Short QT Syndrome: a Case Report and Review of Literatureଝ

Resuscitation (2006) 71, 115—121

CASE REPORT Short QT syndrome: A case report and review of literatureଝ

Li Xiong Lu ∗, Wei Zhou, Xingyu Zhang, Qin Cao, Kanglong Yu, Changqing Zhu

Department of Emergency and critical care, Renji Hospital, Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, China

Received 21 December 2005; received in revised form 15 March 2006; accepted 20 March 2006

KEYWORDS Summary The short QT syndrome has been recently recognised as a genetic ion Tachycardia; channel dysfunction. This new clinical entity is associated with an incidence of sud- Ventricular; den cardiac death, syncope, and atrial fibrillation in otherwise healthy individuals. Genetics; The distinctive ECG pattern consists of an abnormally short QT interval, a short or Death; even absent ST segment and narrow T waves. A 30-year-old resuscitated woman Sudden cardiac; with short QT syndrome is described together with an example of the classic ECG characteristics. A short-coupled variant of torsade de pointes was reveal on Holter Syncope; recordings. The implantable cardioveter defibrillator seems to be the therapy of Short QT syndrome; choice to prevent from sudden cardiac death. Quinidine proved to be efficient in Channelopathy prolonging the QT interval and rendering ventricular tachyarrhythmias non-inducible in patients with a mutation in KCNH2 (HERG). Our preliminary data suggest amio- darone combined with ␤-blocker may be helpful in treating episodes of polymorphic ventricular tachycardia for patients with an unknown genotype. Because the short QT syndrome often involves young patients with an apparently normal heart, it is imperative for physicians to recognize the clinical features of the short QT syndrome in making a timely correct diagnosis. © 2006 Elsevier Ireland Ltd. All rights reserved.

Introduction recurrent life-threatening events and require more attention from the emergency physician. In the Syncope is a common disorder, constituting up to majority of cardiac syncope patients, a structural 3% of all visits to emergency department. Cardiac or functional abnormality can be identified, but in syncope patients are often associated with a risk of 5—10% of sudden cardiac death patients, the heart is apparently normal, so-called ion channel disease or ion channelopathy.1,2 Because the symptoms of ଝ A Spanish translated version of the summary of this article syncope or palpitation are transient and may escape appears as Appendix in the online version at 10.1016/j.resuscitation.2006.03.011. detection, and no identifiable heart disease can be ∗ Corresponding author. Tel.: +86 21 68383242. detected despite thorough clinic examination, it is E-mail address: [email protected] (L.X. Lu). a challenge for emergency physicians to recognise

0300-9572/$ — see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.resuscitation.2006.03.011 116 L.X. Lu et al. ion channel disease. As yet, a few families affected tial episode of ventricular fibrillation suggested with the short QT syndrome have been identified it may be a deterioration from polymorphic ven- but other cases have probably been overlooked.3,4 tricular tachycardia. We report a case of short QT syndrome and the knowledge to date on this little recognised disor- On arrival in the emergency department she der is presented. was alert. General physical examination revealed a puffy woman, mildly dyspnoeic, and pink in colour. Temperature was normal, respiratory rate Case presentation was 22/min. Her oxygen saturation, as measured by pulse oximetry, was 98%. Pulse rate was 64/min and regular. Blood pressure was 110/60 mmHg in At approximately 21:00 h, a 30-year-old Chinese the right upper arm. She had no jugular venous dis- female developed rapid palpitations and chest tention. Precordial examination revealed no chest tightness, followed by a witnessed episode of syn- deformity, with quiet precordium, and no thrill. cope with urinary incontinence. She regained con- Cardiac examination revealed a regular rate and sciousness immediately with no neurological seque- rhythm without murmurs, rubs or gallops. The lung lae. After three similar syncopal attacks within 3 h fields were clear with equal air entry. Neurological she was taken to the nearest hospital by her family examination and the remaining physical examina- members. tion was unremarkable. She had palpitations and chest tightness on exer- No clinical or laboratory evidence of rheumatic tion 3 months ago. fever was found. All laboratory investigations The patient had no history of cardiovascular dis- including three sets of cardiac enzymes were nor- ease and rheumatic fever. There was no history of mal. Two-dimensional echocardiography showed no sudden death in her family. She had no other medi- structural abnormality and a normal ejection frac- cal history and was receiving no regular medication. tion. Chest radiography was normal. She is the youngest of six siblings. No electrolytes A routine 12-lead electrocardiogram showed abnormalities were detected. The patient had an sinus rhythm with a heart rate of 70, a QT interval of urgent computed tomography scan of the head, 270 ms (Bazzett-corrected QT interval of 292 ms), which was normal. On the second day, after a total and a peaked T waves (Figure 2). of five syncopal or presyncope episodes the patient On the evening of hospital admission, the patient was transferred to our hospital for further treat- underwent Holter monitoring for 24 h during which ment. she complained several episodes of rapid palpi- During the transfer to our hospital she suffered a tations. Coinciding with the attack, monitoring cardiac arrest with ventricular fibrillation and was revealed episodes of 6- to 12-beat runs of torsade resuscitated with an external defibrillator in the de pointes with very short coupling intervals. A 24- ambulance (Figure 1). h Holter monitor recorded 57 ventricular ectopic The patient did not have continuous ECG moni- beats/24 h, 10 episodes of self-terminating poly- toring in the ambulance morphic ventricular tachycardia (Figure 3). • A: The left part of the rhythm strip was obtained She was diagnosed to be suffering from short QT in lead II as a routine evaluation in ambulance. syndrome. • B: It happened that the patient developed an After documented episodes of ventricular tachy- episode of syncope and seizure like activity just cardia, it was treated with metoprolol, amio- after the routine ECG was completed, so the ECG darone, and magnesium. Metoprolol (12.5 mg b.d.) was restarted promptly and showed ventricular was stopped the next morning because of con- tachycardia. She was successfully resuscitated cern about bradycardia developing. Amiodarone by cardioversion. Thus, the recording paper in was given as a 150 mg bolus IV over 10 min, fol- Figure 1 is continuous but there was a break in lowed by a continuous infusion of 800 ␮g/min for the ECG trace and the onset of arrhythmia was 24 h, reducing to 400 ␮g/min for 24 h. Finally oral not recorded, but the QRS morphology of the ini- amiodarone was given. Over the next few days,

