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 https://www.uptodate.com/contents/short-qt-syndrome/print 12/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate 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 https://www.uptodate.com/contents/short-qt-syndrome/print 13/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate 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 https://www.uptodate.com/contents/short-qt-syndrome/print 14/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate 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 channel, was reasoned to Kr 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 channel, but also its ability to block other outward currents, Kr particularly I Quinidine's multi-ion channel inhibition may underlie its effectiveness in other Ks. forms of SQTS, particularly SQT4-SQT6 where its I blocking action may provide a therapeutic to 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 than reported for the N588K-hERG variant. Interestingly, all drugs studied, Kr including quinidine and D-sotalol, retained their ability to inhibit the I current recorded with Kr 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 https://www.uptodate.com/contents/short-qt-syndrome/print 15/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate 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.) https://www.uptodate.com/contents/short-qt-syndrome/print 16/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate 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.) https://www.uptodate.com/contents/short-qt-syndrome/print 17/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate 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). 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Short QT syndrome: pharmacological treatment. J Am Coll Cardiol 2004; 43:1494. 73. Mazzanti A, Maragna R, Vacanti G, et al. Hydroquinidine Prevents Life-Threatening Arrhythmic Events in Patients With Short QT Syndrome. J Am Coll Cardiol 2017; 70:3010. 74. McPate MJ, Duncan RS, Witchel HJ, Hancox JC. Disopyramide is an effective inhibitor of mutant HERG K+ channels involved in variant 1 short QT syndrome. J Mol Cell Cardiol 2006; 41:563. 75. Mizobuchi M, Enjoji Y, Yamamoto R, et al. Nifekalant and disopyramide in a patient with short QT syndrome: evaluation of pharmacological effects and electrophysiological properties. Pacing Clin Electrophysiol 2008; 31:1229. 76. El Harchi A, Melgari D, Zhang YH, et al. Action potential clamp and pharmacology of the variant 1 Short QT Syndrome T618I hERG K channel. PLoS One 2012; 7:e52451. 77. Antzelevitch C, Yan GX, Ackerman MJ, et al. J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge. Heart Rhythm 2016; 13:e295. 78. Hong K, Bjerregaard P, Gussak I, Brugada R. Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. J Cardiovasc Electrophysiol 2005; 16:394. 79. Villafa e J, Atallah J, Gollob MH, et al. Long-term follow-up of a pediatric cohort with short QT syndrome. J Am Coll Cardiol 2013; 61:1183. 80. Iribarren C, Round AD, Peng JA, et al. Short QT in a cohort of 1.7 million persons: prevalence, correlates, and prognosis. Ann Noninvasive Electrocardiol 2014; 19:490. Topic 16697 Version 32.0 https://www.uptodate.com/contents/short-qt-syndrome/print 24/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate GRAPHICS Ventricular action potential and QRS-T cycle The QRS-T cycle on the electrocardiogram corresponds to different phases of the ventricular action potential. Graphic 78354 Version 1.0 https://www.uptodate.com/contents/short-qt-syndrome/print 25/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate Genetic basis of SQTS QTc (milliseconds) Gene (cardiac ion channel) [1] ) SQT1 286 6 KCNH2 (I Kr [2] ) SQT2 302 KCNQ1 (I Ks [3] ) SQT3 315-330 KCNJ2 (I K1 [4] ) SQT4 331-370 CACNB2b (I Ca [4] ) SQT5 346-360 CACNA1C (I Ca [5] ) SQT6 330 CACNA2D1 (I Ca [6] SLC22A5 ( carnitine - I SQT7 282-340 ) Kr [7] SQT8 340 18 SLC4A3 (pHi-[Cl-]) References: 1. Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 2004; 109:30. 2. Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 2004; 109:2394. 3. Priori SG, Pandit SV, Rivolta I, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res 2005; 96:800. 4. Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007; 115:442. 