INTRODUCTION — Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) (waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD) [1,2]. The primary symptoms in patients with LQTS include syncope, seizures, aborted cardiac arrest, and SCD. LQTS is associated with an increased risk of a characteristic life-threatening cardiac arrhythmia known as torsades de pointes or "twisting of the points" (waveform 2A-B) [3,4].
LQTS may be congenital or acquired [1,5]. Mutations in at least 17 LQTS-susceptibility genes have been identified thus far (table 1 and figure 1) [5]. However, mutations in the three canonical genes, KCNQ1 (previously called KVLQT1, LQT1), KCNH2 (previously called HERG, LQT2), and SCN5A (LQT3), account for at least 75 to 80 percent of all LQTS, with mutations in the minor LQTS-susceptibility genes contributing only another 5 percent. Less than 15 to 20 percent of patients satisfying a robust clinical diagnosis of LQTS will have a negative LQTS genetic test. Acquired LQTS usually results from undesired QT prolongation and potential for QT-triggered arrhythmias by either QT-prolonging disease states, QT-prolonging medications (www.crediblemeds.org), or QT-prolonging electrolyte disturbances (table 2) [6].
The pathophysiology and genetics of congenital LQTS will be reviewed here. The clinical features, diagnosis, and treatment of congenital LQTS and the characteristics of acquired LQTS are discussed elsewhere. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Congenital long QT syndrome: Diagnosis" and "Congenital long QT syndrome: Treatment" and "Acquired long QT syndrome: Definitions, causes, and pathophysiology" and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".)
PATHOPHYSIOLOGY — Although the relatively simple clinical definition of LQTS applies to both acquired and the variety of congenital forms, the pathophysiology of the disorder is complex, incompletely understood, and probably varies among patients. Two leading pathophysiologic hypotheses have emerged to explain commonly observed features of LQTS:
●Extensive and growing clinical and genetic evidence supports the importance of derangements in cardiac ion channels, resulting in prolongation of the action potential (figure 1). Based on these data, congenital LQTS is considered a disease of ion channels and is the most common "cardiac channelopathy."
●The observation that the immediate trigger for torsades de pointes (TdP) in the inherited form is often a sudden surge in sympathetic tone (a feature not seen in the acquired form) led to the hypothesis that the congenital LQTS may be caused by an imbalance in the sympathetic innervation of the heart.
Derangements in ion channels — The established pathogenic basis for the vast majority of congenital LQTS involves perturbations in three critical ion channels of the heart. Loss-of-function mutations in the KCNQ1-encoded Kv7.1 potassium channel (phase 3 IKs) and KCNH2-encoded Kv11.1 potassium channels (phase 3 IKr) cause prolongation in the action potential duration at the cellular level and hence QT prolongation for at least two-thirds of all patients with LQTS. So-called gain-of-function mutations in the SCN5A-encoded Nav1.5 sodium channel accounts for approximately 5 to 10 percent of LQTS and prolongs the action potential duration by the contribution of increased late sodium currents. This action potential prolongation at the ventricular cardiac cell level sets up the increased vulnerability for early afterdepolarizations and triggered activity via reentrant mechanisms, which then produces the LQTS-associated syncope, seizure, or worse. (See 'Prolonged repolarization and EADs' below.)
The normal action potential — An understanding of normal cardiac cell electrophysiology is required in order to fully appreciate the known perturbations in ion channels and their associated ion currents, and the electrophysiologic mechanisms which cause congenital LQTS. The normal action potential is composed of the following five phases, beginning with phase 4 (figure 2 and movie 1). (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".)
●Phase 4 (resting membrane potential) – Phase 4 represents the normal diastolic resting membrane potential of myocardial cells. Myocardial ventricular cell membranes during diastole are polarized at -90 mv (ie, the resting membrane potential), which largely represents the equilibrium potential for potassium. This occurs because of the inwardly rectifying potassium channel Kir2.1 (IK1 current) that is encoded by KCNJ2.
●Phase 0 (depolarization) – Phase 0 occurs when the membrane potential reaches approximately -70 mV. A rapid inward flow of sodium ions (INa) through the fast Nav1.5 sodium channels (encoded by SCN5A) ensues and depolarizes the cell membrane. Inward current during phase 0 is also sustained by activation of L- and T-type calcium channels (ICa-L and ICa-T).
●Phase 1 (initial repolarization) – Phase 1 represents an initial repolarization after the overshoot of phase 0 and is caused by a transient outward potassium current (Ito1) from the KCND3-encoded Kv4.3 potassium channels.
