Cardiovascular Research

Cardiovascular Research 2005 67(3):357-366; doi:10.1016/j.cardiores.2005.03.026

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Copyright © 2005, European Society of Cardiology

Short QT syndrome

Rainer Schimpf^a,*, Christian Wolpert^a, Fiorenzo Gaita^b, Carla Giustetto^b and Martin Borggrefe^a

^a1st Department of Medicine-Cardiology, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany
^bDepartment of Cardiology, Ospedale Civile Asti, Italy

^* Corresponding author. Tel.: +49 621 3832206; fax: +49 621 3833061. Email address: rainer.schimpf{at}med.ma.uni-heidelberg.de

Received 13 January 2005; revised 18 March 2005; accepted 22 March 2005

	Abstract

Top Abstract 1. Introduction 2. Patients 3. Clinical presentation and... 4. Atrial fibrillation and... 5. ECG characteristics 6. Invasive electrophysiological... 7. Genetics and cellular... 8. Arrhythmogenic substrate 9. Therapy 10. Summary References

 
The short QT syndrome constitutes a new clinical entity that is associated with a high incidence of sudden cardiac death, syncope, and/or atrial fibrillation even in young patients and newborns. Patients with this congenital electrical abnormality are characterized by rate-corrected QT intervals<320 ms. Missense mutations in KCNH2 (HERG) linked to a gain-of-function of the rapidly activating delayed-rectifier current I_Kr have been identified in the first two reported families with familial sudden cardiac death. Recently, two further gain-of-function mutations in the KCNQ1 gene encoding the -subunit of the KvLQT1 (I_Ks) channel and in the KCNJ2 gene encoding the strong inwardly rectifying channel protein Kir2.1 confirmed a genetically heterogeneous disease. The possible substrate for the development of ventricular tachyarrhythmias may be a significant transmural dispersion of the repolarisation due to a heterogeneous abbreviation of the action potential duration. The implantable cardioverter defibrillator is the therapy of choice in patients with syncope and a positive family history of sudden cardiac death. However, ICD therapy in patients with a short QT syndrome has an increased risk for inappropriate shock therapies due to possible T wave oversensing. The impact of sotalol, ibutilide, flecainide, and quinidine on QT prolongation has been evaluated, but only quinidine effectively suppressed gain-of-function in I_Kr with prolongation of the QT interval. In patients with a mutation in HERG, it rendered ventricular tachycardias/ventricular fibrillation non-inducible and restored the QT interval/heart rate relationship towards a normal range. It may serve as an adjunct to ICD therapy or as a possible alternative treatment, especially for children and newborns.

KEYWORDS Heart desease; Short QT syndrome; Sudden cardiac death; Atrial fibrillation

	1. Introduction

Top Abstract 1. Introduction 2. Patients 3. Clinical presentation and... 4. Atrial fibrillation and... 5. ECG characteristics 6. Invasive electrophysiological... 7. Genetics and cellular... 8. Arrhythmogenic substrate 9. Therapy 10. Summary References

 
Sudden death occurs predominantly in individuals with structural heart disease. However, in approximately 10–20% of all sudden deaths, no structural cardiac abnormalities can be identified [1]. In recent years, major advances have been made in the understanding of the molecular substrates of inherited arrhythmogenic diseases. With the contribution of molecular genetics, the genetic bases of numerous cardiac diseases such as the long QT syndrome, the Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and familial atrial fibrillation have been unveiled [2–6]. It is known that the surface electrogram pattern of a prolonged QT interval is associated with an increased risk of life-threatening ventricular tachyarrhythmias [7]. Several reports have defined the upper limit of normal heart rate-corrected QT interval. However, little is known about the clinical implication of a shortened QT interval and the lower limit of normality of the QT interval [8]. In 2000, a family with paroxysmal atrial fibrillation and constantly shortened QT intervals was identified [9]. Meanwhile, a high familial risk for sudden cardiac death associated with a short QT interval was demonstrated by our own group [10]. Thus, the short QT syndrome adds a possible diagnosis for yet unclear sudden cardiac deaths in patients without structural heart disease.

