Genotype-specific clinical manifestation in long QT syndrome

The congenital form of long QT syndrome (LQTS) is characterized by QT prolongation in the electrocardiogram (ECG) and a polymorphic ventricular tachycardia, Torsade de Pointes (TdP) mainly as a result of an increased sympathetic tone during exercise or mental stress. Recent genetic studies have so far identified seven forms of congenital LQTS caused by mutations in genes of the potassium and sodium channels or membrane adapter located on chromosomes 3, 4, 7, 11, 17 and 21. It is of particular importance to examine the genotype-phenotype correlation, especially in the LQT1, LQT2 and LQT3 forms of LQTS, which make up more than 90% of genotyped patients with LQTS, because it would enable us to manage and treat genotyped patients more effectively.     

Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome

OBJECTIVE: To determine the effect of epinephrine on the QT interval in patients with genotyped long QT syndrome (LQTS). PATIENTS AND METHODS: Between May 1999 and April 2001, 37 patients (24 females) with genotyped LQTS (19 LQT1, 15 LQT2, 3 LQT3, mean age, 27 years; range, 10-53 years) from 21 different kindreds and 27 (16 females) controls (mean age, 31 years; range, 13-45 years) were studied at baseline and during gradually increasing doses of intravenous epinephrine infusion (0.05, 0.1, 0.2, and 0.3 microg x k(-1) x min(-1)). The 12-lead electrocardiogram was monitored continuously, and heart rate, QT, and corrected QT interval (QTc) were measured during each study stage. RESULTS: There was no significant difference in resting heart rate or chronotropic response to epinephrine between LQTS patients and controls. The mean +/- SD baseline QTc was greater in LQTS patients (500+/-68 ms) than in controls (436+/-19 ms, P<.001). However, 9 (47%) of 19 KVLQT1-genotyped LQT1 patients had a nondiagnostic resting QTc (<460 milliseconds), whereas 11 (41%) of 27 controls had a resting QTc higher than 440 milliseconds. During epinephrine infusion, every LQT1 patient manifested prolongation of the QT interval (paradoxical response), whereas healthy controls and patients with either LQT2 or LQT3 tended to have shortened QT intervals (P<.001). The maximum mean +/- SD change in QT (AQT [epinephrine QT minus baseline QT]) was -5+/-47 ms (controls), +94+/-31 ms (LQT1), and -87+/-67 ms (LQT2 and LQT3 patients). Of 27 controls, 6 had lengthening of their QT intervals (AQT >30 milliseconds) during high-dose epinephrine. Low-dose epinephrine (0.05 microg x kg(-1) x min(-1)) completely discriminated LQT1 patients (AQT, +82+/-34 ms) from controls (AQT, -7+/-13 ms; P<.001). Epinephrine-triggered nonsustained ventricular tachycardia occurred in 2 patients with LQTS and in 1 control. CONCLUSIONS: Epinephrine-induced prolongation of the QT interval appears pathognomonic for LQT1. Low-dose epinephrine infusion distinguishes controls from patients with concealed LQT1 manifesting an equivocal QTc at rest. Thus, epinephrine provocation may help unmask some patients with concealed LQTS and strategically direct molecular genetic testing.     

Catecholamine-induced T-wave lability in congenital long QT syndrome: a novel phenomenon associated with syncope and cardiac arrest

OBJECTIVE: To determine the effects of phenylephrine and dobutamine on repolarization lability in patients with genotyped long QT syndrome (LQTS). PATIENTS AND METHODS: Between December 1998 and August 2000, 23 patients with genotyped LQTS (13 LQT1, 7 LQT2, and 3 LQT3) and 16 controls underwent electrocardiographic stress testing at the Mayo Clinic in Rochester, Minn. Aperiodic repolarization lability was quantified from digitized electrocardiograms recorded during catecholamine stress testing with phenylephrine and dobutamine. T-wave lability was quantified as a root-mean-square of the differences between corresponding signal values of subsequent beats. The magnitude of aperiodic T-wave lability was quantified by using a newly derived T-wave lability index (TWLI). RESULTS: The TWLI was significantly greater in patients with LQTS than in controls (0.0945 +/- 0.0517 vs 0.0445 +/- 0.0123; P < .003). Marked T-wave lability (TWLI > or = 0.095) was detected in all 3 LQTS genotypes (10/23) but in no controls (P < .003). There was no correlation between the TWLI and the baseline corrected QT interval. All high-risk patients having either a history of out-of-hospital cardiac arrest or syncope had a TWLI of 0.095 or greater. CONCLUSIONS: Beat-to-beat nonalternating T-wave lability occurs in LQT1, LQT2, and LQT3 patients during catecholamine provocation and is associated with a history of prior cardiac events. The quantification of this novel phenomenon may assist in identifying LQTS patients with increased risk of sudden cardiac death.     

