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Long QT syndrome type 2

The long QT syndrome (LQTS) is a heart disease in which there is an abnormally long delay between the electrical excitation (or depolarization) and relaxation (repolarization) of the ventricles of the heart. It is associated with syncope (loss of consciousness) and with sudden death due to ventricular arrhythmias. Arrhythmias in individuals with LQTS are often associated with exercise or excitement. The cause of sudden cardiac death in individuals with LQTS is ventricular fibrillation. more...

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Individuals with LQTS have a prolongation of the QT interval on the ECG. The Q point on the ECG corresponds to the beginning of ventricular depolarization while the T point corresponds to the beginning of ventricular repolarization. The QT interval is measured from the Q point to the end of the T wave. While many individuals with LQTS have persistent prolongation of the QT interval, some individuals do not always show the QT prolongation; in these individuals, the QT interval may prolong with the administration of certain medications.


The two most common types of LQTS are genetic and drug-induced. Genetic LQTS can arise from mutation to one of several genes. These mutations tend to prolong the duration of the ventricular action potential (APD), thus lengthening the QT interval. LQTS can be inherited in an autosomal dominant or an autosomal recessive fashion. The autosomal recessive forms of LQTS tend to have a more severe phenotype, with some variants having associated syndactyly or congenital neural deafness. A number of specific genes loci have been identified that are associated with LQTS. Following is a list of the most common mutations:

  • LQT1 - mutations to the alpha subunit of the slow delayed rectifier potassium channel (KvLQT1 or KCNQ1). The current through the heteromeric channel (KvLQT1+minK) is known as IKs. This mutation is thought to cause LQT by reducing the amount of repolarizing action potential current that prolongs action potential duration (APD). These mutations tend to be the most common yet least severe.
  • LQT2 - mutations to the alpha subunit of the fast delayed rectifier potassium channel (HERG + miRP). Current through this channel is known as IKr. This phenotype is also probably caused by a reduction in repolarizing current.
  • LQT3 - mutations to the alpha subunit of the sodium channel (SCN5A). Current through is channel is commonly referred to as INa. Depolarizing current through the channel late in the action potential is thought to prolong APD. The late current is due to failure of the channel to remain inactivated and hence enter a bursting mode in which significant current can enter when it should not. These mutations are more lethal but less common.
  • LQT4 - mutations in an anchor protein Ankyrin B which anchors the ion channels in the cell. Very rare.
  • LQT5 - mutations in the beta subunit MinK which coassembles with KvLQT1.
  • LQT6 - mutations in the beta subunit MiRP1 which coassembles with HERG.
  • LQT7 - mutations in the potassium channel KCNJ2 which leads to Andersen-Tawil syndrome.
  • LQT8 - mutations in the calcium channel Cav1.2 encoded by the gene CACNA1c leading to Timothy's syndrome

Other mutations affect the beta subunits ion channels. For example LQT6 affects minK (aka KCNE1) which is the beta subunit that coassembles with KCNQ1 to form IKs channels.


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Ca(2+) entry-dependent inactivation of L-type Ca current: A novel formulation for cardiac action potential models
From Biophysical Journal, 1/1/03 by Hirano, Yuji

ABSTRACT Cardiac L-type Ca current (I^sub Ca,L^) is controlled not only by voltage but also by Ca^sup 2+^ -dependent mechanisms. Precise implementation of I^sub Ca,L^ in cardiac action potential models therefore requires thorough understanding of intracellular Ca^sup 2+^ dynamics, which is not yet available. Here, we present a novel formulation of I^sub Ca,L^ for action potential models that does not explicitly require the knowledge of local intracellular Ca^sup 2+^ concentration ([Ca^sup 2+^]^sub i^). In this model, whereas I^sub Ca,L^ is obtained as the product of voltage-dependent gating parameters (d and f), Ca^sup 2+^-dependent inactivation parameters (f^sub Ca^: f^sub Ca-entry^ and f^sub Ca-SR^), and Goldman-Hodgkin-Katz current equation as in previous studies, f^sub Ca^ is not a instantaneous function of [Ca^sup 2+^]^sub i^ but is determined by two terms: onset of inactivation proportional to the influx of Ca^sup 2+^ and time-dependent recovery (dissociation). We evaluated the new I^sub Ca,L^ subsystem in the framework of the standard cardiac action potential model. The new formulation produced a similar temporal profile of I^sub Ca,L^ as the standard, but with different gating mechanisms. Ca^sup 2+^ -dependent inactivation gradually proceeded throughout the plateau phase, replacing the voltage-dependent inactivation parameter in the LRd model. In typical computations, f declined to ~0.7 and f^sub Ca-entry^ to ~0.1, whereas deactivation caused fading of I^sub Ca,L^ during final repolarization. These results support experimental findings that Ca^sup 2+^ entering through I^sub Ca,L^ is essential for inactivation. After responses to standard voltage-clamp protocols were examined, the new model was applied to analyze the behavior of I^sub Ca,L^ when action potential was prolonged by several maneuvers. Our study provides a basis for theoretical analysis of I^sub Ca,L^ during action potentials, including the cases encountered in long QT syndromes.


Voltage-dependent L-type Ca channels (I^sub Ca,L^) play vital roles for cardiac functions, including pacemaker activity in nodal cells, trigger for Ca^sup 2+^ -induced Ca^sup 2+^ release (CICR), and control of cardiac contractility (Bers and Perez-Reyes, 1999). I^sub Ca,L^ also contributes to maintenance of the plateau or elongated depolarization of cardiac action potentials. Because I^sub Ca,L^ is important to our understanding of cardiac functions in physiological as well as pathological conditions, mechanisms of its modulation have been studied extensively (McDonald et al., 1994).

Addendum: After the original manuscript was submitted, a set of papers appeared describing how beta-adrenergic stimulation modulates Ca^sup 2+^ - and voltage-dependent inactivation, including their relative contributions (Findlay, 2002a,b). Their voltage-inactivation curve was similar to that used in this study, when myocytes were under beta-adrenergic stimulation.


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Yuji Hirano and Masayasu Hiraoka

Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan

Submitted April 11, 2002, and accepted for publication August 29, 2002.

Address reprint requests to Yuji Hirano, MD, PhD, Dept. of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Tel.: 81-3-5803-5830; Fax: 81-3-5684-6295; E-mail: hirano.card@mri.tmd.

Copyright Biophysical Society Jan 2003
Provided by ProQuest Information and Learning Company. All rights Reserved

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