Charles Antzelevitch PhD, FACC,
FAHA*, Johnson Francis, MD, DM¶
*Executive Director and Director
of Research, Gordon K. Moe Scholar, Professor of Pharmacology, Masonic
Medical Research Laboratory
¶Associate
Professor of Cardiology, Medical College Calicut, Kerala, India
Address for correspondence: Charles Antzelevitch, PhD, FACC, FAHA,
Executive Director and Director of Research, Gordon K. Moe Scholar,
Professor of Pharmacology, Masonic Medical Research Laboratory, 2150
Bleecker Street, Utica, NY 13501-1787, Email:
ca@mmrl.edu
Long
QT intervals in the ECG have long been associated with sudden cardiac
death. The congenital long QT syndrome was first described in
individuals with structurally normal hearts in 1957.
1 Little was known about the
significance of a short QT interval. In 1993, after analyzing 6693
consecutive Holter recordings Algra et al concluded that
an increased risk of sudden death was present not only in patients with
long
QT interval, but also in patients with short QT interval (<400 ms).
2 Because this was a retrospective
analysis, further evaluation of the data was not possible.
It was not
until 2000 that a short-QT syndrome (SQTS) was proposed as a new
inherited clinical syndrome by Gussak et al.
3
The initial report was of two siblings and their mother all of whom
displayed persistently short QT interval. The youngest was a 17 year
old female presenting with several episodes of paroxysmal atrial
fibrillation requiring electrical cardioversion.
3
Her QT interval measured 280 msec at a heart rate of 69. Her 21
year old brother displayed a QT interval of 272 msec at a heart rate of
58, whereas the 51 year old mother showed a QT of 260 msec at a heart
rate of 74. The authors also noted similar ECG findings in
another unrelated 37 year old patient associated with sudden cardiac
death.
A review on
the subject including a discussion of proposed mechanisms appeared in
2002.
4 The review
highlighted the lack of rate-dependence
of QT interval in cases in which QT abbreviation was constant and the
negative
correlation of QT with RR in cases in which an abnormally short QT was
evident
only at bradycardic rates. Among the principal gene candidates
proposed
to underlie these syndromes were gain of function mutations of I
Kr,
I
Ks, I
K-ACh and I
K-ATP4
(
Figure 1).
I
K-ACh gain of function or other means by which the
influence
of the parasympathetic nervous system could be exaggerated was
considered
as the most likely mechanisms to explain the deceleration-dependent
variant
of the short QT syndrome.
Figure 1. Schematic diagram
illustrating cellular changes attending the abbreviation of the Short
QT Syndrome secondary to an increase in net outward repolarizing
current. Epi=epicardium; ECG=electrocardiogram.
The familial
nature of this sudden death syndrome was confirmed by Gaita et al in
2003.
5 They reported a study
of six patients from two different families, with syncope,
palpitations, resuscitated cardiac arrest and a positive family history
for sudden cardiac death. The QT intervals never exceeded 280 msec or a
QTc 300 msec. There was no evidence of structural heart disease in any
family member. Electrophysiological evaluation yielded short atrial and
ventricular refractory periods in all four patients who underwent
testing. Three of them were also found to have increased vulnerability
to ventricular fibrillation. Four patients received an automatic
defibrillator (ICD).
5
Factors that
abbreviate the QT interval, including tachycardia, hyperthermia,
hypercalcemia and digoxin should naturally be excluded before arriving
at a diagnosis
of congenital short QT syndrome. The mechanism of arrhythmogenesis in
some
cases of digitalis toxicity could be similar to those in congenital
short
QT syndrome.
6
The first gene
responsible for the short QT syndrome was reported by Brugada et al in
January of 2004.
7
A candidate gene approach was used to screen for a causative mutation
in the two families previously reported by Gaita et al.
5 Using direct sequencing
techniques, two
different missense mutations were uncovered in the two families,
resulting in the same amino acid substitution in HERG (KCNH2), the gene
encoding for the rapidly activating delayed rectifier channel, I
Kr.
7 The substitution of lysine for
asparagines at position 588 of KCNH2, was found to cause a loss of the
normal rectification of the current at plateau voltages, thus resulting
in a large increase of IKr during the action potential plateau, leading
to marked abbreviation of the action potential. The short QT syndrome
is the first disease to be linked to a gain of function of I
Kr.
A third short QT family was not associated with a mutation in KCNH2,
pointing to genetic heterogeneity of the disease. Interestingly, the
N588K mutant channel proved to be insensitive to I
Kr
blockers such as d-sotalol both in the clinic and in heterologous
expression systems. Quinidine, by virtue of its greater affinity
for the open state of the channel, its additional I
Ks
blocking actions and anticholinergic activity was found to be more
effective in reducing the repolarizing forces of the ventricle and
prolonging the action potential.
