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The Discovery of Familial Short QT Syndrome
At
Saint Louis University Hospital we have been interested in the short QT
phenomenon for quite some time and prior to the discovery of Short QT
Syndrome observed extreme shortening of the QT interval with slowing of
the heart rate in a 4-year old girl, who died soon after. We published
our findings in an article from 1999 (Gussak I, Liebl N, Nouri S,
Bjerregaard P, Zimmerman F, Chaitman BR. Deceleration-Dependent
Shortening of the QT interval: A New Electrocardiographic Phenomenon?
Clin. Cardiol. 1999:22;124-1126), and raised the concern, that there
might be a relationship between shortening of the QT interval and the
girl’s death.
The first patient with familial short QT
interval
February 16, 1999. a 17 year old, previously healthy, white female,
Shalon Hill, presented with cholelithiasis and
undergoes laparoscopic cholecystectomy at Anderson Hospital, Maryville,
Illinois. At the end of the procedure she
developed atrial fibrillation with fast ventricular response (150-200
beats/min) and acute pulmonary edema. She
underwent successful DC cardioversion and was discharged on digoxin in
normal sinus rhythm. Six weeks later she presented with recurrence of
artial fibrillation and was referred to Dr. Preben Bjerregaard for
further evaluation. He discovered the short interval (225 ms) and
arranged for ECG recording of the patient’s close relatives. At the same
time he initiated prophylactic therapy with propafenone. For six months
she was asymptomatic with no evidence of atrial fibrillation when
propafenone was discontinued. Two months later she was again in atrial
fibrillation and propafenone therapy was re-instituted. For more than
four years she has (took out now) been asymptomatic on propafenone
therapy without any evidence of atrial fibrillation. August 8, 2003
following reports from Italy of sudden cardiac death in several patients
with similar short QT interval, she underwent a programmed electrical
stimulation study with induction of ventricular fibrillation and
received an implantable cardioverter defibrillator. She has so far not
received any shocks.
The first family with short QT interval
When
ECG’s were recovered from her brother, parents and maternal grandfather
it was discovered that her 84 year old grandfather, 51 year old mother
and 21 year old brother also had short QT interval, while her fathers
ECG was normal.
Her
brother is a 21 year old healthy white male with no history of
palpitations, dizziness or syncope. His ECG has a QT interval of 240 ms.
August 13, 2003, he underwent a programmed electrical stimulation study
with induction of ventricular fibrillation followed by implantation of
an implantable cardioverter defibrillator. During follow-up he admited
to occasional palpitations and interrogation of the ICD shows few brief
episodes of atrial fibrillation with fast ventricular response. He has
so far not received any shocks.
Her
mother is a 51 year old healthy white female with a QT interval of 230
ms and a history of 3 episodes of sustained palpitations and two of them
documented as atrial fibrillation. On propafenone since April, 2003 she
has been asymptomatic. She underwent programmed electrical stimulation
study September 29, 2003 with induction of both atrial and ventricular
fibrillation and received an implantable cardioverter defibrillator. She
has so far not received any shocks.
Her
grandfather is an 84 year old white male (born in Italy) with chronic
atrial fibrillation in the setting of coronary artery disease and
arterial hypertension. Following an embolic stroke he dies. ECG’s taken
on several occasions all show short QT interval (240 ms).
BBC article on September 28, 2003 describing Short QT discovery
The first observation of sudden cardiac
death in a patient with short QT interval
During
a conversation with Joseph Brugada, Barcelona, Spain, he recalled a 37
year old female referred to him by Dr Augustine Ardiaca for further
evaluation of syncopal episodes. Before he got a chance to see her she
died suddenly. An ECG taken shortly before she died in 1996 showed a QT
interval of 266 ms at a heart rate of 52 beats/min.
The first publication suggesting a new
clinical syndrome
When
the clinical experience from these first patients with short QT interval
was submitted for publication to Circulation one of the reviewers
strongly suspected that the short QT interval was caused by speed-error
during the ECG recording and therefore unlikely a real phenomenon.
The
paper was turned down despite our attempt at convincing the editor, that
the ECGs were real, and eventually published in Cardiology in 2000 (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). We suggested that we were faced with a new cardiac
syndrome with an increased risk of AF and possibly sudden cardiac death.