	2. Patients

Top Abstract 1. Introduction 2. Patients 3. Clinical presentation and... 4. Atrial fibrillation and... 5. ECG characteristics 6. Invasive electrophysiological... 7. Genetics and cellular... 8. Arrhythmogenic substrate 9. Therapy 10. Summary References

 
At present, 15 patients with familial atrial fibrillation and/or sudden cardiac death and short QT intervals have been reported: 14 patients had familial, 1 patient a sporadic short QT syndrome (Table 1) [9–12]. A further two yet unpublished patients presented with a familial and a sporadic short QT syndrome (#7 and #11, Table 1). All patients presented with a QTc<320 ms (Bazett) or below 80% of the normal QT interval (Fig. 1). In all patients, structural heart disease was excluded. Eight patients received an implantable cardioverter defibrillator for primary or secondary prophylaxis [13,14].

View this table: [in this window] [in a new window]   Table 1 Demographic, clinical, and electrophysiological data of patients with short QT syndrome

 

View larger version (53K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Twelve lead surface ECG of a 16 years old patient with congenital short QT syndrome (QT interval 248 ms, QTc 252 ms, paper speed 25 mm/s).

 
The mean age of the patients with a short QT syndrome including one patient who died suddenly was 40 ± 24 years (7 female, 11 male patients). The first individual described in 2000 by Gussak et al. with a short QT syndrome was a female patient at the age of 17 years, presenting with atrial fibrillation and a QT interval of 225 ms [9]. Her brother, mother, and grandfather revealed short QT intervals. They all suffered from episodes of atrial fibrillation [14]. Syncope or a history of sudden cardiac death has not been reported in the family. In 2003, another seven patients from two different European families (six living patients, one patient who died suddenly) were identified with rate-corrected short QT intervals<300 ms [10]. However, in these families, aside from episodes of atrial fibrillation, sudden cardiac death occurred in four or three generations, respectively.

From a fourth family, reported by Brugada et al., a 51-year-old man was resuscitated with the help of an automatic external defibrillator in a domestic airport and showed a QTc interval of 288 ms [15]. In this family, one asymptomatic son could be discovered with a QTc of 293 ms. During programmed ventricular stimulation in the 51-year-old male, ventricular fibrillation could be easily induced.

One 71-year-old patient (unpublished) with a short QT syndrome (QTc 240 ms) had a syncope at the age of 70 and a family history of sudden cardiac death (mother at 60 years of age). At the age of 64, atrial fibrillation was documented for the first time (Fig. 2).

View larger version (74K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Chest leads of two separate ECGs from a 71 year old patient with a short QT syndrome with sinus rhythm (above) at the age of 63 and after development of permanent atrial fibrillation (below) at the age of 64. The QT interval is constantly short either in sinus rhythm or during atrial fibrillation with varying RR intervals (QT interval 260 ms, QTc 271 ms, paper speed 50 mm/s).

 
One sporadic patient with a short QT syndrome (QTc 302 ms) was reported by Bellocq et al. [11]. This 70-year-old male was successfully resuscitated after an episode of ventricular fibrillation with a negative family history. The second sporadic patient is a 29-year-old male (unpublished) who suffered from paroxysmal atrial fibrillation since the age of 26 years. He presented with a short QT interval at low heart rates (at 40 bpm/QTc 292 ms, at 75 bpm/QTc 324 ms) with normalisation at rates above 85 bpm. During programmed ventricular stimulation, ventricular fibrillation was inducible.

Recently, a further family was described. A 5-year-old asymptomatic child presented with an abnormal ECG with a QTc interval of 315 ms. Her 35-year-old father had a short QT interval (QTc 320 ms) with narrow and peaked T waves. Several nocturnal seizure-like motions of the patient followed by sudden awakening with palpitations have been reported [12].

	3. Clinical presentation and follow-up

Top Abstract 1. Introduction 2. Patients 3. Clinical presentation and... 4. Atrial fibrillation and... 5. ECG characteristics 6. Invasive electrophysiological... 7. Genetics and cellular... 8. Arrhythmogenic substrate 9. Therapy 10. Summary References