8
It is
noteworthy that substitution of aspartic acid for asparagine in the
same position of HERG (N588D) has been linked to the LQT2 form of the
long QT syndrome secondary to a loss of function of I
Kr.
9 This substitution leads to
replacement of a neutral amino acid with a negatively charged one,
whereas the N588K mutation responsible for short QT, secondary to gain
of function of I
Kr, replaces a neutral amino acid with a
positively charged one.
Bellocq et
al recently linked a second gene to the syndrome. A missense
mutation in KCNQ1 (KvLQT1) giving rise to a gain of function in I
Ks,
the slowly activating delayed rectifier, was identified in a 70 year
old male presenting with idiopathic ventricular fibrillation and short
QT intervals in the ECG. Functional studies of the V307L KCNQ1 mutant
revealed a -20-mV shift of the half-activation potential and an
acceleration of the activation kinetics leading to an increase in I
Ks.
10
A distinctive
electrocardiographic feature of the short QT syndrome is the appearance
of tall peaked T waves, similar to those encountered with
hyperkalemia. ICD implantation is currently the treatment of
choice for symptomatic patients with short QT syndrome and a family
history of sudden cardiac death. Despite normal sensing behavior during
device testing, inappropriate shocks due
to T wave over sensing has been reported. This is due to the detection
of
short-coupled and prominent T waves.
11
The problem was corrected by reprogramming to lower sensitivity and
decay
delay. More specific diagnostic criteria will need to be developed as
additional information about this syndrome becomes available in the
coming months and years.
References
1. Jervell A,
Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with
prolongation of the QT interval and sudden death. Am Heart J.
1957;54:59-68.
2. Algra A, Tijssen JGP, Roelandt
JRTC, Pool J, Lubsen J. QT interval variables from 24-Hour
electrocardiography and the 2- Year risk of sudden death. Br Heart J.
1993;70:43-48.
3. Gussak I, Brugada P, Brugada
J, Wright RS, Kopecky SL, Chaitman BR, Bjerregaard P. Idiopathic short
QT interval: a new clinical syndrome? Cardiology. 2000;94:99-102.
4. Gussak
I, Brugada P, Brugada J, Antzelevitch C, Osbakken M, Bjerregaard P. ECG
phenomenon of idiopathic and paradoxical short QT intervals. Cardiac
Electrophysiology Review. 2002;6:49-53.
5. Gaita F, Giustetto C, Bianchi F,
Wolpert C, Schimpf R, Riccardi R, Grossi S, Richiardi E, Borggrefe M.
Short QT Syndrome: a familial cause of sudden death. Circulation.
2003;108:965-970.
6. Cheng TO. Digitalis
administration: an underappreciated but common cause of short QT
interval. Circulation. 2004;109:e152.
7. Brugada R, Hong K, Dumaine R,
Cordeiro JM, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick
GD, Wolpert C, Burashnikov E, Matsuo K, Wu YS, Guerchicoff A, Bianchi
F, Giustetto C., Schimpf R, Brugada P,
Antzelevitch C. Sudden Death associated with Short QT Syndrome linked
to
Mutations in HERG. Circulation. 2004;109:30-35.
8.
Cordeiro JM, Brugada R, Hong K, Antzelevitch C, and
Dumaine R. Short QT
syndrome mutation in HERG abolishes inactivation. Biophysical Journal
86,
134a. 2004. (Abstract)
9.
Splawski
I, Shen J, Timothy KW, Vincent GM, Lehmann MH, Keating MT. Genomic
structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1.
Genomics. 1998;51:86-97.
10.
Bellocq C, van Ginneken
A, Bezzina CR, Alders M, Escande D, Mannens MM, Baro I, Wilde AAM. A
molecular and pathophysiological substrate for the short QT interval
syndrome. Circulation. 2004;In press.
11. Schimpf R, Wolpert C,
Bianchi F, Giustetto C, Gaita F, Bauersfeld U, Borggrefe M. Congenital
short QT syndrome and implantable cardioverter defibrillator treatment:
inherent risk
for inappropriate shock delivery. J Cardiovasc Electrophysiol.
2003;14:1273-1277.
This article has been cited by other articles:
|
 Home
|
Extramiana F, Antzelevitch C.
Amplified transmural dispersion of repolarization as the
basis for arrhythmogenesis in a canine ventricular-wedge model of
short-QT syndrome.
Circulation. 2004 Dec 14;110(24):3661-6. Epub 2004 Nov
29. [Medline]
|
|