Molecular Biology of the Long QT Syndrome: Impact on Management

The long QT syndrome (LQTS) is a familial disease characterized by prolonged ventricular repolarization and high incidence of malignant ventricular tachyarrhythmias often occurring in conditions ofadrenergic activation. Recently, the genes for the LQTS linked to chromosomes 3 (LQT3), 7 (LQT2), and 11 (LQTl) were identified as SCN5A, the cardiac sodium channel gene and as HERG and KvLQTl potassium channel genes. These discoveries have paved the way for the development of gene-specific therapy for these three forms of LQTS. In order to test specific interventions potentially beneficial in the molecular variants of LQTS, we developed a cellular model to mimic the electrophysiological abnormalities of LQT3 and LQT2. Isolated guinea pig ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively. This model has been used to study the effect of sodium channel blockade and of rapid pacing showing a pronounced action potential shortening in response to Na⁺channel blockade with mexiletine and during rapid pacing only in anthopleurin-treated cells but not in dofetilide-treated cells. Based on these results we tested the hypothesis that QT interval would shorten more in LQT3 patients in response to mexiletine and to increases in heart rate. Mexiletine shortened significantly the QT interval among LQT3 patients but not among LQT2 patients. LQT3 patients shortened their QT interval in response to increases in heart rate much more than LQT2 patients and healthy controls. These findings suggest thatLQT3 patients are more likely to benefit from Na⁺ channel blockers and from cardiac pacing because they are at higher arrhythmic risk at slow heart rates. Conversely, LQT2 patients are at higher risk to develop syncope under stressful conditions, because of the combined arrhythmogenic effect of cate-cholamines with the insufficient adaptation of their QT interval. Along the same line of development of gene-specific therapy, recent data demonstrated that an increase in the extracellular concentration of potassium shortens the QT interval in LQT2 patients suggesting that intervention aimed at increasing potassium plasma levels may represent a specific treatment for LQT2. The molecular findings on LQTS suggest the possibility of developing therapeutic interventions targeted to specific genetic defects. Until definitive data become available, antiadrenergic therapy remains the mainstay in the management of LQTS patients, however it may be soon worth considering the addition of a Na + channel blocker such as mexiletine for LQT3 patients and of interventions such as K⁺ channel openers or increases in the extracellular concentration of potassium for LQTl and LQT2 patients.     

QT Interval Variability and Adaptation to Heart Rate Changes in Patients with Long QT Syndrome

Background: Increased QT variability (QTV) has been reported in conditions associated with ventricular arrhythmias. Data on QTV in patients with congenital long QT syndrome (LQTS) are limited.
Methods: Ambulatory electrocardiogram recordings were analyzed in 23 genotyped LQTS patients and in 16 healthy subjects (C). Short-term QTV was compared between C and LQTS. The dependence of QT duration on heart rate was evaluated with three different linear models, based either on the RR interval preceding the QT interval (RR₀), the RR interval preceding RR₀ (RR_-1), or the average RR interval in the 60-second period before QT interval (mRR).
Results: Short-term QTV was significantly higher in LQTS than in C subjects (14.94 ± 9.33 vs 7.31 ± 1.29 ms; P < 0.001). It was also higher in the non-LQT1 than in LQT1 patients (23.00 ± 9.05 vs 8.74 ± 1.56 ms; P < 0.001) and correlated positively with QTc in LQTS (r = 0.623, P < 0.002). In the C subjects, the linear model based on mRR predicted QT duration significantly better than models based on RR₀ and RR_-1. It also provided better fit than any nonlinear model based on RR₀. This was also true for LQT1 patients. For non-LQT1 patients, all models provided poor prediction of QT interval.
Conclusions: QTV is elevated in LQTS patients and is correlated with QTc in LQTS. Significant differences with respect to QTV exist among different genotypes. QT interval duration is strongly affected by noninstantaneous heart rate in both C and LQT1 subjects. These findings could improve formulas for QT interval correction and provide insight on cellular mechanisms of QT adaptation.     