 
The risk for an arrhythmic event is high in patients with a short QT syndrome comprising syncope and/or sudden cardiac death due to ventricular tachyarrhythmias. Furthermore, episodes of atrial fibrillation were documented in patients with a short QT syndrome at different ages even in adolescents [9]. A relevant number of sudden cardiac deaths or aborted sudden cardiac deaths occurred in three or four generations in the two secondly reported families with a short QT interval [10]. These events have been reported in three patients <1 year of age, in two patients <30 years of age (one episode of primary ventricular fibrillation at 17 years of age and one sudden cardiac death in a patient 26 years of age), and in eight middle-aged patients (seven sudden deaths between 37 and 49 years, one aborted sudden cardiac death at 51). Two elderly are affected (sudden cardiac death at the age of 60 and aborted sudden cardiac death at 70 years of age) [9–11]. The mean age at the documented events such as syncope, sudden cardiac death, and aborted sudden cardiac death in patients with a short QT syndrome is 35 ± 25 years (median 39 years). The short QT syndrome constitutes also a cause for sudden infant death syndrome. It may manifest immediately with sudden cardiac death without a preceding syncope as four of the reported sudden cardiac deaths had no history of prior syncope or other arrhythmic events.

	4. Atrial fibrillation and short QT syndrome

Top Abstract 1. Introduction 2. Patients 3. Clinical presentation and... 4. Atrial fibrillation and... 5. ECG characteristics 6. Invasive electrophysiological... 7. Genetics and cellular... 8. Arrhythmogenic substrate 9. Therapy 10. Summary References

 
The first patients with a short QT syndrome were discovered because of symptomatic episodes of atrial fibrillation [9]. The incidence of atrial fibrillation was assessed by available ECGs of 12 patients and one patient who died suddenly. Nine out of 13 patients (70%) had either paroxysmal or permanent atrial fibrillation. The first symptomatic episode of atrial fibrillation occurred at a mean age of 41 ± 19 years. In 4 of 9 patients, the age of the first episode was <30 years and in two patients <20 years. In 7/13 patients (53%), atrial fibrillation was the first symptom of the short QT syndrome. In 7 out of 11 patients, programmed atrial stimulation was performed. Four out of 7 patients revealed inducible atrial fibrillation. The atrial effective refractory periods were extremely short (141 ± 18 ms).

Thus, atrial fibrillation may be the first symptom of the short QT syndrome. Especially in young patients with lone atrial fibrillation, a short QT interval has to be considered.

	5. ECG characteristics

Top Abstract 1. Introduction 2. Patients 3. Clinical presentation and... 4. Atrial fibrillation and... 5. ECG characteristics 6. Invasive electrophysiological... 7. Genetics and cellular... 8. Arrhythmogenic substrate 9. Therapy 10. Summary References

 
5.1. Baseline findings
The 12-lead-ECGs of 16 patients with a short QT syndrome including one further patient who died suddenly showed QTc intervals 300 ms. The mean QTc was 287 ± 18 ms. Retrospective analysis of all available ECGs at different ages displayed a constantly short QT interval (Figs. 1 and 2). One patient with a sporadic short QT syndrome presented with a QTc interval at 40 bpm of 292 ms and at 70 bpm 324 ms. At heart rates above 85/min, the QTc interval was normal.

5.2. Differential diagnosis
Other reversible reasons for a short QT interval such as hyperkalemia, hypercalcemia, acidosis, digitalis toxicity, and hyperthermia have to be excluded. Furthermore, stress hormones like acetylcholine and catecholamines or testosterone may shorten the QT interval [16,17].

5.3. ECG morphology
Apart from constantly short QTc intervals, affected patients present with a short or even absent ST segment and often tall, narrow, and symmetrical T waves in the precordial leads (Figs. 1 and 2). The QTc values of two recently published patients with a short QT syndrome and a gain-of-function mutation in KCNJ2 demonstrated QTc intervals of 315 ms and 320 ms. The T waves in these two patients were narrow and tall comparable to the above described pattern. However, they had an asymmetrical morphology with a rapid terminal phase [12].

5.4. Rate adaptation of the QT interval
Physiologically, the QT interval shortens with increase of the heart rate [8]. In patients with a short QT syndrome, however, a lack of adaptation of the QT interval under exercise with increasing heart rate is present [18].

Three patients underwent bicycle exercise testing of drugs, with two of these patients being on 1000 mg per day of oral quinidine. The QT_pV3 interval (Q until peak of T wave, measured at lead V3) was poorly correlated with heart rate in the absence of drug with slopes of –0.22 ms/beat/min, –0.59 and –0.39 ms/beat/min. In the control group of 10 normal healthy subjects, there was a linear relationship between QT_pV3 and heart rate with a mean slope of 1.29 ± 0.33 ms/beat/min (Fig. 3).