●Phase 2 (plateau phase) – Phase 2 is called the plateau phase, because it represents an equilibrium between the inward calcium (ICa-L/Cav1.2 encoded by CACNA1C and ICa-T) and late sodium (INa) currents and the outward potassium currents coming from the Kv7.1/IKs (KCNQ1) and the Kv11.1/IKr (KCNH2) potassium channels.
●Phase 3 (rapid repolarization) – Phase 3 represents the rapid repolarization which occurs when the outward potassium currents dominate over the decaying inward calcium current. Repolarization is predominantly effected through the aforementioned outward potassium currents (IKs and IKr). These channels open in response to depolarization and allow potassium to flow out of cells and repolarize the membrane potential toward its resting level, until activated KCNJ2-encoded Kir2.1 potassium channels (IK1) drive and hold the membrane potential around -90 mV. The QT interval on the surface electrocardiogram is determined by the activity of these channels.
Prolonged repolarization and EADs — Prolongation of the QT interval increases the probability for early afterdepolarizations (EADs). EADs are single or multiple oscillations of the membrane potential that can occur during phase 2 or 3 of the action potential (figure 2). EADs occur in association with prolongation of the repolarization phase of the action potential. If occurring in phase 2 of the action potential, EADs are thought to be caused by increased inward current through L-type calcium channels [7] or through the sodium-calcium exchanger [8]. Depolarizing currents occurring late in phase 3 are thought to be due to inward currents through T-type calcium channels or sodium channels [9]. Pathologic prolongation of repolarization results most often from a decrease in the outward currents (LQT1 and LQT2) or increases in the sodium current (LQT3). (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs", section on 'Triggered activity'.)
Triggered activity — Triggered responses or triggered activity are EADs that reach threshold potential, depolarize cell membranes, and result in additional action potentials. Propagation of these triggered responses produce ventricular premature depolarizations that may initiate polymorphic ventricular tachycardia (TdP) in susceptible subjects. EADs and triggered responses are particularly easy to induce in Purkinje fibers and M cells, a group of cells in the left ventricular free wall which have been identified as the site of EAD-induced triggered activity after exposure to drugs such as quinidine, sotalol, and erythromycin [10,11]. (See "Acquired long QT syndrome: Definitions, causes, and pathophysiology", section on 'Causes of acquired QT prolongation'.)
Common precipitants of EADs and triggered activity — The development of EADs is potentiated by bradycardia, hypokalemia, hypomagnesemia, and a long list of medications. (See "Acquired long QT syndrome: Definitions, causes, and pathophysiology", section on 'Medications'.)
●Bradycardia – Slow heart rates are associated with increased inactivation of the outward repolarizing potassium current and a reduction in the Na-K-ATPase pump outward current (3 Na out/2 K in = net outward positive current). Slow heart rates also enhance the activity of certain antiarrhythmic drugs on repolarization (ie, repolarization and the QT interval are more prolonged). This property is called reverse use dependence, and can lead to ion fluxes that facilitate EADs and TdP.
●Hypokalemia – Low potassium levels lead to a decreased outward repolarizing current via reductions in electrogenic Na-K-ATPase pump activity and outward potassium channel activity.
Role of sympathetic activity — Evidence supporting the significance of sympathetic activity in LQTS includes observations on the impact of the stellate ganglia. The left cardiac sympathetic nerves (left stellate ganglion and first four thoracic ganglia) are quantitatively dominant in terms of release of NE in the heart compared to the right sided sympathetic nerves. In addition, the left stellate ganglion innervates the majority of the ventricle [12,13]. In addition, sympathetic stimulation can also facilitate the induction of triggered activity and early after potentials.
Experimental studies have demonstrated that right stellectomy or stimulation of the left stellate ganglion both prolong the QT interval and alter T wave morphology in a manner that mimics the surface ECG found in patients with LQTS [14]. Antiadrenergic therapies, including beta blockers and left cardiac sympathetic denervation (LCSD), substantially reduce the risk of TdP in patients with LQTS, despite the fact that their effect on the QT interval is variable [13]. (See "Congenital long QT syndrome: Treatment".)