Figure 1 Rhythm strip showing ventricular fibrillation recorded during seizure in ambulance. Short QT syndrome 117

Figure 2 Twelve-lead electrocardiogram. she did not have any further episodes of ventric- spectively in 1993. It was not until 2000 that Gussak ular tachycardia. The QT interval remained short, et al.6 proposed a short QT syndrome as a new however, and small fluctuations of QTc interval was inherited clinical syndrome. In 2003, the definitive documented which could not be explained by the familial link between short QT syndrome and sud- variation of the heart rate, the use of drugs and den death was demonstrated by Gaita et al.7 other probable factors influencing the QT interval. The short QT syndrome forms a distinct clinical For economic considerations, she did not have elec- entity. It is characterized by a short QT interval, trophysiological testing and an ICD implant. Two a short or even absent ST segment and tall, nar- weeks later, she was discharged on amiodarone. row and peaked T waves in the precordial leads, During the 12-month follow-up period, the patient and sudden cardiac death in individuals with an did not have any further syncope or palpitations. apparently normal heart.3,4,6—8 These subjects also had a high incidence of atrial arrhythmia. Individu- als with short QT syndrome frequently complain of Discussion palpitations and may have syncope. Short QT syn- drome is associated with an increased risk of sudden Long QT intervals in the ECG have been associ- cardiac death, most likely due to ventricular fibril- ated with sudden cardiac death. Little is known lation. Most individuals will have a family history about the clinical implication of a short QT inter- of unexplained or sudden death at a young age, val. Tremendous strides have been made in recent palpitations, or atrial fibrillation. The electrocar- years in the diagnosis and treatment of sudden car- diographic characteristics of short QT syndrome are diac death in individuals with an apparently normal a short QT interval, typically ≤320 ms, that does heart. Algra et al.5 first suggested that patients not change significantly with the heart rate. Some- with a short QT interval had an increased risk of times a lack of adaptation or paradoxical behavior sudden death by analyzing Holter recordings retro- of the QT interval with various heart rates was 118 L.X. Lu et al.

Figure 3 Holter monitoring showed self-terminating polymorphic ventricular tachycardia and short QT interval. The coupling interval of the first beat of the polymorphic ventricular tachycardia was very short.