The Long QT Syndrome and Torsade De Pointes

The LQTS is a prime example of how molecular biology, ion channel, cellular, and organ physiology, coupled with clinical observations, promise to be the future paradigm for advancement of medical knowledge. Both the congenital and acquired LQTS are due to abnormalities (intrinsic and/or acquired) of the ionic currents underlying cardiac repolarization. In this review, the continually unraveling molecular biology of congenital LQTS is discussed. The various pharmacological agents associated with the acquired LQTS are listed. Although it is difficult to predict which patients are at risk for TdP, careful assessment of the risk-benefit ratio is important before prescribing drugs known to be able to cause QT prolongation. The in vivo electrophysiological mechanism of TdP in the LQTS is described using, as a paradigm, the anthopleurin-A canine model, a surrogate for LQT3. In the LQTS, prolonged repolarization is associated with increased spatial dispersion of repolarization. Prolongation of repolarization also acts as a primary step for the generation of EADs. The focal EAD induced triggered beat(s) can infringe on the underlying substrate of inhomogeneous repolarization to initiate polymorphic reentrant VT, sometimes having the characteristic twisting QHS configuration known as TdP. The review concludes by discussion of the clinical manifestations and current management of both the congenital and acquired LQTS. The initial therapy of choice for the large majority of patients with the congenital LQTS is a beta-blocking drug. This therapy seems to be effective in LQT1 and LQT2 patients, but may not be as effective in LQT3 patients. Other therapeutic options include pacemakers, cervicothoracic sympathectomy, and the implantable cardioverter defibrillator. Recent molecular genetic studies have suggested several genotype specific therapies; however, long-term efficacy data are not available.     

Catecholamine-provoked microvoltage T wave alternans in genotyped long QT syndrome

Macrovoltage T wave alternans (TWA) has been described in congenital long QT syndrome (LQTS). Microvoltage T wave alternans (microV-TWA) at low heart rate (HR) is a marker of arrhythmogenic risk in many conditions, but its significance in LQTS has not been established. Twenty-three genotypically heterogeneous patients with LQTS and 16 control subjects were studied at rest and during phenylephrine and dobutamine provocation. Genotyping was established by PCR amplification and DNA sequencing of the three most common LQTS genes; KCNQ1/KVLQT1 (LQT1), KCNH2/HERG (LQT2), and SCN5A (LQT3). microV-TWA was determined using Fast Fourier transform. Precluded by ectopy, microV-TWA could not be assessed in 8 of 23 patients with LQTS. In the remaining 15 patients with LQTS, microV-TWA occurred at lower HR in LQTS than in controls (117 +/- 49 vs 153 +/- 37 beats/min; P < 0.05). Patients with LQTS developed microV-TWA at HR < 150 beats/min more often than controls (10/15 vs 2/16; P = 0.003). However, microV-TWA was not detected in the 3 individuals with a history of out-of-hospital cardiac arrest including a 14-year-old male with an F339del-KVLQT1 mutation (LQT1) who had dobutamine-provoked polymorphic ventricular tachycardia requiring external defibrillation. Catecholamine-provoked microV-TWA occurs at lower HR in patients with LQTS than in healthy people but does not identify high risk subjects.     

Cardiac K+ channels and drug-acquired long QT syndrome

The hallmark of long QT syndromes (LQTS) is an abnormal ventricular repolarization characterized by a prolonged QT interval on the electrocardiogram and a propensity to the occurrence of syncopes resulting from polymorphic ventricular tachycardia, called torsades de pointes. They may degenerate to ventricular fibrillation, possibly causing sudden death. Congenital LQTS, which implicates at least six chromosomal loci, LQT1 to LQT6, three of them corresponding to mutations concerning the coding of K+ channel proteins, give useful information about the mechanism underlying the arrhythmia. One of the potassium channel genes implicated in congenital LQTS is HERG, which encodes the IKr current channel protein. This current has provided a relevant insight into the occurrence of drug-acquired LQTS, since all drugs associated with torsades, such as erythromycin, terfenadine, haloperidol, or cisapride, also block IKr.     