Dispersion of repolarization and reentry — Both the dispersion of repolarization and reentry may be other potential mechanisms for the development of TdP. Dispersion of repolarization refers to an inhomogeneity in repolarization or recovery of excitability in a region of myocardium. A specific population of cells in the myocardium, called M cells, demonstrate marked prolongation of action potential duration in response to drugs such as quinidine, sotalol, and erythromycin [10,11]. Dispersion of repolarization could therefore occur in response to these drugs if the action potential is prolonged in M cells but not in the surrounding myocardium. The result is a functional block in the M cell region, providing the necessary milieu for the development of a reentrant arrhythmia [10].
Initiation and maintenance of VT — EADs and triggered activity are thought to be the most common initiating mechanism for the ventricular ectopy and polymorphic VT associated with long QT intervals [15,16]. Alterations in sympathetic activity and dispersion of repolarization probably contribute to the electrophysiologic milieu that facilitates malignant arrhythmias, at least in certain cases.
TYPES OF CONGENITAL LQTS — Mutations in at least 17 genes have been identified thus far in patients with congenital LQTS (table 1 and figure 1) [5]. However, as clinical genetic testing evolves and the available data becomes more robust, some previously associated LQTS-susceptibility genes have been reconsidered as unlikely to be causative for congenital LQTS. Additionally, the classifications and nomenclature are evolving, with the historical naming convention (LQT followed by the next number in sequence) being replaced by more descriptive monikers [17,18].
Mutations in the three canonical genes, KCNQ1 (LQT1; 35 to 40 percent), KCNH2 (LQT2; 25 to 30 percent), and SCN5A (LQT3; 5 to 10 percent), account for at least 75 to 80 percent of all LQTS, with mutations in the minor LQTS-susceptibility genes contributing another 5 percent. The remaining 15 to 20 percent of patients with an established clinical diagnosis of congenital LQTS will not have an identifiable gene mutation, and are referred to as either genetically elusive LQTS or genotype negative LQTS.
Canonical LQTS-causative genes
Type 1 LQTS (LQT1) — The first association between a chromosomal marker and congenital LQTS was identified by analysis of a Utah family with a high prevalence of this disorder [19]. Linkage was found between the LQTS phenotype and a marker on the short arm of chromosome 11. Investigators using positional cloning techniques identified the involved gene, now called KCNQ1 [20].
LQT1 accounts for up to 45 percent (35 to 40 percent in most countries and most cohorts) of cases of LQTS [21]. Most patients with LQT1 show paradoxical prolongation of the QT interval during an exercise stress test, especially during the recovery phase of the stress test, which can be used to unmask patients with electrocardiographically concealed LQT1 [22,23].
The protein product of KCNQ1 (Kv7.1 alpha-subunit), when coexpressed with the cardiac protein minK (IsK or beta-subunit, which is encoded by KCNE1), forms the slowly acting component of the outward-rectifying potassium current (IKs) [24-26]. Suppression of IKs by mutations in the KCNQ1 gene, in the absence or presence of minK, can be correlated with and likely underlie prolongation of human ventricular action potentials [27]. Mutations in the KCNE1-encoded minK (LQT5), produces a similar defect in IKs (figure 3). Gain-of-function mutations in KCNQ1 have been associated with familial atrial fibrillation [28] and with the congenital short QT syndrome, designated as type 2 short QT syndrome or SQT2 [29]. (See "Epidemiology of and risk factors for atrial fibrillation", section on 'Genetic factors' and "Short QT syndrome".)
Many missense mutations, and some other types of mutations, have been identified in KCNQ1. The severity of the clinical features of LQT1 vary with the specific mutation. In particular, mutations in the transmembrane region are associated with more frequent cardiac events (syncope, aborted cardiac arrest, or sudden cardiac death) than mutations in the C-terminal region (55 versus 21 percent) [30].
A mutation (KCNQ1-A341V) is associated with high clinical severity independent of ethnic origin [31]. In a study comparing 244 patients with A341V mutations with 205 patients with non-A341V LQT1 mutations, at a median follow-up of approximately 30 years, patients with A341V mutations were significantly more likely to have cardiac events (75 versus 24 percent), were younger at first event (6 versus 11 years), and had a longer QTc (485±43 versus 465±38 ms).
Homozygous mutations of KCNQ1 can cause the Jervell and Lange-Nielsen syndrome [32,33]. Deafness can also be induced by the loss of functional minK protein, which seems to disrupt the production of endolymph. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Congenital sensorineural deafness'.)