observed.9 Tall, symmetrical and peaked T waves testing. There are currently no guidelines for the often also are noted. Individuals may also have an diagnosis of short QT syndrome. underlying atrial fibrillation. In the electrophysio- Even if ion channel disease is rare, its clinical logical study, individuals with short QT syndrome impact is high because it often concerns young, are noted to have short refractory periods, both in active and otherwise healthy individuals.1,2,10 In the atria as well as in the ventricles. Also, ven- contrast to the other types of ion channelopathies, tricular fibrillation is frequently induced on pro- the electrocardiologic characteristics of the short grammed stimulation.6,7,9 The diagnosis of short QT syndrome are less remarkable. The incidence QT syndrome is made up of a characteristic his- of ion channelopathies may have been underesti- tory and findings on ECG and electrophysiological mated. It is essential for the emergency physician Short QT syndrome 119 to be aware of this syndrome so that an accurate atrial fibrillation in patients with a mutation in diagnosis can be made. KCNH2 (HERG),9 and in this specific patient pop- It is noteworthy the short QT interval is dif- ulation, quinidine showed it was efficient in pro- ficult to record when the heart rate exceeds longing the QT interval and rendered ventricular 100 beats/min. Special attention should be given tachycardia non-inducible.9,16 However, no corre- in cases when the patients have fever, anaemia, lations have been identified between the magni- respiratory failure, etc., particularly in the pedi- tude of the QT shortening and the proclivity for atric population. Because atrial fibrillation may be an arrhythmic event. The heterogeneity of local the first symptom of the short QT syndrome, the refractoriness may play a more important role short QT syndrome should be excluded in young in the development of the malignant ventricular patients with lone atrial fibrillation.3,4,6,7 It should tachyarrhythmia than the shortness of refractory be emphasized that some cases at risk, like our period. The significance of programmed ventricular patient, may show periods of a normal QT inter- stimulation is unclear concerning risk stratification val, leading to underestimation of the syndrome. in patients with inherited channelopathies. More- Differential diagnosis of VT includes long QT syn- over, quinidine-associated mortality is high for the drome, Wolff—Parkinson—White syndrome (WPW treatment of other arrhythmias in the literature, syndrome), fascicular VT,arrhythmogenic right ven- therefore, further clinical evidence with quinidine tricular dysphasia (ARVD) and myocarditis. The first in patients with a mutation in KCNH2 (HERG) are three conditions can be safely excluded after ana- needed before this therapy can be recommended lyzing the ECG tracings. The causes of acquired as safe and effective for patients with a mutation short QT interval should be kept in mind when eval- in KCNH2 (HERG). uating QT changes, such as increased heart rate, To date, three genes — KCNH2 (SQT1), KCNQ1 hyperthermia, hypocalcaemia, hyperkalaemia, aci- (SQT2) and KCNJ2 (SQT3) — encoding different dosis, administration of digitalis preparations and potassium ion channels involved in repolarisa- altered autonomic tone.6,7 tion have been linked to the short QT syndrome, The aetiology of short QT syndrome is unclear. A which not only demonstrates the inherited het- current hypothesis is that the mutated ion channels erogeneity of the disease, but also is likely to shorten the plateau phase of the action potential, make the therapeutic options unique to each leading to a non-homogeneous overall shortening gene/mutation.3,4,8,9,16—20 Little data are available of refractory periods and the QT interval. The con- about gene/mutation-specific pharmacologic ther- sequence is a heterogeneous abbreviation of the apy of short QT syndrome. As an allelomorphic dis- action potential duration and refractoriness at both ease to long QT syndrome, it was not surprising that atrial and ventricular level. Short and amplification all three genes associated with short QT syndrome of transmural or other spatial heterogeneities of are also involved in long QT syndrome. SQT1 and refractory periods at three different cell types of LQT2 involve the same gene that encodes potassium the left ventricular myocardium favour reentry and IKr, SQT2 and LQT1 involve the same IKs gene, SQT3 thus arrhythmogenesis.11—14 and LQT7 involve the same Kir2.1 gene. Therefore, The optimal management of arrhythmias in the treatment of the short QT syndrome may ben- patients with short QT syndrome remains a criti- efit from the experience of treatment of the long cal issue. The implantable cardioverter defibrillator QT syndrome. (ICD) may be the only effective intervention for The long QT syndrome was the first to be dis- preventing sudden death.3,4,15 However, drugs will covered and is the best-known channelopathy. To remain essential in many clinical situations. Phar- date, mutations in at least eight different genes macological therapy is important and may serve as have been associated with long QT syndrome. an adjunct to ICD therapy to suppress atrial fibril- The classification of the long QT syndrome into lation, which is a major clinical problem in short various genetic classes has led to a number of QT syndrome, to suppress ventricular tachyarrhyth- genotype—phenotype studies that demonstrated mias, and especially to treat electrical storm. Phar- that the underlying genetic defect impacts on macological treatment is also needed and may con- ECG morphology, trigger and onset of symptoms, stitute an alternate treatment to ICD if a defibrilla- prognosis and, most importantly, treatment. Since tor implant is denied or impossible for any reason. potassium ion channels are the primary contribu- Currently, there are no specific pharmacological tors to the repolarisation process, the genes KCNQ1 