| The hereditary Long QT Syndrome (LQTS) is a familial disorder
in which most affected family members have delayed ventricular repolarization
manifest on the ECG as QT prolongation.
This genetic
channelopathy
has variable penetrance with affected individuals
having an increased
propensity to syncope,
polymorphous ventricular tachycardia and sudden arrhythmic death.
Presently, LQTS mutations have been identified in three cardiac
potassium ion-channel genes (KCNQ1 [LQT1],
HERG [LQT2], KCNJ2 [Kir2.1,
LQT7]), two potassium ion-channelregulators (KCNE1 [mink, LQT5],
KCNE2 [MIRP1, LQT6]),
one cardiac sodium channel gene (SCN5A [LQT3]),
and most recently, a gene possibly involved in intracellular calcium
signaling (ankyrin-B gene [LQT4]). Mutations in the seven LQT genes
account for an estimated 60% of the known families affected with
LQTS, and
additional mutant LQT genes are likely to exist. In addition,
there may be polymorphic variants in the seven ion-channel genes
and in other genes that modify the expression/penetrance of LQTS.
The most common form of LQTS (Romano-Ward syndrome, RWS) is a heterogeneous,
autosomal dominant genetic disease caused by muta
tions of ion channel
genes involving the cellular membranes of the cardiac myocytes.
This channelopathy is associated with delayed ventricular repolarization
and is clinically manifest by syncope and sudden death from ventricular
arrhythmias, notably torsade de pointes (TdP). LQTS is identified
by abnormal QT interval prolongation on the ECG. The QT prolongation
may arise from either a decrease in repolarizing cardiac membrane
currents or an increase in depolarizing cardiac currents. Most commonly,
QT prolongation is produced by delayed repolarization due to reductions
in either the rapidly 
or slowly activating repolarizing cardiac
potassium (K+) currents, IKr or IKs. It less commonly results from
prolonged depolarization due to a small persistent inward “leak”
in the cardiac sodium (Na+) current INa. A rare form of LQTS (Jervell
and Lange-Nielsen syndrome, JLNS) is autosomal recessive and is
characterized by congenital bilateral neural deafness, more marked
QT prolongation, and a high risk for recurrent syncope and sudden
death.
Clinical criteria have been developed to determine the probability
of having LQT, and genotype screening of suspect LQTS individuals
and of family members from known LQTS families has progressively
increased the number of subjects with genetically confirmed LQTS.
Current prophylactic and preventive therapy for LQTS to reduce the
incidence of syncope and sudden death has involved beta-blockers,
left cervico-thoracic sympathetic ganglionectomy, pacemakers, implanted
defibrillators, and gene/mutation-specific pharmacotherapy.
During the past several years, a number of approved and marketed
drugs, both cardiovascular and non-cardiovascular agents, have been
associated with QT prolongation, TdP, and sudden cardiac death.
Drugs that are known to affect the QT interval include quinidine,
terfenadine, erythromycin, cisapride, and mellaril, to name but
a few. Almost all the non-cardiovascular drugs associated with QT
prolongation adversely affect the HERG channel. The association
between the magnitude of drug-induced QT prolongation and the risk
of malignant ventricular arrhythmias is complex. Patients with the
inherited form of LQTS are particularly vulnerable to drug-induced
QT prolongation problems.
This First Virtual (Internet) Symposium on LQTS will focus on the
clinical features of both the hereditary and acquired forms of long
QT syndrome, with particular emphasis on the accurate diagnosis
of the condition and the use of appropriate therapies to prevent
syncope and sudden death. |