Type 2 LQTS (LQT2) — LQT2, which accounts for 25 to 40 percent of cases of congenital LQTS [21,34,35], is caused by mutations in a different potassium channel gene, localized to chromosome 7 [36-38]. The disease-causative gene is called KCNH2 (formerly HERG), which encodes the Kv11.1 potassium channel which underlies the rapidly acting component of the outward-rectifying potassium current (IKr) (figure 3) [39-42]. This current is largely responsible for repolarization and thus the QT interval duration. The KCNH2-encoded Kv11.1 channels have unique electrophysiologic features that may normally protect against early afterdepolarizations (EADs) [41]. Virtually all of the drugs that cause acquired/drug-induced LQTS block these Kv11.1 channels. (See "Acquired long QT syndrome: Definitions, causes, and pathophysiology".)
The mutations localize throughout the entirety of the Kv11.1 channel [38,43]. In a study of 201 patients, those with mutations localizing to the pore region had a significantly greater risk of a cardiac event (74 versus 35 percent with mutations in the nonpore region) and of SCD or aborted cardiac arrest (15 versus 6 percent); these manifestations occurred at an earlier age in the patients with mutations in the pore region [38]. Patients with the pore mutation had a significantly greater risk of a cardiac event at a QTc of 500 ms (hazard ratio 11); each 10 ms change in the QTc above or below 500 ms increases or decreases the risk by 16 percent.
In some reports, non-pore mutations are more likely to be associated with TdP in the presence of hypokalemia [43]. However, a malignant phenotype has been described in a family with a novel mutation in the nonpore region [44].
In contrast to LQT2-associated loss-of-function mutations in KCNH2, there are gain-of-function mutations in KCNH2 that result in accentuated IKr activity and patients with such mutations are classified as SQT1. (See "Short QT syndrome".)
Type 3 LQTS (LQT3) — LQT3, which accounts for 5 to 10 percent of cases [21,34,35], is caused by mutations in the sodium channel gene (SCN5A) located on chromosome 3; multiple mutations have been associated with LQT3 [45,46]. The LQT3-causative mutations result in so-called gain-of-function by either increasing the late sodium current (like one of the originally discovered mutations, DeltaKPQ), increasing the window current through biophysical alterations of the kinetics of activation or inactivation, or through both mechanisms. One of the most interesting mutations in SCN5A is the missense mutation E1784K, which demonstrates most clearly the phenomenon of host-dependent disease expressivity, as E1784K is not only the most common LQT3-associated mutation published to date but also the single most common SCN5A mutation associated with a completely different genetic arrhythmia syndrome known as Brugada syndrome [47,48].
Sporadic (de novo) SCN5A mutations have also been described in which neither parent had either the mutation or a long QT interval. In contrast to the heritable mutations, one of these mutations resulted in a prolonged opening and early reopening of the sodium channel, and therefore a three-fold prolongation of sodium current decay [49]. Mutations in SCN5A have been associated with sudden infant death syndrome, at least some of which are sporadic [50-52]. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Sudden infant death syndrome'.)
Other SCN5A mutations — Different mutations in SCN5A can also cause a variety of other cardiac abnormalities, including Brugada syndrome, a related disorder, the sudden unexpected nocturnal death syndrome, an isolated familial atrioventricular conduction defect, congenital sinus node dysfunction, and familial dilated cardiomyopathy with conduction defects and susceptibility to atrial fibrillation. In addition, some mutations are associated with both LQT3 and the Brugada syndrome, with or without a conduction block [53,54].
The differences in clinical manifestations are probably due to differences in the electrophysiologic abnormalities induced by the specific mutations [55,56]. (See "Brugada syndrome: Epidemiology and pathogenesis", section on 'Genetics' and "Etiology of atrioventricular block", section on 'Familial disease' and "Genetics of dilated cardiomyopathy" and "Sinus node dysfunction: Epidemiology, etiology, and natural history", section on 'Childhood and familial disease' and "Approach to sudden cardiac arrest in the absence of apparent structural heart disease", section on 'Brugada syndrome'.)
Compound mutations — In different large series, 4.5 and 7.9 percent of unrelated individuals who were each the first in their families to be diagnosed with LQTS (probands) had two disease-causing mutations [57,58]. This unexpectedly high incidence of compound mutations could be a reflection of selection bias, since such individuals would be more likely to develop clinical disease. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Epidemiology'.)
Consistent with this hypothesis is the observation that patients with multiple mutations, compared to those with only one mutation, have significantly longer QT intervals and are more likely to experience a life-threatening cardiac arrhythmia [58,59].
The presence of two mutations can also affect the success of genetic testing. (See 'Genetic testing' below.)
