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Topical Review |
1 Department of Cell Biology and Physiology
2 Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
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Abstract |
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(Received 5 August 2006;
accepted after revision 3 October 2006;
first published online 5 October 2006)
Corresponding author B. London: Cardiovascular Institute, University of Pittsburgh Medical Center, Scaife S-572, 200 Lothrop Street, Pittsburgh, PA 15213, USA. Email: londonb{at}upmc.edu
Human long QT syndrome
Congenital long QT syndrome is a rare inherited condition characterized by syncope, unexplained seizures, and sudden death (Schwartz & Priori, 2004). The autosomal dominant form was first described in the early 1960s, while the autosomal recessive form associated with congenital deafness was described in 1957 (Jervell & Lange-Nielsen, 1957; Ward, 1964; Romano, 1965). The electrocardiographic manifestations of the disease include a prolonged QT interval and an abnormal T-wave morphology on the surface ECG (Fig. 1A), although the degree of QT interval prolongation varies considerably and some affected individuals have QT intervals in the normal range. Long QT syndrome is one of the causes of sudden cardiac death in otherwise healthy adolescents and young adults, along with the other inherited arrhythmia syndromes (arrhythmopathies such as Brugada syndrome, catecholaminergic ventricular tachycardia), arrhythmogenic right ventricular dysplasia, hypertrophic cardiomyopathy, myocarditis and cocaine use. Syncope and sudden death in long QT syndrome usually result from Torsade de Pointes, a form of polymorphic ventricular tachycardia in which the electrical axis rotates and the amplitude of the QRS complex in any given lead oscillates in a sinusoidal pattern (Fig. 1B). This potentially lethal rhythm is triggered by exercise, emotional disturbances and sleep, and can degenerate into ventricular fibrillation. The primary treatment for most forms of long QT syndrome is 
-adrenergic blockade, although some patients are refractory. Internal cardioverter-defibrillators (ICDs), subcutaneous devices that continually monitor heart rate and can deliver an electric shock when a potentially life-threatening arrhythmia is identified, are recommended for patients not responsive to medical therapy or at high risk from sudden death. The precise risk of sudden death in most patients is difficult to quantify, however, and the use of ICDs in patients with long QT syndrome varies widely between centres.
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Mutations that interfere with inactivation of the cardiac Na+ channel (SCN5A) and prolong the inward Na+ current (INa) were identified in long QT syndrome families linked to the LQT3 locus. The late inward Na+ current causes action potential prolongation (Bennett et al. 1995). Mutations in the ankyrin-B gene have been shown to cause the LQT4 variant of long QT syndrome (Mohler et al. 2003). Ankyrin-B interacts with a number of cardiac ion channels, receptors and exchangers, and alterations in INa and/or the inward L-type Ca2+ current (ICa,L) may lead to the QT prolongation and arrhythmias.
Among long QT syndrome patients where a genetic cause can be identified, KvQLT1 mutations are most frequent (
50%), HERG mutations are relatively frequent, SCN5A mutations are uncommon (< 5%), and minK, MiRP1 and ankyrin-B mutations are rare. Sudden infant death syndrome (SIDS) is also associated with QT prolongation, and both de novo and familial mutations in the long QT genes are responsible for some SIDS cases (Schwartz et al. 2000).
Andersen syndrome (Andersen-Tawil syndrome, LQT7) and Timothy syndrome (LQT8) are congenital disorders associated with musculoskeletal abnormalities, QT prolongation, and arrhythmias distinct from Torsade de Pointes. Andersen syndrome is caused by loss of function mutations in KCNJ2, the gene encoding the inward rectifier K+ channel Kir2.1, and results from a decrease in the inward rectifier K+ current (IK1) which sets the resting membrane potential of cardiac myocytes (Plaster et al. 2001). Timothy syndrome is caused by mutations of CACNA1C that disrupt inactivation of Cav1.2, the gene responsible for ICa,L, and lead to prolonged inward currents (Splawski et al. 2004). It is debated whether Andersen syndrome and Timothy syndrome should be included with the other forms of long QT syndrome.