Detection of spatial repolarization abnormalities in patients with LQT1 and LQT2 forms of congenital long-QT syndrome

The aim of this study is to detect the spatial current dispersion that appears in the T-wave of patients with congenital long-QT syndrome (LQTS). To observe this dispersion, magnetocardiograms (MCGs)--which have a high spatial resolution--of LQT1 patients (n = 7), LQT2 patients (n = 9) and a control group (n = 33) were recorded. The dispersion was evaluated by plotting current-arrow maps (CAMs) calculated from the MCG signals. In the case of LQT1, abnormal current arrows in the CAMs appeared above the inferior part of the heart in two LQT1 patients with a long corrected QT interval (QTc) (>0.6), and the current direction was from the left (origin side) to the right ventricular muscle (110 degrees). In six out of nine LQT2 patients, abnormal current arrows with angles below 20 degrees were observed above the right inferior part or lower septum; the current direction was from the right (origin side) to the left ventricular muscle. However, in the case of the LQT2 patients, the QTc values did not correlate with the abnormal current. These findings suggest that the origin of abnormal repolarization in LQT1 is the left ventricular muscle and the origin of that in LQT2 is the right ventricular muscle or lower septum. The estimation of the origin in LQTS patients can provide important information such as the risk factor of sudden death.     

Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome

Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of IKs and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type alpha subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.     

Congenital Myocardial Sympathetic Dysinnervation (CMSD)—A Structural Defect of Idiopathic Long QT Syndrome

Concerning the pathogenetic mechanism of idiopathic long QT syndrome (LQTS), the hypothesis of a specific sympathetic imbalance has gained general acceptance, but its validity has never been proven. To test this hypothesis I-123-MIBG, an analogue of norepinephrine and guanethidine, was used to provide scintigraphic display of the efferent cardiac sympathetic innervation. Twelve members of four LQTS families (mean age 38.2 +/- 17.2 years, eight males) and eight healthy volunteers (mean age 48.2 +/- 13.3 years, five males) were studied by means of I-123-MIBG single photon emission computed tomography (SPECT). A quantitative analysis of all scans was performed. All scans of the healthy volunteers show a uniform tracer uptake with sometimes slightly decreased activity in the apex. (1) All patients with QTc greater than 440 msec (n = 5); (2) all, who had suffered from at least one episode of torsade de pointes, ventricular fibrillation (VF) or syncope (n = 5); and (3) all symptomatic patients with QTc prolongation (n = 4) have reduced or abolished (P less than 0.02) MIBG uptakes in the inferior and inferior septal parts of the left ventricle (congenital myocardial sympathetic dysinnervation [CMSD]). Additionally, one female without symptoms or QTc prolongation (LQT) shows an abnormal MIBG SPECT similar to the one of her daughter, who has LQT and symptoms. One male without LQT, who had suffered from VF shows CMSD similar to his father, who has LQT, but no symptoms. All members of the families with normal MIBG SPECTs have neither LQT nor symptoms. In all families CMSD fulfills the criteria of autosomal-dominant inheritance. Normal QTc-interval predicted only in 57% normal cardiac sympathetic innervation in the present LQTS families. Therefore, quantitative I-123-MIBG SPECT enables to identify myocardial sympathetic dysinnervation as structural defect in LQTS. CMSD is associated with and without LQT and presents a pattern of autosomal-dominant inheritance. LQT at rest or during exercise was specific (100%), but less sensitive (63%) in the assessment of CMSD than I-123-MIBG SPECT.     

Pharmacological targeting of long QT mutant sodium channels.