Minor LQTS-susceptibility genes — Since the discovery of the three canonical LQTS-causative genes over 20 years ago, up to 14 additional, albeit minor, LQTS-susceptibility genes have been discovered by either hypothesis driven, candidate gene research or genomic triangulation strategies using whole exome sequencing [17]. The LQTS genotypes stemming from these minor genes (table 1) have been annotated in the past as LQT4-17. More recently, however, these subtypes are best described by their gene, such as CACNA1C-LQTS (instead of LQT8) and TRDN-LQTS (instead of LQT4-17) for example. Some of these minor genetic subtypes converge upon the so-called final common pathway of one of the canonical subtypes. For example, LQT5 as mentioned previously (now preferred to be called KCNE1-LQTS) mimics LQT1, while CAV3-LQTS results in accentuation of the late sodium current akin to primary mutations in SCN5A (LQT3).
The most common of the minor LQTS-susceptibility genes is probably CACNA1C-mediated LQTS (previously called LQT8) [60]. Gain-of-function mutations in CACNA1C-encoded Cav1.2 were first discovered in a complex multi-system disorder called Timothy syndrome, which included marked QT prolongation [61]. More recently however, other CACNA1C mutations have been associated with cardiac only, autosomal dominant LQTS.
Among all of the minor LQTS-susceptibility genes, the most penetrant ones have involved either autosomal dominant or sporadic de novo mutations in one of the three CALM genes that encode the 100 percent identical 103 amino acid-containing calmodulin proteins or homozygous/compound heterozygous, autosomal recessive inherited mutations in TRDN-encoded triadin [62,63]. The CALM1-3-LQTS subtypes are referred to collectively as the calmodulinopathies, since the phenotype overlaps with not only LQTS but also catecholaminergic polymorphic ventricular tachycardia [64]. There is now an International Calmodulinopathy Registry [65]. Similarly, patients with autosomal recessive mutations in TRDN are referred to as having Triadin Knockout Syndrome (TKOS) because of phenotypic overlap also, and there is now an International TKOS Registry to enroll patients with this severe channelopathy [65]. Presently, children with these severe forms of disease (calmodulinopathies and TKOS) continue to experience breakthrough cardiac events despite conventional LQTS therapies.
GENETIC TESTING — Genetic testing is available to identify specific mutations that result in LQTS [66-69]. However, such testing is subject to limitations given the complexity and heterogeneity of the disorder. It has been estimated that a specific mutation in one of the three canonical genes (KCNQ1, KCNH2, and SCN5A) will be identified in at least 75 to 80 percent of patients who express a robust phenotype consistent with the diagnosis of LQTS [21]. Approximately 4 percent of controls have a rare variant of uncertain significance (in just KCNQ1, KCNH2, and SCN5A) which represents a lower point estimate for the potential false positive rate for genetic testing [70,71].
In a series of 541 unrelated patients from the Mayo Clinic, the overall yield of genetic testing was also approximately 50 percent and correlated with clinical measures of disease severity [72]:
●The likelihood of identifying a mutation increased progressively with increasing QTc, ranging from 0 to 62 percent as the QTc increased from the lowest (<400 ms) to the highest (>480 ms) category.
●A clinical LQTS diagnostic tool, the Schwartz LQTS score is derived from QTc, symptoms, and family history, and predicts the likelihood of LQTS [73].
Patients with a score ≥4, suggesting a strong probability of LQTS, had a mutation identified more frequently than those with a score <4 (72 versus 44 percent). (See "Congenital long QT syndrome: Diagnosis", section on 'Diagnosis'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Cardiac implantable electronic devices".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Long QT syndrome (The Basics)")
SUMMARY AND RECOMMENDATIONS
●At least 17 congenital LQTS-susceptibility genes have been identified (table 1). LQT1, LQT2, and LQT3 account for approximately 75 to 80 percent of cases of congenital LQTS, while the minor LQTS-susceptibility genes are indeed minor, collectively accounting for <5 percent of LQTS, some of them being demoted to limited/refuted evidence LQTS-gene status and others better viewed as their own distinct entity: CALM1-3-mediated LQTS as a Calmodulinopathy instead, and TRDN-mediated LQTS as triadin knockout syndrome. (See 'Types of congenital LQTS' above.)
●LQT1 accounts for up to 45 percent of cases of the LQTS and is caused by loss-of-function mutations in the KCNQ1-encoded Kv7.1 potassium channel. Most patients with this defect show paradoxical prolongation of the QT interval during the recovery phase after treadmill stress testing, which can be used to unmask patients with otherwise electrocardiographically concealed LQT1. Events triggered by exercise, particularly swimming, are characteristic of (but not specific for) LQT1. (See 'Type 1 LQTS (LQT1)' above.)