The mouse as a model for long QT syndrome
Although ion channels in humans and mice are highly conserved, significant electrophysiological differences are present between the species (Fig. 2) (London, 2001; Nerbonne et al. 2001). Mice have heart rates 10 times higher than humans, requiring shorter action potentials and different repolarizing K+ currents. In humans, the major repolarizing currents are IKs (encoded by KvLQT1 and minK) and IKr (encoded by HERG1). The low expression levels of these channels can limit the utility of models designed to knock down expression. In the mouse, the major repolarizing currents are the fast and slow components of the transient outward K+ current (Ito,f, encoded by Kv4.3 and Kv4.2; Ito,s, encoded by Kv1.4), and rapidly activating, slowly inactivating delayed rectifier currents (IK,slow1, encoded by Kv1.5, and IK,slow2, encoded by Kv2.1). Disruption of these channels leads to a more robust phenotype in the mouse, but the relevance of the findings to human arrhythmias is less certain. In addition, the ECG of the mouse differs significantly from that in humans and sudden death from tachyarrhythmias is uncommon in the mouse.
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The 
-myosin heavy chain promoter is most commonly used to drive expression of transgenes in the adult mouse ventricle. A dominant negative transgenic strategy can be used to decrease the expression of K+ channel genes in the heart (London, 2004). This takes advantage of the fact that four related -subunits coassemble to form a functional K+ channel and that subunits containing certain point mutations or truncations will coassemble with the wild-type subunits. If a single mutant subunit is sufficient to inhibit functional channel formation and mutant subunits randomly coassemble with native subunits, a heavily expressed transgenic subunit will effectively eliminate functional wild-type channels. Of note, several channel subunits may be affected by a single transgene. This allows for rapid testing of the role of a class of ion channels in the heart, but complicates the determination of which channels are actually disrupted by the transgene.
Transgenic overexpression of K+ channels in the mouse heart can lead to a number of potential problems unrelated to the specific function of the transgene. The transgene inserts into one of the mouse chromosomes in a rather random manner; if this should occur inside another gene, it may disrupt the function of that gene at the insertion site (London, 2004). Two or more independent lines of mice expressing the transgene are usually studied to ascertain that the observed phenotype results directly from transgene expression. Massive overexpression of a mutant protein can also titrate away important factors such as -subunits or have direct toxic effects on cardiac myocytes, as illustrated by the dilated cardiomyopathy caused by overexpression of green fluorescent protein (Huang et al. 2000).
Individual genes can be targeted (gene knockout, gene knockin, targeted mutagenesis) in the mouse using homologous recombination in embryonic stem cells (London, 2004). In gene-targeting, pluripotent embryonic stem cells are modified in vitro to be heterozygous for the desired chromosomal modification and injected into blastocysts to generate chimeras that transmit the mutation into the germ line. Offspring heterozygous for the mutation are then mated to yield homozygotes. This technique can be used to completely inactivate ion channel genes, or to directly engineer human mutations in the mouse. Gene targeting also has several important limitations. The targeted allele is present in all cell types in which the gene is expressed, and the phenotype reflects the loss of the gene not only from the heart, but also from the nervous system and potentially other tissues. In addition, the targeted allele is present throughout embryonic development, the phenotype of the adult mouse may be modified by long-term compensatory changes in other genes (e.g. electrical remodelling), and embryonic lethality may limit the study of the role of some genes. The ability to engineer gene knockouts in a time- and tissue-restricted manner has been developed using the cre/lox system and can circumvent a number of these problems.