treatments for preventing sudden death in indi- and KCNH2 are vulnerable to mutate and up to viduals with short QT syndrome. One study sug- 90% of genotyped patients with long QT syndrome gested that the class Ic agent propafenone could carry mutations in KCNQ1 and KCNH2. The IKs and be effective to prevent episodes of paroxysmal IKr component have been shown previously to be 120 L.X. Lu et al. under control of the sympathetic nervous system, ular tachycardia in our case was short. Therefore, Cardiac events in LQT2 and LQT1 patients were it is possible that some patients with a short QT syn- associated with elevated sympathetic nerve activ- drome may be thought to have a short-coupled vari- ity. In concordance with the predominant adrener- ant of torsade de pointes, because of little interest gic triggers, ␤-blocker therapy is most effective in in short QT intervals.28 preventing recurrence of cardiac events and low- Our patient’s QT interval measured 270 ms at ering the death rate in LQT1 and to some extent a heart rate of 70. Her 7-year-old daughter was in LQT2 but is much less effective in other long QT asymptomatic and showed a QT interval of 290 ms syndrome. It is noteworthy that the QT prolongation at a heart rate of 68, whereas the 53 year-old alone, if not accompanied by an increase in trans- mother displayed a QT interval of 290 ms (QTc mural dispersion of repolarization, is not in itself 300 ms) at a heart rate of 64 and episode of parox- sufficient to cause polymorphic ventricular tach- ysmal atrial fibrillation. Her husband and her father yarrhythmia. ␤-Blockers have minimal effects on had normal QT intervals. The family patterns sug- the QTc interval but are associated with a signif- gested autosomal dominant inheritance. However, icant reduction in cardiac events in patients with this disorder, like most other genetic conditions, long QT syndrome.21—24 has variable expression of severity (i.e. variable In our patient, it is noted she experienced her penetrance). An affected individual within a given cardiac events during psychological stress, and dur- family with a specific mutation may be asymp- ing Holter monitoring, although her mean heart rate tomatic, such as her daughter and her mother, was slow (62 beats/min), paroxysmal variations at whereas another family member with the same several minutes intervals in heart rate were notice- gene mutation may experience recurrent syncope able and there also appeared to be an increase in and sudden cardiac death, such as the patient in underlying heart rate before the onset of episode our case. Three forms of the disease have been of arrhythmia, suggesting a role for adrenergic acti- so far identified: SQT1, caused by a gain of func- vation. These findings provide the rationale for tion substitution in the HERG (IKr) channel, SQT2, a novel approach toward the prevention of sud- caused by a gain of function substitution in the den death in this patient with short QT syndrome KvLQT1 (IKs) channel, and SQT3, which has a unique of unknown genotype: Amiodarone plus ␤-blocker. ECG phenotype characterized by tall and asymmet- Compared with other antiarrhythmic drugs, amio- rically shaped T waves, caused by a defect in the darone has a distinct pharmacological profile and gene coding for the inwardly rectifying Kir2.1 (IK1) can inhibit both IKr and IKs potassium currents, channel, but the fact that no mutation was found which are most probably responsible for short QT in some patients with a short QT syndrome indi- syndrome. The concomitant modulation of IKs, IKr cates further genetic study is necessary.3,4,7,17—20 and adrenergic blockade may constitute a poten- The pedigree described herein is large enough to tial pharmacologic strategy for prevention of malig- undertake a genome scan and provides an excellent nant ventricular arrhythmias. Meanwhile, sympa- model for the molecular mechanism of the short QT thetic stimulation is known to modulate a number syndrome. of currents, by virtue of its multi-channel proper- In recent years, many genetic causes of ion chan- ties and unique antiadrenergic properties, amio- nel diseases have been revealed. The identifica- darone combination with ␤-blocker can interact tion of the gene defects has revolutionized our synergistically to show more effective antiadren- understanding of the basic mechanisms underlying ergic interventions and protect against malignant numerous disease processes. Identification of muta- arrhythmia.25—27 tions in the HERG K+ channel as the molecular basis The prognosis and natural history of short QT syn- of congenital long QT syndrome led to the discov- drome still remains obscure. Our patient was free ery that HERG is the molecular target for the vast from any further episodes of syncope for 1 year majority of drugs that cause drug-induced arrhyth- with such therapeutic interventions and behavioral mias. This has had profound implications not only recommendations. However, it has to be empha- for the development of antiarrhythmic agents, but sized that because of the ‘‘random’’ nature of the also for drug development in general. Although clin- malignant arrhythmia, the safety and efficacy of ical presentation is determined by complex interac- amiodarone in patients of unknown genotype with tions between causal genes, genetic background, life-threatening arrhythmia that tend to be adren- and environmental factors, with increasing knowl- ergic dependent remain questionable. Confirmation edge about identification of underlying ion chan- of these preliminary data is required. nel defects and new details of the mechanisms It may be of interest to note that the coupling of arrhythmogenesis, it is expected that an indi- interval of the first beat of the polymorphic ventric- vidually tailored approach to the basis of patient- Short QT syndrome 121 specific genetic information will gain more impor- 15. Schimpf R, Bauersfeld U, Gaita F, Wolpert C. 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