View larger version (17K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Heart rate relationship in a healthy female and a patient with a short QT syndrome off drugs and on 1000 mg of oral quinidine/day. The relationship between QTpV3 and the increase in heart rate is linear in the normal proband but not linear in the patient. On oral quinidine, a linear relationship between QTpV3 and heart rate is restored. Used with permission from Blackwell Publishing (Wolpert C et al. J Cardiovasc Electrophysiol 2005; 16:54–8).

 
Furthermore, a paradoxical behaviour of the QT interval with shortening during low heart rates has been observed in two symptomatic patients. The underlying mechanism is unclear at present, but may constitute a variant of a short QT syndrome [19].

Measurements of the QT interval should be performed at resting heart rates as rate correction at high heart rates may lead to pseudonormal QTc intervals. Holter ECGs should be performed to exclude bradycardia associated shortening of the QT interval.

	6. Invasive electrophysiological findings

Top Abstract 1. Introduction 2. Patients 3. Clinical presentation and... 4. Atrial fibrillation and... 5. ECG characteristics 6. Invasive electrophysiological... 7. Genetics and cellular... 8. Arrhythmogenic substrate 9. Therapy 10. Summary References

 
Eleven patients have undergone an invasive electrophysiological analysis. During programmed atrial and ventricular stimulation, the atrial and ventricular effective refractory periods were extremely short (atrial refractory periods 141 ± 18 ms and ventricular effective refractory periods 147 ± 18 ms). Additionally, in a very high percentage of the patients, ventricular tachyarrhythmias, predominantly ventricular fibrillation/ventricular flutter, were inducible (10/11 patients, 91%). The role of inducibility of ventricular tachyarrhythmias in short QT syndrome cannot be determined at present because of the limited number of patients. However, inducibility is a common finding in patients with short QT intervals.

In two patients with a short QT syndrome, ventricular tachyarrhythmias could be reproducibly induced during programmed ventricular stimulation at prehospital discharge testing after implantable cardioverter defibrillator (ICD) implantation [18].

One interesting observation was that in three patients, instrumentation of the ventricle mechanically induced ventricular fibrillation (right ventricle n = 2 patients, left ventricle n = 1 patient). Although mechanical induction of ventricular tachycardias/ventricular fibrillation can occur during electrophysiological studies, it is an extremely rare event. The fact that 3/11 patients with a short QT syndrome showed this phenomenon is noteworthy, and it may point to an increased excitability or vulnerability in patients with a short QT syndrome. Interestingly, this finding has been previously reported in another species with short QT intervals. O'Rourke et al. described the development of ventricular fibrillation in 10/14 anaesthetised kangaroos during instrumentation of the left ventricle (QTc intervals 262 ± 50 ms) [20,21].

	7. Genetics and cellular mechanism

Top Abstract 1. Introduction 2. Patients 3. Clinical presentation and... 4. Atrial fibrillation and... 5. ECG characteristics 6. Invasive electrophysiological... 7. Genetics and cellular... 8. Arrhythmogenic substrate 9. Therapy 10. Summary References

 
Genetic screening in the first two reported families with a short QT syndrome and familial sudden cardiac deaths has identified two different missense mutations that resulted in the same amino acid change of the cardiac I_Kr channel HERG (KCNH2) (Table 2) [10,15]. In one family, a missense mutation with a cytosine to guanine substitution at nucleotide 1764 in KCNH2 was reported. The mutation substituted the asparagine at codon 588 in KCNH2 (HERG) for a positively charged lysine. The residue is located in the S5-P loop region of HERG at the outer mouth of the channel. The mutation was present in all affected members but not in any of the unaffected members. No other mutations were detected in HERG or in further analyzed candidate genes encoding ion channels which contribute to the repolarisation of the ventricular action potential such as KCNE2, KCNQ1, KCNE1, SCN5A, and KCNJ2. In the second family, a different missense mutation in the same nucleotide (1764) was found (cytosine to adenine substitution). Both mutations resulted in the same amino acid substitution of asparagine at codon 588 in the KCNH2 (HERG) by lysine [15]. The fact that no mutation was found in 4/14 individuals with a short QT syndrome indicates that further genetic heterogeneity exists.