Methods for studying mouse long QT syndrome models
The molecular analysis of transgenic and gene-targeted long QT syndrome mouse models includes standard techniques for quantifying and localizing RNA (Northern blot, ribonuclease protection assay, reverse transcription polymerase chain reaction (PCR), quantitative real time PCR, in situ hybridization) and protein (Western blots, the enzyme-linked immunosorbent assay (ELISA), immunofluorescence, immunohistochemistry). In transgenic models, tissue localization of the transgene depends on the promoter. In gene-targeted knockout models, the native gene product is usually decreased in the heterozygous and absent in the homozygous mice, although compensatory mechanisms may lead to normal protein levels in the heterozygotes. In gene-targeted knockin models, expression levels and tissue specificity of the modified gene are usually similar to those of the native gene. In both transgenic and gene-targeted models, changes in the expression of other ion channel genes (electrical remodelling) are common. For example, in mice with a targeted replacement of the K+ channel Kv1.5, up-regulation of the K+ channel Kv2.1, which encodes the non-4-aminopyridine-sensitive current IK,slow2, compensates for the absence of the 4-aminopyridine-sensitive cardiac current IK,slow1 (London et al. 2001).
Neonatal and adult cardiac myocytes are used for current and voltage clamp studies (Wang & Duff, 1997; London et al. 1998a). Neonatal mouse cardiac myocytes are produced using trypsin-based digestion adapted from rat protocols, and single adult cardiac myocytes are produced using retrograde perfusion of the mouse heart via the aorta on a Langendorff apparatus with collagenase-containing solutions. Action potentials and ionic currents can be recorded with the amplifier in the current clamp and voltage clamp modes, respectively, using the perforated patch or whole-cell dialysis methods. Action potentials in wild-type adult mouse myocytes have a triangular shape and no plateau, with the time to 75% (APD75) and 90% (APD90) repolarization of the action potential 15 ms and 40 ms, respectively (Fig. 2).
A number of techniques can be used to study electrical activity on the epicardial surface of the intact mouse heart. In open chest preparations or Langendorff-perfused isolated hearts, extracellular suction electrodes can be used to measure monophasic action potentials (MAPs) and to determine action potential shape and duration (Knollmann et al. 2001). Activation and repolarization on the epicardial surface of the mouse heart can also be mapped using electrode arrays, although the small size of the mouse heart and the spatial resolution of electrode arrays limits the utility of this technique (Guerrero et al. 1997). Optical mapping techniques using membrane-bound dyes that change their fluorescence intensity as a function of voltage are the method of choice to study electrophysiology in the isolated perfused heart (Fig. 3A) (Morley et al. 1999; Baker et al. 2000). Action potentials can be recorded with high spatial and temporal resolution, allowing measurement of action potential duration, conduction velocity, and restitution properties. Programmed stimulation (extrasystolic beats, burst pacing) can be used to induce ventricular or atrial arrhythmias (Fig. 3B–D). The optical mapping technique has also been adapted to study the adult mouse conduction system and developmental changes in embryos and neonates (Tamaddon et al. 2000; Rentschler et al. 2001). Similarly, calcium-sensitive dyes can be used to map Ca2+ transients in the mouse heart (London et al. 2003). The short depth of focus and poor penetration of the emission light from current optical dyes limits the technique to studying the surface of the heart, although novel dyes are currently being developed along with 3-dimensional mapping techniques (Salama et al. 2005). Motion artifact is also a limitation of all the methods used to study action potentials and repolarization in the intact heart, especially since uncouplers of excitation and contraction such as diacetyl monoxime and cytocholasin-D cause significant changes in the action potential morphology of the mouse (Baker et al. 2000).
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Implanted subcutaneous radio-telemetry ECG monitors are commonly used to record cardiac rhythm in ambulatory mice, including those at the time of sudden death (Fig. 4A). Surprisingly, the majority of transgenic mouse models are bradyarrhythmic at the time of death (London, 2004). The response to pharmaceutical agents, indices of heart rate variability, and T-wave alternans can also be determined using telemetry from awake, ambulatory mice (Gehrmann et al. 2000; Shusterman et al. 2002). The interpretation of rhythms in the mouse remains difficult, however. For example, although a wide complex ventricular rhythm at 500 beats min–1 in a transgenic mouse may be called ventricular tachycardia, it may actually represent an accelerated ventricular escape rhythm in an animal with a native heart rate of over 600 beats min–1. Similarly, episodes of high degree atrioventricular block occur spontaneously in some wild-type mice (Fig. 4A).