The congenital long QT syndrome (LQTS) is an inherited disorder characterized by a delay in cardiac cellular repolarization leading to cardiac arrhythmias and sudden death often in young people. One form of the disease (LQT3) involves mutations in the voltage-gated cardiac sodium channel. The potential for targeted suppression of the LQT defect was explored by heterologous expression of mutant channels in cultured human cells. Kinetic and steady state analysis revealed an enhanced apparent affinity for the predominantly charged, primary amine compound, mexiletine. The affinity of the mutant channels in the inactivated state was similar to the wild type (WT) channels (IC50 approximately 15-20 microM), but the late-opening channels were inhibited at significantly lower concentrations (IC50 = 2-3 microM) causing a preferential suppression of the late openings. The targeting of the defective behavior of the mutant channels has important implications for therapeutic intervention in this disease. The results provide insights for the selective suppression of the mutant phenotype by very low concentrations of drug and indicate that mexiletine equally suppresses the defect in all three known LQT3 mutants.     

Prolonged QT syndrome in children: an uncommon but potentially fatal entity

Prolonged QT syndrome may be either congenital, as in Jervell and Lange-Nielsen or Romano-Ward syndromes, or acquired in nature. Affected children are at risk for syncope, seizures, dysrhythmias and sudden death. Physicians should consider long QT syndrome (LQTS) in all patients who present with syncope. A thorough personal and family history should be documented, with particular attention to prior syncopal episodes, congenital deafness, and unexplained sudden death. Syncope that is either recurrent or induced by exercise or stress is concerning and also should be noted. An electrocardiogram with manual calculation of the QT interval should be performed on all patients with a suggestive history. Furthermore, the diagnosis of LQTS warrants evaluation of all other family members. With recognition and appropriate treatment of affected patients, the potentially fatal consequences of LQTS may be prevented.     

Long QT Syndrome:

MILLER, R.F., et al .: Long QT Syndrome: First and Fatal Events Provoked by Hemodialysis. Long QT syndrome (LQTS) involves both congenital and acquired predispositions toward the characteristic torsades de pointes (TP) ventricular arrhythmia. Congenital long QT syndrome generally manifests with TP, syncope, or sudden death early in life. This is a documented case of previously undiagnosed congenital LQTS in a 48-year-old woman where the first and fatal episodes of TP were provoked by hemodialysis. (PACE 2003; 26[Pt. I]:103–104)     

Congenital long QT syndromes: clinical features, molecular genetics and genetic testing

Congenital long QT syndrome (LQTS) is a primary electrical disease characterized by a prolonged QT interval in the surface electrocardiogram and increased predisposition to a typical polymorphic ventricular tachycardia, termed Torsade de Pointes. Most patients with LQTS are asymptomatic and are diagnosed incidentally based on an electrocardiogram. Symptomatic patients may suffer from severe cardiac events, such as syncope and/or sudden cardiac death. Autosomal dominant forms are caused by heterozygous mutations in genes encoding the components of the ion channels. The autosomal recessive form with congenital deafness is also known as Jervell and Lang-Nielsen syndrome. It is caused by homozygous mutations or certain compound heterozygous mutations. Depending on the genetic defects, there are differences in the age of onset, severity of symptoms, and number of cardiac events and event triggers. With advances in gene technology, it is now feasible to perform genetic testing for LQTS, especially for those with family history. Identification of the mutation will lead to better management of symptoms and more targeted treatment, depending on the underlying genetic defect, resulting in a reduction of mortality and cardiac events.     

Clinical Value of Electrocardiographic Parameters in Genotyped Individuals with Familial Long QT Syndrome

MOENNIG, G., et al. : Clinical Value of Electrocardiographic Parameters in Genotyped Individuals with Familial Long QT Syndrome. Rate corrected QT interval (QTc) and QT dispersion (QTd) have been suggested as markers of an increased propensity to arrhythmic events and efficacy of therapy in patients with long QT syndrome (LQTS). To evaluate whether QTc and QTd correlate to genetic status and clinical symptoms in LQTS patients and their relatives, ECGs of 116 genotyped individuals were analyzed. JTc and QTc were longest in symptomatic patients (  n = 28  ). Both QTd and JTd were significantly higher in symptomatic patients than in asymptomatic (  n = 29  ) or unaffected family members (  n = 59  ). The product of QTd/JTd and QTc/JTc was significantly different among all three groups. Both dispersion and product put additional and independent power on identification of mutation carriers when adjusted for sex and age in a logistic regression analysis. Thus, symptomatic patients with LQTS show marked inhomogenity of repolarization in the surface ECG. QT dispersion and QT product might be helpful in finding LQTS mutation carriers and might serve as additional ECG tools to identify asymptomatic LQTS patients.     

