxical ECG phenomenon called deceleration-dependent shortening of QT interval (DDSQTI) should also be considered in the differential diagnosis of SQTS [6]. Strong parasympathetic stimulation can lead to bradycardia and concurrent activation of myocardial acetylcholine-sensitive K⁺ channels (K_ACh). In such cases, the QT interval abbreviates paradoxically with a decrease in heart rate instead of lengthening. Such shortening of the QT interval may be transient and should resolve as parasympathetic tone decreases.

MANAGEMENT OF PATIENTS WITH A SHORT QT INTERVAL — As discussed previously, the sole presence of a shorter-than-normal QT interval on an ECG does not appear to be diagnostic for the short QT syndrome and, in isolation, may not be associated with an increased risk of sudden cardiac death (SCD). Because the rate of serious complications of implantable cardioverter-defibrillator (ICD) therapy is not trivial, particularly over the life of a young patient, it is important to discriminate between patients with an isolated short QT interval and those who meet the criteria for SQTS (table 2). Prior to making a final decision regarding the management of these patients, acquired causes of a shortened QT interval should be excluded. (See 'Acquired causes of short QT interval' above.)

Patients with low/intermediate probability of SQTS — There are no randomized trials and few observational studies of patients assessing the prognosis of patients with isolated short QT intervals who have no apparent clinical history, family history, or genetic criteria suggestive of SQTS [68]. As such, the following management strategies for such patients are based on expert opinion [7]:

●Patients with a short QT interval (330 to 360 milliseconds) who have none of the clinical history, family history, or genotype criteria proposed for the diagnosis of SQTS are classified as low probability for the diagnosis of SQTS.

For these low-probability patients, we suggest no specific pharmacologic or device-based therapy. This approach is consistent with the published recommendations in the 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of SCD [69].

●Patients with a markedly shortened QT interval (<330 milliseconds) are classified as intermediate-probability for the diagnosis of SQTS despite having none of the clinical history, family history, or genotype criteria proposed for the diagnosis of SQTS.

For these intermediate-probability patients, there are limited data available to guide management. However, we suggest no specific pharmacologic or device-based therapy. We do suggest referral to an electrophysiologist for comprehensive testing, including genetic screening, if this has not yet been completed.

Patients with a high probability of SQTS — Most patients with a QT interval <350 milliseconds and at least one criterion from the list of clinical history, family history, or genotype criteria will be classified as high-probability for the SQTS. Because of the association between SQTS and sudden cardiac death due to arrhythmias, therapy with an ICD is recommended in these patients, along with consideration of antiarrhythmic therapy if appropriate shocks are frequent.

Implantable cardioverter-defibrillator — Patients with SQTS are at a very high risk for SCD [15]. As such, we recommend ICD implantation for both primary and secondary prevention of SCD in patients with SQTS unless absolutely contraindicated or refused by the patient. Because the sensitivity of inducibility of ventricular fibrillation (VF) is only 50 percent, failure to induce VF during EP study does not preclude future risk of SCD [20,49]. Accordingly, a negative EP study should not defer a clinician's decision to implant an ICD. Professional society guidelines recommend ICD implantation as a class I indication in symptomatic patients with a diagnosis of SQTS who are survivors of a cardiac arrest and/or have documented spontaneous sustained ventricular tachycardia with or without syncope [67,69]. ICD implantation may be considered (class IIb) in asymptomatic patients with a diagnosis of SQTS and a family history of SCD [67].

Oversensing of the T wave is a frequent clinical problem encountered in patients with SQTS who receive an ICD [70]. The tall, peaked, and closely coupled T waves are often mistakenly sensed as R waves, leading to inappropriate ICD shocks. Reprogramming the decay delay, the sensitivity, or both generally prevents such inappropriate discharges. Caution must be exercised to avoid programming modifications that prevent the detection of lethal ventricular tachyarrhythmia. (See "Cardiac implantable electronic devices: Long-term complications".)

Ablation therapy — There is limited evidence regarding the use of ablation therapy in SQTS. In a single case report, radiofrequency ablation of PVCs appeared to be successful in controlling ventricular arrhythmic events [71]. Further studies are needed.

Pharmacologic therapy — Pharmacologic therapy is primarily used as an adjunct to ICD placement, with a goal of reducing the likelihood of additional ICD shocks. However, pharmacologic therapy may be the primary treatment modality in patients who refuse ICD placement, patients with an absolute contraindication to ICD placement, or in very young patients in whom ICD implantation is problematic. For patients with SQTS who have refused or are not candidates for ICD therapy, or in those with recurrent ventricular arrhythmias resulting in frequent ICD therapy, we recommend adjunctive pharmacologic therapy with QT-prolonging drugs. In the case of SQT1, we recommend quinidine rather than a class IC or class III (table 4) antiarrhythmic drug [69]. In other forms of SQTS, data are too limited to permit specific suggestions or recommendations.