5. Templin C, Ghadri JR, Rougier JS, et al. Identi cation of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6). Eur Heart J 2011; 32:1077. 6. Roussel J, Labarthe F, Thireau J, et al. Carnitine de ciency induces a short QT syndrome. Heart Rhythm 2016; 13:165. 7. Thorsen K, Dam VS, Kjaer-Sorensen K, et al. Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome. Nature communications 2017; 8:1696. Graphic 72304 Version 6.0 https://www.uptodate.com/contents/short-qt-syndrome/print 26/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate Action potential currents Major cardiac ion currents and channels responsible for a ventricular action potential are shown with their common name, abbreviation, and the gene and protein for the alpha subunit that forms the pore or transporter. The diagram on the left shows the time course of amplitude of each current during the action potential, but does not accurately reflect amplitudes relative to each of the other currents. This summary represents a ventricular myocyte, and lists only the major ion channels. The currents and their molecular nature vary within regions of the ventricles, and in atria, and other specialized cells such as nodal and Purkinje. Ion channels exist as part of multi-molecular complexes including beta subunits and other associated regulatory proteins which are also not shown. Courtesy of Jonathan C Makielski, MD, FACC. Graphic 70771 Version 4.0 https://www.uptodate.com/contents/short-qt-syndrome/print 27/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate Electrocardiographic characteristics of the short QT syndrome (A) A 12-lead ECG showing ECG characteristic of SQT1. (B) A 12-lead ECG showing ECG characteristic of SQT4 displaying combined ECG phenotype of Brugada and short QT syndromes. Note that ECG shows Brugada type ST elevation in V1 and V2 after administration of ajmaline in addition to short QT intervals. Reproduced with permission from: Patel C, Yan GX, Antzelevitch C. Short QT syndrome: from bench to bedside. Circ Arrhythm Electrophysiol 2010; 3:401. Copyright 2010 Lippincott Williams & Wilkins. Graphic 51616 Version 6.0 https://www.uptodate.com/contents/short-qt-syndrome/print 28/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate Proposed diagnostic criteria for short QT syndrome Criteria Points QTc, milliseconds <370 1 <350 2 <330 3 J T point peak interval <120 milliseconds 1 Clinical history* History of sudden cardiac arrest 2 Documented polymorphic VT or VF 2 Unexplained syncope 1 Atrial fibrillation 1 Family history* First- or second-degree relative with high probability of SQTS 2 First- or second-degree relative with autopsy-negative sudden cardiac death 1 Sudden infant death syndrome 1 Genotype* Genotype positive 2 Mutation of undetermined significance in a culprit gene 1 Total High-probability SQTS: 4 points. Intermediate-probability SQTS: 3 points. Low-probability SQTS: 2 points. VF: ventricular fibrillation; VT: ventricular tachycardia; SQTS: short QT syndrome; QT: Bazett corrected QT interval. A minimum of 1 point must be obtained in the electrocardiographic section in order to obtain additional points. Original table modi ed for this publication. Gollob MH, Redpath CJ, Roberts JD: The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol 2011; 57:802. Table used with the permission of Elsevier Inc. All rights reserved. https://www.uptodate.com/contents/short-qt-syndrome/print 29/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate Graphic 65743 Version 5.0 https://www.uptodate.com/contents/short-qt-syndrome/print 30/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate Secondary causes of short QT interval on ECG Hyperkalemia Hypercalcemia Hyperthermia Acidosis Effect of catecholamine Activation of ATP-sensitive potassium current Activation of acetylcholine-sensitive potassium current Effects of drugs like digitalis Myocardial ischemia Increased vagal tone Bufatolin (toad extract and antineoplastic, traditional Chinese medicine) Graphic 59159 Version 2.0 https://www.uptodate.com/contents/short-qt-syndrome/print 31/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/short-qt-syndrome/print 32/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/short-qt-syndrome/print 33/34 7/6/23, 1:45 PM Short QT syndrome - UpToDate Contributor Disclosures