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Mouse models of human long QT syndrome gene mutations (Table 1)
Gene targeting and dominant negative techniques have been used to disrupt KvLQT1 and minK, the channels that encode IKs in the hearts of large mammals and lead to the LQT1 and LQT5 forms of long QT syndrome, respectively (Drici et al. 1998; Kupershmidt et al. 1999; Lee et al. 2000; Casimiro et al. 2001; Demolombe et al. 2001). Lee et al. found no ECG abnormalities in their KvLQT1–/– mouse, while Casimiro et al. reported QT prolongation in the mouse but not in isolated hearts. A dominant negative KvLQT1 mouse, on the other hand, had QT prolongation and bradycardia associated with decreased levels of both IK1 and Ito. The cardiovascular phenotype of the minK knockout mice is also controversial; Drici et al. reported an abnormal QT response as a function of heart rate while Kupershmidt et al. did not. Differences in anaesthesia may explain some of the discrepancies. In summary, the studies show that minK expression and IKs in the adult mouse heart are limited, and their loss does not appear to lead to a robust long QT phenotype.
The targeted replacement of minK by lacZ helped to localize the expression of minK to the mouse conduction system (Kupershmidt et al. 1999). Deafness in minK–/– knockout mice suggested a role for the genes encoding IKs in the autosomal recessive Jervell and Lange-Nielsen syndrome (Drici et al. 1998). In addition, the absence of IKs in the mouse can be circumvented (Marx et al. 2002). Transgenic overexpression of KvLQT1-minK using the -myosin heavy chain expression led to a humanized mouse with robust IKs, and was used to define the components of the macromolecular complex that respond to -adrenergic stimulation.
Merg1, the mouse homolog of the LQT2 gene HERG, is expressed in the mouse heart. Overexpression of a HERG dominant negative construct in the mouse produced mild APD prolongation in myocytes but not in muscle strips (Babij et al. 1998). Targeted disruption of Merg1 is homozygous embryonic lethal. Merg1+/– heterozygotes showed mild QT prolongation and developed arrhythmias following treatment with -adrenergic agonists (London et al. 1998b). Merg1b, a cardiac isoform with an alternate short N-terminal intracellular domain, coassembles with Merg1a to speed deactivation (London et al. 1997). Targeted disruption of the Merg1b eliminated IKr in adult myocytes, and these Merg1b–/– mice appeared susceptible to bradyarrhythmias (Lees-Miller et al. 2003). The relationship of these findings to the human disease is unclear.
Unlike the K+ channel genes responsible for IKr and IKs, SCN5A is responsible for the majority of the depolarizing Na+ current in both humans and mice. Gene-targeted mice carrying the LQT3 Scn5a 
KPQ deletion mutation had APD and QT prolongation, along with arrhythmias (Nuyens et al. 2001). The polymorphic ventricular tachycardia in these mice bears a significant resemblance to Torsade de Pointes. An additional feature of these mice was the unexpected prolongation of APD and early afterdepolarizations following an abrupt increase in heart rate or a premature beat. The relevance of this finding to humans is uncertain.
Ankyrin-B knockout mice had action potential prolongation and rate-related QT interval prolongation, associated with a decreased total INa amplitude and late channel openings (Chauhan et al. 2000). Ankyrin-B can affect multiple ion channels, however, and the mice may be useful in determining which channel defect leads to the long QT phenotype in LQT4 families.
Homozygous mice with a targeted deletion of Kir2.1 died shortly after birth from a cleft palate (Zaritsky et al. 2001). APD prolongation and sinus bradycardia were seen in neonatal mice, but ventricular ectopy was not observed. Targeted deletion of Kir2.2 in the mouse resulted in a 50% decrease in IK1 but no other significant phenotype (Zaritsky et al. 2001).
