Short QT Syndrome

Case Presentation

A previously healthy 29-year-old man collapsed at work and was brought to the hospital after a sudden cardiac arrest and was found to have ventricular fibrillation (VF). He was successfully resuscitated and was found to have a normal coronary angiogram. His baseline electrocardiogram was normal sinus rhythm with QTc 358 ms and an uncorrected J point- T peak interval (JTp) of 140 ms (Figure 1A). The patient had several episodes of non-sustained polymorphic ventricular tachycardia (VT) (Figure 1B), as well as ventricular fibrillation that was successfully defibrillated. He had a normal transthoracic echocardiogram. He had a high probability of short QT syndrome (SQTS) according to the diagnostic criteria proposed by Gollob et al. He had improvement in his neurologic function and did not fail the screening test designed to identify patients susceptible to T-wave oversensing. He had a subcutaneous implantable cardioverter defibrillator (ICD) (Figure 1C) via a two-incision technique (Figure 1D). The patient is doing well after a 4-month follow-up.

Figure 1

Introduction

Short QT (SQT) refers to the electrocardiographic manifestation of accelerated cardiac repolarization. Gussak et al. were the first to suggest an association with atrial and ventricular fibrillation in 2000. The familial nature and arrhythmogenic potential of SQT were confirmed by Gaita et al. in 2003. Acquired disease –the most common cause– results from electrolyte disturbances or drugs, in addition to hypercalcemia, hyperkalemia, and acidosis; SQT manifests with digoxin, androgen use, increased vagal tone and after ventricular fibrillation (Cheng, 2004; Hancox, Choisy, & James, 2009; Ramakrishna et al., 2015). SQTS is a rare, sporadic or autosomal dominant disease that manifests with atrial and ventricular arrhythmias, sudden cardiac death and shortened QT (Brugada et al., 2004). Cardiac arrest occurs as the presenting symptom in up to 40% of the cases (Mazzanti et al., 2014).

Molecular Basis and Genetics

Mutations in potassium (KCNH2, KCNQ1, KCNJ2) and calcium (CACNA1C, CACNB2, CACNA2D1) channels have been identified as disease causing (Table 1). Calcium channel mutations lead to a spectrum of genotype/phenotype correlation encompassing diseases, such as Brugada syndrome or early repolarization syndrome. New research has also linked carnitine deficiency with electrocardiogram (ECG) manifestations of SQT (Roussel et al., 2016); however, many patients have no identifiable genes yet (Giustetto et al., 2011).

Gain of function mutations in the potassium channels have been shown to hasten earlier repolarizing currents during the plateau phase of the action potential (Table 1), which shortens the action potential duration permitting lower threshold for arrhythmias and sudden death. Calcium channel mutations have been shown to cause loss of function in the slow inward calcium channel or L-type channel (Antzelevitch et al., 2007; Templin et al., 2011).

Mouse models of Carnitine deficiency showed response of ECG QT interval to Carnitine supplementation with reduction in ventricular arrhythmias. The mechanism proposed by the authors links indirect effect of long chain fatty acid on the regulation of the potassium channels (Roussel et al., 2016).

Table 1: Genes Linked to Short QT Syndrome

SQTS

Gene

Mutations Reported

Action

Potassium Channels

SQTS1

KCNH2 (Brugada et al., 2004; Hong, Bjerregaard, Gussak, & Brugada, 2005)

N588K

Increase in IKr current.

SQTS2

KCNQ1 (Bellocq et al., 2004)

V307L

Increase in IKs current.

SQTS3

KCNJ2 (Priori et al., 2005)

D172N

Increase in the IK1 current.

Calcium Channels

SQTS4

CACNA1C (Antzelevitch et al., 2007)

G490R
A39V

Reduction in L Type Ca-channel current

SQTS5

CACNB2 (Antzelevitch et al., 2007)

S481L

Reduction in L Type Ca-channel current

SQTS6

CACNA2D1 (Templin et al., 2011)

S755T

Reduction in L Type Ca-channel current

Carnitine Deficiency

 

 

 

Altered regulation of the potassium channels

Diagnosis

Due to the rarity of the disorder, defining cutoff values of corrected QT intervals for disease characterization has been unrewarding. Using a 2-standard deviation cutoff test is sensitive, but detects a large number of normal people who fall below this level (350 ms for men and 360 ms for women) (Giudicessi & Ackerman, 2013). According to the HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes, SQTS is diagnosed in the presence of a QTc ≤ 330 ms, and it can be diagnosed, like in our patient, in the presence of a QTc< 360 ms and one of the following: a pathogenic mutation, family history of SQTS, family history of sudden death at age ≤ 40, or survival of a VT/VF episode in the absence of heart disease (Priori S et al., 2013).

In 2011, Gollob et al. proposed diagnostic criteria for the assessment of patients with suspected SQTS (Table 2). The criteria included ECG findings as well as family history, clinical history, and genotyping (Gollob, Redpath, & Roberts, 2011). An overall score of 4 or more was considered to indicate a high probability diagnosis of SQTS.