View this table: [in this window] [in a new window]   Table 2 Genetic and molecular mechanism of short QT syndrome

 
To further elucidate the mechanism of QT interval shortening, the mutated KCNH2 channel (N588K) was coexpressed with and without the β-subunit MiRP1 (KCNE2) in human embryonic kidney cells (TSA201) and patch-clamp experiments were performed [15]. Whole-cell recordings demonstrated that wild-type HERG/KCNH2 currents reached maximum steady state currents at 0 mV and decreased at positive potentials. Furthermore, large tail currents are generated during repolarisation, whereas the N588K/KCNE2 showed a steady increase without a prominent tail current. The mutation causes a loss of the normal rectification of the current at plateau voltages, which results in a significant increase of I_Kr during the action potential plateau and leads to an abbreviation of the action potential and refractoriness. Additionally, the N588K currents showed a much larger relative current at the initial phase of the action potential [15].

The short QT syndrome represents the first ion channelopathy that is associated with a gain-of-function of I_Kr. Notably, a missense mutation leading to substitution of asparagine by aspartatic acid in HERG (N588D) leads to the contrary: a loss of function of I_Kr with a decrease in the outward repolarising current, causing long QT 2 syndrome [22,23].

Furthermore, KCNH2 is the target of acquired forms of the long QT syndrome as a side effect of a variety of antiarrhythmic agents or of primary non-cardiac drugs [24]. Genetic heterogeneity in the short QT syndrome is stressed by findings of Bellocq et al. who defined a further mutation in a 70-year-old patient with a short QT syndrome (QTc 302 ms) and aborted sudden cardiac death [11]. They identified a mutation in the KCNQ1 gene encoding the KvLQT1 K⁺ channel that forms the slow component of the cardiac delayed rectifier K⁺ current I_Ks together with the β-subunit IsK. Analysis of the KCNQ1 gene identified a substitution of guanine to cytosine (nucleotide 919) that altered valine to leucine at position 307 (V307L). The gain-of-function mutation affecting I_Ks resulted in an abbreviation of the action potential duration and shortening of the QT interval. Other gain-of-function mutations of KCNQ1 and KCNE2, the β-subunit of the KCNQ1–KCNE2 channel responsible for a background potassium current, were reported. The patients presented clinically with atrial fibrillation but the ECGs show normal QT intervals [6,25]. Conversely, a loss of function in the KCNQ1 gene causes the long QT1 syndrome.

Finally, a further new variant of the short QT syndrome has been recently identified. Two affected members of a family had a single base pair substitution (G514A) in the KCNJ2 gene that led to an amino acid change from aspartic acid to aparagine at position 172 of the Kir2.1 potassium channel (Table 2). It has not been found in the phenotypically non-affected family members. Functional characterization of the mutant in Chinese hamster ovarian cells by Priori et al. demonstrated a significant increase in the outward component of the current–voltage relation of the strong inwardly rectifyer current I_K1 [12]. On the other hand, a loss of function in the KCNJ2 gene was identified in patients with the Anderson syndrome, also referred as a long QT syndrome (LQT7) [26].

Potential further mutations may be unveiled in the future, because it has been increasingly observed that aside from altered transmembrane cardiac ion channels, also intracellular channel and non ion-conducting proteins may be associated with inherited arrhythmias and sudden cardiac death.

	8. Arrhythmogenic substrate

Top Abstract 1. Introduction 2. Patients 3. Clinical presentation and... 4. Atrial fibrillation and... 5. ECG characteristics 6. Invasive electrophysiological... 7. Genetics and cellular... 8. Arrhythmogenic substrate 9. Therapy 10. Summary References

 
Initially, the mechanism of the increased vulnerability in patients with idiopathic ventricular fibrillation remained completely unclear. However, the identification of the molecular determinants of inherited arrhythmogenic disorders represents the pivotal point in an advanced understanding of the mechanisms of arrhythmogenesis. Important for the electrophysiologic basis of arrhythmogenicity in ion channelopathies was the finding that the left ventricular myocardium is electrophysiologically not uniform. Three different cell types localized in the epicardium, endocardium, and the M-cells in between could be distinguished. The different myocardial cell types are characterized by a heterogeneous electrophysiologic profile as e.g. the action potential duration of the M-cells is prolonged, because of a smaller slowly activating delayed rectifier current I_Ks and a larger late sodium current I_Na [27]. Hence, differences in the time course of repolarisation between the different cell layers generate a transmural voltage gradient. In Brugada syndrome, the transmural dispersion of repolarisation is exacerbated, thus providing the electrophysiologic basis of a vulnerable window [28]. The latter represents the target of an extrasystole to trigger a ventricular reentrant tachyarrhythmia.