Data regarding pharmacologic therapy in SQTS are very limited, with much of the data pertaining to patients with SQT1:

●Four different antiarrhythmic drugs, flecainide, sotalol, ibutilide, and hydroquinidine, were tested in six patients with SQT1 to determine their effects on various electrophysiologic properties [72]. Only hydroquinidine, a class IA antiarrhythmic drug (table 4), normalized the QT interval, increased ventricular ERP, and rendered VF noninducible. In a one-year follow-up, patients treated with hydroquinidine remained asymptomatic, and no further episodes of ventricular arrhythmia were detected [57].

●Long-term treatment with hydroquinidine (hydroquinidine 584±53 mg/day) was evaluated in a cohort of 17 patients with SQTS (82 percent male, mean age 29 years, mean QTc pretreatment 331 milliseconds [QTc <320 milliseconds in four patients], previous aborted SCD in six patients), among whom 15 patients continued treatment for an average of six years (two discontinued treatment due to gastrointestinal intolerance) [73]. The QTc increased by an average of 60 milliseconds with treatment, and no life-threatening ventricular arrhythmias were seen during the six years of treatment. The annual rate of life-threatening arrhythmic events in patients with a previous cardiac arrest dropped from 12 to 0 percent on hydroquinidine therapy.

●Similarly, disopyramide has proved to be effective in prolonging the QT interval and restoring the ventricular effective refractory period towards normal [74]. The combination of disopyramide and nifekalant, a class III agent available primarily in Japan, was reported in one patient to increase QTc to >410 milliseconds [75].

●Amiodarone has been shown to prolong the QT interval in two patients with SQTS of unknown genotype [48].

The failure of class IC and pure class III antiarrhythmic drugs in SQT1 caused by the N588K mutation in KCNH2 is due to the fact that this mutation by removing inactivation of the I_Kr channel results in a desensitization of the channel to these agents. Class III agents such as sotalol, E-4031, and dofetilide have a greater affinity for the inactivated state of the channel. Quinidine, by virtue of its effect to block the activated state of the I_Kr channel, was reasoned to be more effective in this setting in which the inactivated state of the channel is lost.

It is thought that the efficacy of quinidine in SQT1 is due to its ability to inhibit the N588K channel at pharmacologically relevant concentrations, presumably due not only to its ability to block the activated state of the I_Kr channel, but also its ability to block other outward currents, particularly I_Ks. Quinidine's multi-ion channel inhibition may underlie its effectiveness in other forms of SQTS, particularly SQT4-SQT6 where its I_to blocking action may provide a therapeutic edge over other antiarrhythmic drugs by reducing the substrate and trigger for Brugada syndrome. Prolongation of the QT interval by quinidine has been reported in one patient with SQT4 [28].

One study has identified another missense mutation in hERG (T618I), which produces a more modest increase in I_Kr than reported for the N588K-hERG variant. Interestingly, all drugs studied, including quinidine and D-sotalol, retained their ability to inhibit the I_Kr current recorded with this genetic variant [76].

The 2013 HRS/EHRA/APHRS guidelines indicate that quinidine and sotalol may be considered (class II) in asymptomatic patients with a diagnosis of SQTS and a family history of SCD [67].

The available data, both experimental and clinical, suggest that all agents with Class III (QT prolonging) actions should be effective in all SQTS types with the exception of SQT1. This hypothesis remains to be more fully tested in clinical experience.

In the case of SQT3-6, representing an overlap between SQTS and BrS, the combination of quinidine and isoproterenol has been shown to be effective, particularly in patients presenting with a VT/VF storm [77].

Atrial fibrillation (AF) is another common clinical problem in SQTS. Some patient with SQTS exhibit only AF [78]. Propafenone as well as quinidine have been shown to be therapeutically effective is a small case series [14]. (See 'Clinical presentation' above.)

PROGNOSIS — Timely diagnosis and optimal treatment improve the prognosis of patients with SQTS, although an accurate long-term prognosis in these patients remains difficult to assess. In contrast to the long QT syndrome, there is a paucity of data regarding SQTS in terms of its clinical presentation, diagnosis, genotype-phenotype correlation, risk-stratification, and treatment.

●In a cohort of 25 pediatric patients (84 percent male, median age 15 years) who were followed for an average of six years, 14 patients (56 percent) experienced symptoms during follow-up, including aborted SCD and syncope [79]. Patients with a higher clinical risk score (table 2) were more likely to be symptomatic.

