Short QT Syndrome: How Frequent Is It and What Are Its Peculiar Features?
F. GAITA
During the last 20 or 30 years the literature on long QT has constantly increased, while short QT has been substantially ignored. Algra et al. [1], however, reported in 1992 that in a group of 6693 patients who underwent 24-h Holter monitoring a mean QTc below 400 ms was associated with a two-fold risk of sudden death compared to an intermediate QTc value (400–440 ms), and with a similar risk to a mean QTc above 440 ms.
Only recently the association of sudden death [2] and atrial fibrillation [3] with short QT interval has been recognised and short QT syndrome iden- tified as a genetic disorder [4, 5]. In 2003 our group established the relation between short QT and sudden death with the description of two families having a short QT interval at baseline ECG and several cases of sudden death in the family history [2]. Factors that shorten QT interval include an increase in heart rate, hyperthermia, increased calcium or potassium plasma levels, acidosis, and alterations of the autonomic tone. Secondary causes of tran- sient QT interval reduction were excluded in these patients. This alteration of the repolarisation could be documented in all available ECGs recorded at different time points and ages, with a QT interval always less than 300 ms, without significant dynamic changes during heart rate variations or on exer- tion. A QT interval constantly below 300 ms was proposed as the definition of short QT.
Patients with short QT syndrome present with a wide spectrum of clini- cal manifestations, ranging from mild symptoms, such as palpitations and dizziness, to syncope and sudden death. Sudden death may occur at any time during the life span, sometimes in children in the first months of life. Sudden
Department of Cardiology, Cardinal Massaia Hospital, Asti, Italy
death is often the first clinical presentation. Syncope and palpitations with documentation of atrial fibrillation even at a young age and of ventricular extrasystoles are other symptoms related to short QT syndrome. In the observed patients non-invasive and invasive evaluation confirmed the pres- ence of structurally normal hearts, and autopsies did not reveal any cardiac disease.
To understand how a short QT interval may be related to life-threatening arrhythmias, we have to remember that QT interval is the electrocardio- graphic expression of ventricular repolarisation, and there is a constant rela- tionship between the ventricular effective refractory period (ERP) and the QT interval. On electrophysiological study these patients show very short atrial and ventricular ERPs. The duration of the refractory periods of the myocardium is known to be an important parameter for the vulnerability of the heart to fibrillation at both atrial and ventricular levels.
Sudden death in the presence of short QT interval in the described fami- lies occurred in several generations, in both male and female subjects, sug- gesting an autosomal dominant mode of inheritance. Ventricular repolarisa- tion is determined by the inward sodium and calcium currents and by the outward potassium currents. The molecular substrate of short QT interval and related arrhythmic events should thus be either a factor that reduces sodium or calcium inward currents or a factor that increases potassium out- ward currents. Two different missense mutations in HERG (KCNH2), the gene encoding for the rapidly activating delayed rectifier potassium channel, IKr, causing a gain of function in the channel were first identified [4], and later this variety of short QT syndrome was called SQTS 1. Subsequently, congenital short QT was also linked to a mutation in KCNQ1 (KvLQT1), caus- ing a gain of function in IKs, the slowly activating delayed rectifier potassium current [5], and this was designated SQTS 2. A mutation has been recently identified in a third gene, KCNJ2 (Kir2.1) encoding for another potassium channel, IK1, causing a gain in function of the channel (SQTS 3) [6].
However, the prevalence of these mutations does not seem high, since only in two of the six families we have so far collected was a mutation in HERG found, and none showed other known mutations. It is reasonable to suppose that mutations involving other genes are present, similarly to what happens in long QT syndrome.
Analysing the data from 23 patients with a personal and/or familial histo- ry of sudden death or aborted sudden death, QT interval values up to 320 ms and QTc up to 340 ms were noted [7]. No statistically significant relationship between QT and QTc interval duration and history of sudden death was found; therefore so far it does not seem possible to establish a value of QT interval that would identify patients with short QT who are at higher risk of sudden death.
324 F. Gaita
Short QT interval is easier to recognise at low heart rates; with increasing heart rates it tends to be closer to the normal values. At higher rates, howev- er, QT values are still always below the normal values, and this makes the diagnosis possible even in infants, who typically have high heart rates. This is particularly important considering that sudden death frequently occurs in the first months of life.
Concerning the mechanism of arrhythmogenesis in short QT syndrome, it is likely that the short atrial and ventricular refractory periods observed in these patients represent the substrate of atrial and ventricular arrhythmias;
in fact it is well known that the shorter the refractory periods, the shorter the wavelengths are and more likely reentry is to occur.
Because of the high incidence of sudden cardiac death and the absence of known pharmacological therapy, implantation of a cardioverter–defibrillator (ICD) is currently the treatment of first choice [2, 8]. Quinidine prolongs the QT interval and the ventricular ERP and prevents induction of ventricular arrhythmias [9, 10]; however, long-term follow-up of patients with ICD who also receive this drug is needed to clarify whether it may be an alternative to ICD implantation.
In conclusion, short QT syndrome is an arrhythmogenic genetic disorder with a high incidence of sudden death. Short QT syndrome should always be considered in the presence of a family history of sudden death, but also in patients with idiopathic atrial fibrillation and in patients with syncope and a structurally normal heart.
325 Short QT Syndrome: How Frequent Is It and What Are Its Peculiar Features?
Fig. 1.Electrocardiogram of a patient with short QT syndrome. Heart rate 95 bpm, QT 220 ms, QTc 277 ms
References
1. Algra A, Tijssen JGP, Roelandt JRTC et al (1993) QT interval variables from 24 hour electrocardiography and the two year risk of sudden death. Br Heart J 70:43–48 2. Gaita F, Giustetto C, Bianchi F et al (2003) Short QT syndrome. A familial cause of
sudden death. Circulation 108:965–970
3. Gussak I, Brugada P, Brugada J et al (2000) Idiopathic short QT interval: a new cli- nical syndrome? Cardiology 94:99–102
4. Brugada P, Hong K, Dumaine R et al (2004) Sudden death associated with short QT syndrome linked to mutations in HERG. Circulation 109:30–35
5. Bellocq C, van Ginneken A, Bezzina C (2004) Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 109:2394–2397
6. Priori SG, Pandit SV, Rivolta I et al (2005) A novel form of short QT syndrome (SQTS3) is caused by a mutation in the KCNJ2 gene. Circ Res 96:800–807
7. Giustetto C, Wolpert C, Anttonen O et al (2005) Clinical presentation of the patients with short QT syndrome. Heart Rhythm 2:S61
8. Schimpf R, Wolpert C, Bianchi F et al (2003) Congenital short QT syndrome and implantable cardioverter defibrillator. Inherent risk for inappropriate shock deli- very. J Cardiovasc Electrophysiol 14:1273–1277
9. Gaita F, Giustetto C, Bianchi F et al (2004) Short QT syndrome: pharmacological treatment. J Am Coll Cardiol 43:1294–1299
10. Wolpert C, Schimpf R, Giustetto C et al (2005) Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG. J Cardiovasc Electrophysiol 16:1–5
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