Furthermore, in animal models of the long QT syndrome, a prominent prolongation of the action potential of the M-cells was documented, thus creating an increase of transmural dispersion of repolarisation. The transmural dispersion of the repolarisation provides the substrate for the development of torsade de pointes tachycardias [29,30].

Finally, the latest results propose a heterogeneous abbreviation of the action potential and an increased transmural dispersion of repolarisation in patients with a short QT syndrome as a potential substrate for the development of ventricular tachyarrhythmias. In patients with a short QT syndrome, the T waves appear often tall, peaked, and symmetrical. Prolonged T_peak–T_end intervals indicate an augmented transmural dispersion of repolarisation. Extramiana and Antzelevitch tested the hypothesis of an augmented transmural dispersion of the repolarisation in a canine left ventricular wedge preparation [31]. They pharmacologically induced a short QT interval by application of pinacidil, which is an activator of the ATP-sensitive potassium current (I_K-ATP). Pinacidil generated both a shortening of the QT interval as well as a significant prolongation of the T_peak–T_end interval and augmentation of the transmural dispersion of repolarisation. Programmed electrical stimulation was able to induce ventricular tachyarrhythmias but failed to induce in the absence of pinacidil under control conditions with a normal QT time and T_peak–T_end interval. The addition of isoproterenol produced a further shortening of the QT interval and augmentation of the T_peak–T_end interval, which could be explained by a preferential abbreviation of the M-cell action potential duration. The induced polymorphic ventricular tachyarrhythmias were subsequently more enduring. Thus, the study demonstrated an association of the level of transmural dispersion of repolarisation to the inducibility to polymorphic ventricular tachyarrhythmias. The clinical syndromes with a gain-of-function mutation in HERG encoding I_Kr and KCNQ1 encoding I_Ks are phenotypically different from the discussed model that shows inverted T waves. However, the model is consistent with the clinical syndrome characterized by an association of significant QT interval shortening with an accentuation of the transmural dispersion of repolarisation.

Shortening of the QT interval is most prominent at lower heart rates. Therefore, a potential trigger, like short coupled ventricular extrasystoles, may have a greater impact on the induction of ventricular tachyarrhythmias at rest and during sleep in patients with a short QT syndrome.

	9. Therapy

Top Abstract 1. Introduction 2. Patients 3. Clinical presentation and... 4. Atrial fibrillation and... 5. ECG characteristics 6. Invasive electrophysiological... 7. Genetics and cellular... 8. Arrhythmogenic substrate 9. Therapy 10. Summary References

 
9.1. Drug effects in short QT syndrome
Although the ICD in patients with a short QT syndrome is the therapy of choice, antiarrhythmic drug therapy may constitute a potential adjunct or an alternative therapy in children or in newborns, where ICD implantation is most difficult. To date, several antiarrhythmic drugs have been evaluated in patients with a gain-of-function mutation in HERG (KCNH2) [16,18,32]. The antiarrhythmic effects of I_Kr blockers such as sotalol and ibutilide have been tested. Sotalol was administered orally or intravenously in three patients, but did not prolong the QT interval. The response of heterologously expressed KCNH2/KCNE2 currents to sotalol in mutated and wild-type channels was studied [15]. In vitro electrophysiological studies confirmed the clinical findings that the N588K mutation leads to a reduced ability of d-sotalol to block the channel. The same lack of QT prolongation was documented in two patients for ibutilide, another I_Kr blocker. Flecainide, a Na⁺ channel blocker which has also a blocking effect on I_Kr and the transient outward potassium current (I_to), leads to an increase in ventricular effective refractory periods. However, acute administration of flecainide led to a prolongation of refractoriness, but only slight prolongation of the QT interval [32].

