Short QT: The Novel Gaita Syndrome? F. G

Short QT: The Novel Gaita Syndrome?

F. G

, C. G

, F. D

M

, R. S

, C. W

, M. B

Ventricular fibrillation is the main cause of sudden death. It may occur in subjects with known heart disease, but also in subjects with an apparently normal heart. In the last 50 years inherited heart conditions have been described which may cause sudden death in the absence of heart disease.

They share the common feature of being caused by genes encoding defective ion channel proteins. In most of the cases the diagnosis may be made from the 12-lead electrocardiogram. The most studied is long QT syndrome, described for the first time by Jervell and Lange-Nielsen [1] at the end of the 1950s and characterised by a long QTc interval at 12-lead ECG. During the last few decades the literature on long QT has constantly increased (even if in the first 10 years only 25 cases were described), while short QT has been substantially ignored. Algra et al. [2], however, in 1993 reported that in a group of 6693 patients who underwent 24-h Holter monitoring, a mean QTc

< 400 ms was related to a two-fold risk of sudden death compared to an intermediate QTc value (400–440 ms) and similarly to patients with a mean QTc > 440 ms.

Only recently has the association between short QT interval and sudden death [3] on the one hand and atrial fibrillation [4] and short QT interval on the other been recognised and short QT syndrome identified as a genetic disorder [5, 6]. 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 ECG and several cases of sudden death in the family history [3].

Factors that shorten the QT interval include an increase in heart rate, hyper- thermia, increased calcium or potassium plasma levels, acidosis, and alter- ations of the autonomic tone. Secondary causes of transient QT interval

1

Divisione di Cardiologia, Ospedale Civile, Asti, Italy;

1st Department of Medicine,

University Hospital Mannheim, University of Heidelberg, Germany

reduction were ruled out in these patients. This alteration of the repolarisa- tion was documented in all available ECGs recorded at different time points and ages, with a QT interval always less than 300 ms (Fig. 1), without signif- icant dynamic changes during heart rate variations or on exertion. A QT interval constantly below 300 ms was proposed to define 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 life, sometimes in children in the first months of life. Sudden death is often the first clinical presentation. Syncope and palpitations with documen- tation of atrial fibrillation even at a young age and of ventricular extrasys- toles are other symptoms related to short QT syndrome. In the observed patients invasive and non-invasive evaluation confirmed 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 consider that QT interval is the electrocardiographic expression of ventricular repolarisation, and there is a constant relationship between the ventricular effective refractory period (ERP) and the QT inter- val. At 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.

252 F. Gaita et al.

Fig. 1. Twelve-lead ECG of a 31-year-old patient who had experienced palpitations and

presyncope. Sinus rhythm; heart rate 96 bpm; normal atrioventricular conduction; left

axis deviation; narrow, tall, and peaked T waves in V2–V3; QT interval 220 ms; QTc 270

ms

Sudden death in the presence of short QT interval occurred in several generations in the described families, in both male and female subjects, sug- gesting an autosomal dominant mode of inheritance. Ventricular repolarisa- tion is determined by the properties and the equilibrium of the inward sodi- um and calcium currents and of the outward potassium currents. The molec- ular 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 outward currents. Two different missense mutations were first identified in HERG (KCNH2), the gene encoding for the rapidly activating delayed rectifier potassium channel, I

, causing a gain of function in the channel [5]. Subsequently, congenital short QT was linked also to a mutation in KCNQ1 (KvLQT1), causing a gain of function in I

, the slowly activating delayed rectifier potassium current [6].

Because of the high incidence of sudden cardiac death and the absence of

known drug therapy, placement of an implantable cardioverter–defibrillator

(ICD) is presently the first-choice therapy [2, 7]. ICD implantation, however,

is not feasible in every patient. For this reason we administered various anti-

arrhythmic drugs to patients with short QT syndrome to evaluate whether

they could prolong the QT interval into the normal range and thus potential-

ly prevent symptoms and arrhythmia recurrences [8]. As the mutations

found in our first families increase the activity of I

, leading to heteroge-

neous abbreviation of action potential duration and refractoriness, the first

drugs we administered were the class III anti-arrhythmic agents sotalol and

ibutilide, which are selective I

blockers. However, these drugs did not pro-

long the QT interval. The mutation must cause the loss of some of the physi-

ological regulatory mechanisms, and I

become no longer sensitive to drugs

that normally have a specific action on it. Quinidine, on the other hand, pro-

duced a marked prolongation of the QT interval, which then entered the nor-

mal range, and of ventricular ERPs, preventing induction of ventricular fib-

rillation. Furthermore, quinidine treatment produced the appearance of an

obvious ST segment and of broader T waves. The effect of quinidine may be

explained by the fact that this drug has a widespread effect of blocking the

potassium currents; besides acting on I

, it also blocks the slow component

of the delayed rectifier potassium current (I

), the inward rectifier (I

), the

ATP-sensitive potassium channel (I

), and the transient outward potassi-

um current (I

). This finding is particularly important because these

patients are at risk of sudden death from birth, and ICD implant is not feasi-

ble in very young children. Moreover, quinidine therapy could be proposed

to patients who refuse an ICD or to those who are getting frequent shocks

from the device to limit ICD intervention, and in the prevention of atrial fib-

rillation episodes. Long-term follow-up of patients with ICD who receive

253

Short QT: The Novel Gaita Syndrome?

quinidine, however, is needed to clarify whether this drug may be an alterna- tive to ICD implantation.

In conclusion, short QT syndrome is an autosomal dominant genetic dis- order with a high incidence of sudden death. Short QT should always be con- sidered 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.

References

1. Jervell A, Lange-Nielsen F (1957) Congenital deaf-mutism, functional heart disease with prolongation of the QT interval and sudden death. Am Heart J 54:59–68 2. 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 3. Gaita F, Giustetto C, Bianchi F et al (2003) Short QT syndrome. A familial cause of

sudden death. Circulation 108:965–970

4. Gussak I, Brugada P, Brugada J et al (2000) Idiopathic short QT interval: a new cli- nical syndrome? Cardiology 94:99–102

5. 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

6. Bellocq C, van Ginneken A, Bezzina C et al (2004) Mutation in the KCNQ1 gene lea- ding to the short QT-interval syndrome. Circulation 109:2394–2397

7. 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 14:1273–11277

8. Gaita F, Giustetto C, Bianchi F et al (2004) Short QT syndrome: pharmacological treatment. J Am Coll Cardiol 43:1294–1299

254 F. Gaita et al.