The first description of a family with short
QT interval and sudden cardiac death
At the
American College of Cardiology meeting in Chicago, March 2003 a paper
from Ospedale Mauriziano Umberto I, Torino, Italy, describing a family
with history of sudden death and short QT interval in their ECG’s was
presented (Gaita F, Giustetto C, Bianchi F, Riccardi R, Grossi S,
Richiardi E. Short QT: A New Electrocardiographic Pattern Related to
Familial Sudden Death. JACC 2003;4(Supplement A): 818-3 (Abstract).It
described 16 members from 5 generations of a family where 6 had died
suddenly at the ages of 3 months, 6, 39, 39 and 49 years respectively
and one unknown. Three family members had ECG’s with short QT interval,
including one of the sudden cardiac deaths victims. August of that year
the same family was presented in more detail in Circulation along with
23 members from 5 generations of a family from University Hospital
Mannheim, University of Heidelberg, Mannheim, Germany, where 3 had died
suddenly at the ages of 26, 45 and 62 years of age and 4 had short QT
interval including one who died suddenly (Gaita F, Giustetto C, Bianchi
F, Wolpert C, Schrimpf R, Riccardi R, Grossi S, Richiardi E, Borggrefe
M. Short QT Syndrome. A Familial Cause of Sudden Death. Circulation
2003;108:965-970). During electrophysiological studies, short atrial and
ventricular refractory periods were documented in all tested, and
increased ventricular vulnerability to fibrillation in 3 of 4 patients.
The first description of a genetic mutation
in patients with Short QT Syndrome
January 2004 the first report of an association between Short QT
Syndrome and mutations in KCNH2 or the HERG gene appeared from the
Masonic Medical Research Laboratory in Utica, New York (Brugada R, Hong
K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J,
Pollevick GD, Wolpert C, Burachnikov E, Matsuo K, Wu YS, Guerchicoff A,
Bianchi F, Giustetto C, Schrimpf R, Brugada P, Antzelevich C. Sudden
Death Associated With Short-QT Syndrome Linked to Mutations in HERG.
Circulation 2004,109:30-35). Three families including the two from the
August, 2003 publication were studied and in two of them, two different
missense mutations resulting in the same amino acid change (N588K) in
the S5-P loop region of the cardiac IKr channel HERG (KCNH2) were
identified. The net effect of such mutations is to increase the
repolarizing currents active during the early phases of the action
potential, leading to abbreviation of the action potential and thus to
abbreviation of the QT interval. The authors speculate that the
heterogeneous distribution of ion currents within the heart including
short action potentials in short QT syndrome patients, may lead to
accentuation of dispersion of repolarization and provide the substrate
for the development of both atrial and ventricular arrhythmias.
The first experience with ICD implantation
in patients with Short QT Syndrome
An
ICD was implanted prophylactically in 5 members of the two European
families with Short QT Syndrome, but shortly after implantation 3 of the
patients experienced inappropriate shock therapy for T wave oversensing
(Schrimpf 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).It was considered due to
detection of short-coupled and prominent T-waves in these patients and
eliminated by reprogramming sensing levels and decay delays in the ICDs.
The first evaluation of pharmacological
treatment of short QT syndrome
The
efficacy of flecainide, sotalol, ibutilide and hydroquinidine at
prolonging the QT interval into the normal range and preventing
ventricular arrhythmias was recently evaluated in 6 previously published
patients with short QT syndrome (Gaita F, Giustetto C, Bianchi F,
Schrimpf R, Haissaguerre M, Calo L, Brugada R, Antzelevitch C, Borggrefe
M, Wolpert C. Short QT Syndrome: Pharmacological Treatment. JACC
2004;43:1494-1499). It showed that class IC and III antiarrhythmic drugs
did not produce any significant QT interval prolongation, whereas
hydroquinidine increased the QT interval from 263 +/- 12 msec to 362
+/-25 msec. Ventricular programmed stimulation which was only done
during hydroquinidine therapy showed prolongation of ventricular
refractory period to >/= 200 msec, and ventricular fibrillation was no
longer inducible.
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