We recently demonstrated that in contrast to sotalol and ibutilide, quinidine, a class IA antiarrhythmic agent, is able to normalise the QT interval at resting heart rates [18,32]. An obvious ST segment recurred as well as broader T waves. Quinidine prolonged the ventricular effective refractory period in five patients with a gain-of-function mutation in HERG (KCNH2). In vitro electrophysiologic studies showed a much lesser reduced sensitivity of the N588K current to quinidine in comparison to sotalol. The basis of the greater effectiveness of quinidine in comparison to sotalol is not fully understood. A greater affinity of quinidine for the open state of the HERG channel and its ability to block the slowly activating delayed rectifier current I_Ks that contributes to the repolarisation could explain the effect of the prolongation of the QT interval. As discussed above, one of the characteristics of the short QT syndrome is the lack of dependence of QT interval on heart rate. Quinidine restored the heart rate dependence of the QT interval towards an adaptation range of normal subjects. For quinidine, a linear relationship was observed with slopes of –0.75 and 0.56 ms/beat/min (Fig. 3). Notably, in serial testing, oral quinidine rendered ventricular tachyarrhythmias non-inducible in two patients in whom baseline electrophysiologic studies demonstrated reproducible induction of ventricular tachycardias/ventricular fibrillation [18].

Finally, concerning the genetic heterogeneity in patients with a short QT syndrome, it should be emphasized that the findings on drug effects apply only to patients with mutations in HERG and thus could be different from patients carrying mutations in KCNH2, KCNQ1, or in other genes.

9.2. ICD therapy
Facing the high risk for ventricular tachyarrhythmias, the implantable cardioverter defibrillator is to date the therapy of choice in patients with a short QT syndrome. For 8 patients with a short QT syndrome, it is known that they received an ICD for primary or secondary prophylaxis [13,14]. In four of the five initially implanted patients, T wave oversensing and inappropriate ICD shock therapy occurred during follow-up. Short coupled intracardiac T waves with high amplitudes led to inappropriate therapies due to double counting of the R and T wave. In one patient, adapting the sensitivity to lower values prevented initially further inappropriate shock therapies (Medtronic Inc., Minneapolis, MN, USA) [13]. In the other three patients, reprogramming of multiprogrammable sensitivity parameters (start threshold, decay delay, sensitivity) prevented effectively additional inappropriate therapies (St. Jude Medical Inc., St. Paul, MN, USA). A further three patients who received an ICD did not experience inappropriate therapies during short-term follow-up (Guidant, Indianapolis, IN, USA) [14].

9.3. Clinical follow-up
Follow-up data are available in 10 patients. All patients remained free of syncope. However, one 16-year-old adolescent presented 19 months after implantation with an appropriate intervention of his ICD (Fig. 4). The patient received an ICD for primary prophylaxis in February, 2003 (QTc 252 ms, Fig. 1). Although ventricular tachyarrhythmias could not be induced during programmed ventricular stimulation at the initial work-up, an ICD was implanted based on the strong positive family history of sudden cardiac death. The father of the patient had died suddenly at the age of 27 years and his grandmother at the age of 61 years. At the time of implantation, genetic screening was not completed. The episode represents the first successful prevention of sudden cardiac death in a patient with a familial short QT syndrome [33].

View larger version (72K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4 Stored endocardial electrogram derived from the ICD-memory showing an episode of primary ventricular fibrillation in short QT syndrome. Panel A shows the initiation of the ventricular tachyarrhythmia with a short coupled premature ventricular beat (180 ms), panel B shows the ongoing ventricular fibrillation, and panel C shows the termination of ventricular fibrillation by shock delivery (upper electrogram strip in panels A–C: shock electrogram, lower electrogram strip: rate electrogram, ICD markers: CE=charging end, CD=capacitor discharge, FS=fibrillation sensing, FD=fibrillation detection, TS=tachycardia sensing, VS=ventricular sensing).

 
Notably, the adolescent experienced the first episode of primary ventricular fibrillation despite the fact that he was the only one from 10 invasively studied patients in whom ventricular tachyarrhythmias could not be induced. Therefore, the finding of non-inducibility of ventricular tachycardias/ventricular fibrillation during programmed ventricular stimulation has to be assessed with caution. Conversely, the impact of a positive family history in decision making is stressed.