●LQT2, which accounts for 25 to 40 percent of cases of congenital LQTS, is caused by a variety of loss-of-function mutations in the KCNH2-encoded Kv11.1 potassium channels.
●LQT3, which accounts for 5 to 10 percent of cases, is caused by gain-of-function mutations in the SCN5A-encoded Nav1.5 sodium channel. Events occurring at rest or during sleep are characteristic of (but not specific for) LQT3. (See 'Type 3 LQTS (LQT3)' above.)
●LQTS genetic testing has been available clinically/commercially since 2004 in the United States, and LQTS genetic testing is a class I recommendation for any patient being considered to have this diagnosis to enable genotype-guided risk stratification and treatment and to then permit cascade variant-specific testing of the relatives. (See 'Genetic testing' above.)
1 : The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy.
2 : Long QT Syndrome.
3 : Torsade de pointes.
4 : Polymorphic ventricular tachycardia, long Q-T syndrome, and torsades de pointes.
5 : Impact of genetics on the clinical management of channelopathies.
6 : Predicting the Unpredictable: Drug-Induced QT Prolongation and Torsades de Pointes.
7 : Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current.
8 : Role of Na+:Ca2+ exchange current in Cs(+)-induced early afterdepolarizations in Purkinje fibers.
9 : Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS.
10 : Clinical relevance of cardiac arrhythmias generated by afterdepolarizations. Role of M cells in the generation of U waves, triggered activity and torsade de pointes.
11 : Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes.
12 : Torsades de pointes and proarrhythmia.
13 : Torsades de pointes and proarrhythmia.
14 : Electrical alternation of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome.
15 : Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes.
16 : Phase 2 early afterdepolarization as a trigger of polymorphic ventricular tachycardia in acquired long-QT syndrome : direct evidence from intracellular recordings in the intact left ventricular wall.
17 : The genetic architecture of long QT syndrome: A critical reappraisal.
18 : Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing.
19 : The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis.
20 : Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.
21 : HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA).
22 : Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome.
23 : Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome.
24 : K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current.
25 : Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel.
26 : Mutations in the hminK gene cause long QT syndrome and suppress IKs function.
27 : Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome.
28 : KCNQ1 gain-of-function mutation in familial atrial fibrillation.
29 : Mutation in the KCNQ1 gene leading to the short QT-interval syndrome.
30 : Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: multicenter study in Japan.
31 : The common long-QT syndrome mutation KCNQ1/A341V causes unusually severe clinical manifestations in patients with different ethnic backgrounds: toward a mutation-specific risk stratification.
32 : Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death.
33 : The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome.
34 : Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.
35 : Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.
36 : Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity.
37 : Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel.
38 : Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel.
39 : A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.
40 : A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
41 : The inconstancy of the human heart.
42 : I(Kr): the hERG channel.
43 : C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.
44 : Novel mutation in the Per-Arnt-Sim domain of KCNH2 causes a malignant form of long-QT syndrome.
45 : SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome.
46 : Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel.
47 : Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.
48 : An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.
49 : Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel.
50 : A molecular link between the sudden infant death syndrome and the long-QT syndrome.
51 : De novo mutation in the SCN5A gene associated with early onset of sudden infant death.
52 : Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.
53 : Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation.
54 : Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism.
55 : Electrophysiological characterization of SCN5A mutations causing long QT (E1784K) and Brugada (R1512W and R1432G) syndromes.
56 : Defective cardiac ion channels: from mutations to clinical syndromes.
57 : Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice.
58 : Compound mutations: a common cause of severe long-QT syndrome.
59 : Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations.
60 : Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome.
61 : Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia.
62 : CALM3 mutation associated with long QT syndrome.
63 : Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest: Elucidation of the Triadin Knockout Syndrome.
64 : Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G.
65 : International Triadin Knockout Syndrome Registry.
66 : Novel insights in the congenital long QT syndrome.
67 : Genetic and molecular basis of cardiac arrhythmias: impact on clinical management parts I and II.
68 : Current concepts in long QT syndrome.
69 : Genetic and molecular basis of cardiac arrhythmias: impact on clinical management part III.
70 : Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome.
71 : Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing.
72 : Effect of clinical phenotype on yield of long QT syndrome genetic testing.
73 : Diagnostic criteria for the long QT syndrome. An update.