Table 2: The Short QT Syndrome diagnostic scoring scheme

 

Points

QTc, ms

 

<370

1

<350

2

<330

3

Jpoint-Tpeak interval <120 ms

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 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

The QTc remains relatively fixed and short in relation to changing heart rate of patients with SQTS (Redpath, Green, Birnie, & Gollob, 2009). This failure of adaptation to a faster heart rate (HR) has allowed more specific identification of subjects with QTc intervals between 340 and 360 ms, and a QT/HR slope under –0.9 ms/beat/min (Giustetto et al., 2015). Such findings are yet to be standardized as gender and gene mutations variables affect test results. Interestingly, it should be noted that narrower intervals have been documented in case reports of SQTS and sudden cardiac death (Bellocq et al., 2004; Gaita et al., 2003).

Another ECG finding noted in SQTS is the high prevalence of early repolarization patterns (ERP) (Tikkanen et al., 2012; Watanabe et al., 2010). Watanabe et al. depict that the presence of ERP in patients with SQTS is associated with arrhythmic events. Anttonen et al. looked at the uncorrected Jpoint-Tpeak interval (JTp) and found that patients with symptomatic SQTS had shorter uncorrected JTp (< 150 ms), shorter uncorrected Jpoint – T end interval [JTe] (< 230 ms) and a high rate-corrected Tpeak-Tend c/QTc ratio (mean 0.30 ± 0.04).

The echocardiographic diagnosis of the disease has only recently grabbed attention. SQTS patients have normal ejection fractions but significant systolic dysfunction (Frea et al., 2015). Low global longitudinal strain is prevalent in patients with SQTS and is associated with shorter QT intervals. Myocardial performance index is prolonged likely due to both accelerated repolarization and reduced contractility. The short action potential alters calcium loading and thus reduces contractile activity affecting strain (Adeniran, Hancox, & Zhang, 2013), while a short repolarization at the end of contraction favored mechanical dispersion on tissue Doppler imaging (TDI) affecting the end of the contraction (Frea et al., 2015).

The role of genetic screening for the diagnosis is not clear. In a study of 35 patients from Spain with unexplained cardiac arrest, only one was found to harbor a mutation in a known SQTS gene (Jiménez-Jáimez et al., 2015); however, there is no functional proof that the disease was caused by that mutation.

Management

According to the HRS/EHRA/APHRS expert consensus statement on the management of patients with SQTS, ICD implantation is recommended (Class I) for all survivors of sudden cardiac arrest or patients with documented spontaneous sustained VT with or without syncope (Priori et al., 2013). Such management protects against future events, as arrest on presentation is the only predictor of subsequent arrest (Mazzanti et al., 2014). Appropriate programming of the ICD is needed to prevent inappropriate ICD shocks from T-wave oversensing due to the tall T waves. In the setting of resuscitated sudden cardiac arrest, cascade/familial screening is needed.

ICD implantation, quinidine (especially in SQTS type 1) and sotalol (in SQTS subtypes other than type 1) may be considered for asymptomatic patients with SQTS if family history of sudden cardiac death is present according to the HRS/EHRA/APHRS expert consensus [Class IIb] (Priori et al., 2013). In an observational study of 53 patients from the European Short QT Registry, hydroquinidine was effective in preventing ventricular tachyarrhythmia induction and arrhythmic events after a follow-up of 64±27 months (Giustetto C et al, 2011). Class IC antiarrhythmics did not normalize QT interval in four different patients with SQTS, while quinidine administered to those patients and two others increased the QT interval and normalized the early repolarization pattern. More importantly, VF was not induced on programmed simulation (Gaita et al., 2004). Quinidine acts by reducing the dispersion of repolarization and protects from VF induction in animal models (Milberg et al., 2007).

References

  1. Adeniran I, Hancox J C, Zhang H. In silico investigation of the short QT syndrome, using human ventricle models incorporating electromechanical coupling. Front Physiol 2013;4:166.
  2. Anttonen O, Junttila MJ, Maury P, et al. Differences in twelve-lead electrocardiogram between symptomatic and asymptomatic subjects with short QT interval. Heart Rhythm 2009;6:267-71.
  3. 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;115:442-9.
  4. Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 2004;109:2394-7.
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  10. Giudicessi JR, Ackerman MJ. Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes. Trans Res 2013;161:1-14.
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  19. Milberg P, Tegelkamp R, Osada N, et al. Reduction of dispersion of repolarization and prolongation of postrepolarization refractoriness explain the antiarrhythmic effects of quinidine in a model of short QT syndrome. J Cardiovasc Electrophysiol 2007;18:658-64.
  20. 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;96:800-7.
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Clinical Topics: Arrhythmias and Clinical EP, Congenital Heart Disease and Pediatric Cardiology, Clinical Topic Collection: Dyslipidemia, Implantable Devices, EP Basic Science, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Congenital Heart Disease, CHD & Pediatrics and Arrhythmias, CHD & Pediatrics and Prevention, CHD & Pediatrics and Quality Improvement, Lipid Metabolism, Novel Agents, Statins

Keywords: Acidosis, Atrial Fibrillation, Brugada Syndrome, Carnitine, Death, Sudden, Cardiac, Defibrillators, Implantable, Digoxin, Electrocardiography, Electrolytes, Genotype, Heart Conduction System, Heart Defects, Congenital, Heart Rate, Hypercalcemia, Hyperkalemia, Potassium, Potassium Channels, Quinidine, Registries, Sudden Infant Death, Syncope, Tachycardia, Ventricular, Ventricular Fibrillation


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