●In an analysis of 34 patients (from a larger 73 patient cohort) who had all the required data available to assess the performance of the proposed prognostic SQTS score (table 2), 21 patients had a score of ≤3, corresponding to a relatively "good" prognosis, with the remaining 13 patients having a score of 4 or greater, indicating a "poor" prognosis [52]. Among the eight patients who experienced a cardiac event, five of whom had a SQTS score ≤3, there was no significant difference in risk based on SQTS score, with an incidence of cardiac events of 4.6 percent per year in the "good" prognosis group and 4.2 percent per year in the "poor" prognosis group.

Markedly shortened QTc values ≤300 ms have been shown to be associated with increased risk of SCD, especially during sleep or rest, in young individuals, in whom the median QTc was 285 ms [79,80].

There is a scarcity of information concerning the long-term effectiveness of pharmacologic therapy. As such, pharmacologic therapy remains, for most patients, an adjunct to ICD treatment. (See 'Pharmacologic therapy' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".)

SUMMARY AND RECOMMENDATIONS

●Definition – Short QT Syndrome (SQTS) is an inherited channelopathy associated with marked shortening of QT intervals and sudden cardiac death (SCD) in individuals with structurally normal hearts. (See 'Introduction' above.)

In SQTS, typical electrocardiogram (ECG) features include a QT interval <360 milliseconds (range 220 to 360 milliseconds), absence of the ST segment, tall and peaked T waves in the precordial leads, and poor rate adaptation of the QT interval. (See 'Electrocardiographic findings' above.)

●Genetic basis – SQTS is a genetically heterogeneous disease with pathogenic variants in eight different genes (three gain-of-function and five loss-of-function) that encode different cardiac ion channels, a carnitine transporter, and chloride-bicarbonate anion exchanger (table 1). (See 'Genetic basis' above.)

●Clinical presentation and diagnosis – Whereas many patients are asymptomatic, the majority present with one or more of the following: SCD, palpitations, syncope, and atrial fibrillation. (See 'Clinical presentation' above.)

The sole presence of a shorter-than-normal QT interval is not always diagnostic of SQTS and may represent a normal variant. Diagnostic criteria have been developed to facilitate the evaluation of individuals suspected to have SQTS with a scoring system based on ECG characteristics, clinical presentation, family history, and genetic findings (table 2). (See 'Diagnosis and diagnostic criteria' above.)

●Variant-specific genetic evaluation – This is recommended for all family members and relatives suspected of SQTS following the identification of the SQTS-causative mutation in an index case. Family members who test positive for the familial mutation should be seen by a cardiologist with expertise in SQTS for further management. (See 'Screening family members' above.)

●Acquired causes – These include hyperkalemia, acidosis, hypercalcemia, hyperthermia, effect of drugs like digitalis, increased vagal tone, and deceleration-dependent shortening of QT interval. (See 'Differential diagnosis' above.)

●Management – This depends on whether the short QT interval occurs in isolation or is associated with other clinical history, family history, or genetic criteria (table 2) that increase the probability of SQTS.

•Patients with a short QT interval (330 to 360 milliseconds) who have none of the clinical history, family history, or genotype criteria proposed for the diagnosis of SQTS are classified as low probability for the diagnosis of SQTS. For these low-probability patients, we suggest no specific pharmacologic or device-based therapy (Grade 2C).

•Patients with a markedly shortened QT interval (<330 milliseconds) are classified as intermediate probability for the diagnosis of SQTS, despite having none of the clinical history, family history, or genotype criteria proposed for the diagnosis of SQTS. For these intermediate-probability patients, we suggest no specific pharmacologic or device-based therapy (Grade 2C). We do refer to an electrophysiologist for comprehensive testing, including genetic screening, if this has not yet been completed.

•Patients with SQTS are at a very high risk for SCD. As such, we recommend implantable cardioverter-defibrillator (ICD) implantation for both primary and secondary prevention of SCD (Grade 1B). (See 'Implantable cardioverter-defibrillator' above.)

•Pharmacologic therapy in patients with SQTS is primarily used as an adjunct to ICD placement. However, it may also be the primary treatment modality in patients who refuse or have contraindications to ICD placement or very young patients in whom ICD implantation is problematic.

For patients with SQTS who have refused or are not candidates for ICD therapy, or in those with recurrent ventricular arrhythmias resulting in frequent ICD therapy, antiarrhythmic treatment is required.

In the case of SQT1, we recommend quinidine rather than a class IC or class III (table 4) antiarrhythmic drug (Grade 1C). This recommendation is based on the positive electrophysiologic effects of quinidine (eg, QT prolongation to the normal range) in patients with SQTS studied thus far. (See 'Pharmacologic therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff thank Dr. Jonathan M. Cordeiro for his contributions as an author to prior versions of this topic review.