New Insight into Repolarization Abnormalities in Patients with Congenital Long QT Syndrome: the Increased Transmural Dispersion of Repoiarization

There is evidence from experimental studies that the time interval from the peak to the end of T-wave reflects the transmural dispersion in repolarization (electrical gradient) between myocardial "layers" (epicardial, M-cells, endocardial). Since Congenital Long QT Syndrome (LQTS) is considered to be classical disease or repolarisation abnormalities, we performed the present study to assess the transmtiral dispersion of repolarization in LQTS patients. The study group consisted of 17 patients: 7 LQTS pts and 10 pts from the control group. In each patient the 24-hour ECG recording was performed on magnetic tape. The interval from the peak to the end of the T-wave (TpTo) was automatically measured by Holter system during every hour as a measure of transmural dispersion of repolarisation. Thereafter the mean TpTo from 24-hours was calculated. In addition the spatial QT dispersion was measured from 12 lead ECG and 3 channel Holter tape as a difference between the shortest and the longest QT interval between leads. The values were compared between groups using the Anova test.
TpTo was 79,6±9,6 ms (72–92 ms) in LQTS group and 62,4±7,5 ms (51–70) in the control group (p< 0.001). In LQTS group TpTo was significantly longer at night hours 72,5±2 when compared to day hours 87,4±8 (p<0.01). The spatial QT dispersion was significantly higher in LQTS patients when compared to control, both in 12-lead standard and Holter ECG.
Congenital long QT syndrome is associated with increase in both transmural and spatial dispersion of repolarization. The extent of prolongation of the terminal portion of QT in patients with congenital long QT syndrome is greater at night sleep hours compared to daily activity.     

Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome

OBJECTIVE: To determine the spectrum, frequency, and ethnic-specificity of channel variants in the potassium channel genes implicated in congenital long QT syndrome (LQTS) among healthy subjects. SUBJECTS AND METHODS: Genomic DNA from 744 apparently healthy individuals-305 black, 187 white, 134 Asian, and 118 Hispanic--was subject to a comprehensive mutational analysis of the 4 LQTS-causing potassium channel genes: KCNQ1 (LQT1), KCNH2 (LQT2), KCNE1 (LQT5), and KCNE2 (LQT6). RESULTS: Overall, 49 distinct amino acid-altering variants (36 novel) were identified: KCNQ1 (n = 16), KCNH2 (n = 25),KCNE1 (n = 5), and KCNE2 (n = 3). More than half of these variants (26/49) were found exclusively in black subjects. The known K897T-HERG and the G38S-min K common polymorphisms were identified in all 4 ethnic groups. Excluding these 2 common polymorphisms, 25% of black subjects had at least 1 nonsynonymous potassium channel variant compared with 14% of white subjects (P < .01). CONCLUSIONS: To our knowledge, this study represents the first comprehensive determination of the frequency and spectrum of cardiac channel variants found among healthy subjects from 4 major ethnic groups. Defining the population burden of genetic variants in these critical cardiac ion channels is crucial for proper interpretation of genetic test results of individuals at risk for LQTS. This compendium provides a resource for epidemiological and functional investigation of variant effects on the repolarization properties of cardiac tissues, including susceptibility to lethal cardiac arrhythmias.     

Long QT syndrome

The long QT syndrome (LQTS) is characterized by prolongation of the QT interval, causing torsade de pointes and sudden cardiac death. This syndrome can be divided into idiopathic (congenital) and acquired forms. The idiopathic form is a familial disorder that can be associated with sensorineural deafness (Jervell and Lange--Nielsen syndrome, autosomal recessive) or normal hearing (Romano--Ward syndrome, autosomal dominant). The acquired form has a long QT interval caused by various drugs such as quinidine sotalol and dofetilide, also by noncardiovascular drugs such as antihistamine, antibiotics, antipsychotics and others. Also, the QT interval is prolonged by electrolyte abnormalities such as hypokalemia and hypomagnesemia, central nervous system lesions, significant bradyarrhythmias, cardiac ganglionitis, mitral valve prolapse and probucol. DNA variants appearing to predispose to drug-associated acquired long QT syndrome have been reported in congenital long QT.