In this patient, it is of note that a very short coupled premature ventricular beat induced ventricular fibrillation. This is consistent with the extremely short ventricular effective refractory periods demonstrated in all patients whom have been studied so far (150 ms in the present patient, mean 147 ± 18 ms). Patients with a short QT syndrome have to be considered as highly vulnerable to premature ventricular beats below 180 ms, to which normal hearts would be refractory. Finally, the QT interval is most abnormal during low heart rates in patients with a short QT syndrome. Therefore, transmural dispersion of repolarisation as the potential substrate for the genesis of ventricular tachyarrhythmias may be most pronounced at low rates. Short coupled premature ventricular beats could be potential triggers, especially during low heart rates at rest and during sleep.

One unpublished patient is different from the other patients. He presented with a short QT interval of 292 ms at a heart rate of 40 bpm and 324 ms at 75 bpm, but the QTc interval normalises at higher heart rates (85 bpm/QTc 357 ms and 97 bpm/400 ms). Thus, QT shortening is pronounced at low heart rates. The patient suffers from atrial fibrillation since the age of 26, and during programmed ventricular stimulation, ventricular fibrillation was inducible. The family history for sudden cardiac death, atrial fibrillation, and syncope is negative. The mechanism of paradoxical QT shortening is unclear, and a mutation has not yet been identified. In the literature, one patient with a bradycardia-associated short QT interval has been reported. However, paradoxical shortening of the QT interval was not associated with ventricular tachyarrhythmias, whereas intermittent total AV-block could be documented [19].

	10. Summary

Top Abstract 1. Introduction 2. Patients 3. Clinical presentation and... 4. Atrial fibrillation and... 5. ECG characteristics 6. Invasive electrophysiological... 7. Genetics and cellular... 8. Arrhythmogenic substrate 9. Therapy 10. Summary References

 
With the detection of the arrhythmogenic risk of a short QT interval, a new primary electrical abnormality is identified. It must nowadays be considered in the evaluation of patients with syncope, aborted sudden cardiac death, atrial fibrillation, and/or a positive family history for syncope and sudden death.

Affected patients are characterized by constantly short QT intervals (QTc 320 ms), a short or even absent ST segment, and often tall, narrow, and symmetrical T waves in the precordial leads. Patients present with atrial fibrillation, syncope, and/or familial sudden cardiac death at all ages, even in newborns. All patients revealed short atrial and ventricular effective refractory periods during electrophysiological analysis. Furthermore, ventricular tachycardias/ventricular fibrillation are inducible in 90% of patients. Genetic screening revealed a genetically heterogeneous disease with gain-of-function mutations of I_Kr (KCNH2) and I_Ks (KCNQ1). A heterogeneous abbreviation of the action potential duration may generate a transmural dispersion of the repolarisation and thus establish a potential substrate for the development of ventricular tachyarrhythmias. At present, therapy of choice in the prevention of sudden cardiac death is the implantable cardioverter defibrillator. However, the potential for inappropriate therapies due to possible T wave oversensing is increased in these patients. Several antiarrhythmic drugs such as ibutilide, sotalol, and flecainide have been demonstrated to be ineffective in prolongation of the QT interval. Only quinidine, a class IA antiarrhythmic agent, has been effective in the normalisation of QT interval and restoration of the QT interval/heart rate relationship and ventricular effective refractory periods. Furthermore, it rendered ventricular tachycardias/ventricular fibrillation non-inducible. Quinidine may serve as either an adjunct to ICD therapy in the treatment of paroxysmal episodes of atrial fibrillation and recurrent ventricular tachyarrhythmias or as an alternative in young patients. However, these drug effects have only been shown for patients with mutations in HERG and could vary in patients carrying different mutations leading to a short QT syndrome. The limit for a pathological rate-corrected QT interval is to date below 320 ms. However, it is unclear and remains to be answered in the future whether borderline shortened QT intervals, bradycardia-associated shortened QT intervals, or, finally, fluctuating QT intervals are of clinical significance.

	Notes

 
Time for primary review 18 days

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Top Abstract 1. Introduction 2. Patients 3. Clinical presentation and... 4. Atrial fibrillation and... 5. ECG characteristics 6. Invasive electrophysiological... 7. Genetics and cellular... 8. Arrhythmogenic substrate 9. Therapy 10. Summary References

 

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