Models of long QT syndrome from mouse cardiac gene mutations (Table 2)
The transient outward currents are of great importance to repolarization in the mouse heart, and transgenic mice with decreased expression of the channels encoding Ito have been extensively characterized. Dominant negative transgenic mice overexpressing a pore mutant of Kv4.2 lacked Ito,f, leading to APD and QT prolongation without arrhythmias (Barry et al. 1998). These Kv4.2 DN mice had a compensatory up-regulation of Kv1.4 and Ito,s, a component of the transient outward current normally found only in the interventricular septum. Mice with a targeted deletion of Kv4.2 completely lacked Ito,f, showed compensatory up-regulation of Ito,s and down-regulation of the accessory subunit KChIP2, and lacked APD or QT prolongation (Guo et al. 2005). Targeted mice lacking Kv1.4 had no APD prolongation, QT prolongation, or arrhythmias (London et al. 1998c; Guo et al. 2000). Crossing the Kv4.2 DN mice with Kv1.4–/– mice yielded mice that completely lacked Ito and had marked QT prolongation and arrhythmias. Myocytes isolated from the hearts of these mice showed substantial APD prolongation and early afterdepolarizations.
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Dominant negative mice expressing an N-terminal fragment of Kv1.1 lacked the 4-aminopyridine (4-AP)-sensitive current IK,slow1, had APD and QT prolongation, and spontaneous and inducible arrhythmias (London et al. 1998a). Of interest, the major arrhythmias were monomorphic ventricular tachycardia (VT), as opposed to the polymorphic VT and Torsade de Pointes seen in human long QT syndrome. The mechanism of increased arrhythmia susceptibility, as determined by optical mapping studies, was enhanced dispersion of repolarization and refractoriness between the apex and base of the heart (Baker et al. 2000). The mice did not die from the tachyarrhythmias, a general finding of long QT mouse models. Of note, rescue of the phenotype of this mouse was demonstrated using adenoviral gene delivery of Kv1.5 (Brunner et al. 2003).
Dominant negative transgenic mice overexpressing Kv1.5 with a point mutation in the pore lacked the 4-AP-sensitive current IK,slow1, and had APD and QT prolongation (Li et al. 2004). These mice did not have spontaneous ventricular arrhythmias, however. Gene-targeted mice in which Kv1.5 was replaced by Kv1.1 also lacked IK,slow1, although there is no APD or QT prolongation due to up-regulation of Kv2.1 (London et al. 2001). These mice were protected from drug-induced QT prolongation by 4-AP, and the mice did not have spontaneous arrhythmias. Dominant negative mice lacking Kv2.1 (IK,slow2) had APD and QT prolongation without spontaneous arrhythmias (Xu et al. 1999). Mice lacking both IK,slow1 and IK,slow2 had more marked APD and QT prolongation along with arrhythmias (Kodirov et al. 2004). Mice lacking IK,slow1 and both components of Ito, however, had APD and QT prolongation without arrhythmias (Brunner et al. 2001).
Electrophysiological studies have been performed on numerous other transgenic and gene-targeted mouse models not directly targeted at ion channels (London, 2004). Electrophysiological abnormalities are present in a number of these mice. Identifying the mechanisms leading to the changes and the importance of the findings poses a significant challenge.
Conclusion
Transgenic and gene-targeted mice have confirmed the molecular basis of the ionic currents determined by voltage clamp studies in mouse cardiac myocytes, and driven rapid advances in techniques to study cardiac electrophysiology in the mouse. Mouse models of human long QT genes do not fully reproduce the human phenotype, especially for the K+ channel-associated syndromes. This probably reflects the differential importance of individual channels in the cardiac repolarization of the two species. In addition, the phenotype can vary radically between different mouse models targeting similar currents, due in part to differences in electrical remodelling. Despite these weaknesses, mouse long QT syndrome models have led to a better understanding of electrical remodelling in the heart, suggested novel mechanisms associated with arrhythmias, and identified new genes potentially related to arrhythmias and sudden death. In addition, transgenic long QT models in larger animals such as the rabbit will circumvent many of these difficulties.
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