Long QT Patients Research Articles

Experience with bisoprolol in long-QT1 and long-QT2 syndrome.

The protective effect of beta-blockers in patients with inherited Long-QT syndrome is well established. Recent reports have suggested that beta-blockers are not equally effective in Long-QT (LQT). Bisoprolol is an attractive candidate for use in LQT because of its cardioselective properties and favorable side-effect profile. We performed a retrospective cohort study of 114 consecutive patients with gene-positive Long-QT syndrome type 1 (LQT1) or Long-QT syndrome type 2 (LQT2) treated with bisoprolol, nadolol or atenolol with a total of 580 person-years of follow-up. Electrocardiogram (ECG) parameters and cardiac events during follow-up were compared. In addition, exercise treadmill testing was performed in bisoprolol-treated patients. Fifty-nine patients were treated with bisoprolol, 39 with atenolol and 16 with nadolol. Overall, 59% were females and 62% had LQT1. Baseline heart rate and corrected QT (QTc) interval were similar between the groups. QTc shortening was observed in individuals on bisoprolol (ΔQTc -5 ± 31ms; p = 0.049) and nadolol (ΔQTc -13 ± 16ms; p = 0.02) but not on atenolol (ΔQTc +9 ± 24ms; p = 0.16). Median follow-up was similar for bisoprolol and nadolol (3years), but longer for atenolol (6years; p = 0.03); one cardiac event occurred in the bisoprolol group (1.7%) and two events occurred in the atenolol group (5.1%; p = 0.45), whereas none occurred in nadolol-treated patients. Beta-blocker efficacy was not affected by the underlying genotype. The antiadrenergic effect of bisoprolol correlated with the reduction of peak heart rates at exercise testing. Bisoprolol treatment results in QTc shortening in gene-positive LQT1 and LQT2 patients and is well tolerated during long-term administration. The equivalence of bisoprolol for protection from ventricular arrhythmia in LQT patients compared to established beta-blockers remains unknown. Further large-scale studies are required.

0395: Prevalence of early repolarization in congenital long QT syndrome. A combination of early and delayed repolarization

early repolarization (ER) in Brugada or short QT syndrome is common and has been associated with a less favourable outcome. Even if apparently paradoxical, ER can also be seen in long QT (LQT) but prevalence and correlations to other variables are unknown. ECG of 105 LQT patients (44 men, 36±21 yo) and 269 age and gender matched controls (135 men, 36±18 yo) were reviewed. LQT was diagnosed by a positive genetic testing (n=71) or by showing abnormal T wave and long QT interval spontaneously or during epinephrin infusion in pts without discovered genetic mutation (n=34). ER was defined by > 1mm J point elevation in the inferior or lateral leads with notch or slurring pattern. QT in lead II was 433±68 msec in LQT patients and 338±41 in controls (p<0.0001) (QTc 446±52 versus 377±30 msec, p<0.0001). Heart rate wq lower in LQT patients (66±14 vs 79±19 bpm) (p<0.0001). Twenty LQT patients presented with resuscitated sudden death or torsades de pointes and 11 with syncope. 33/105 LQT patients (31%) had ER compared to 31/269 (12%) controls (p<0.0001). ER was more frequent in LQT men (19/44, 43%) compared to women (14/61, 23%) (p=0.03) but was not correlated to age (41±20 yo with ER vs 35±21 bpm, p=0.17). LQT patients with ER had lower heart rates (61±11 vs 69±15 bpm, p=0.02). There was a trend toward longer QT in patients with ER (449±73 versus 426±64 msec in lead II, p=0.1) but not for corrected QT intervals (442±48 versus 448±54 msec, p=0.5). There was more frequent ER in case of HeRG (14/26) than KCNQ1 (6/34) or KCNJ2 (2/10) mutations (p=0.008). ER in LQT patients was not correlated to symptoms or cardiac events (5/20 patients with SD, 3/11 in patients with syncope and 25/72 asymptomatic LQT) (p=0.6). ER is very common in LQT patients and is related to the gender and to the heart rate but not to age or to the corrected QT duration. ER is not correlated to cardiac events in this series but may is to HeRG mutations

Response of QT interval in methadone maintenance treated patients to the rapid changes in heart rate provoked by brisk standing: Comparison to healthy controls and patients with long QT syndrome

BackgroundPatients on methadone maintenance therapy are somehow similar to patients with congenital long QT syndrome (LQTS) because they have malfunction of potassium channels caused by a drug that cannot be easily discontinued. We tested patients on methadone therapy with the “stand-up” test, which has been shown to unravel pathologic QT-prolongation in congenital long-QT patients. Methods“Stand-up” test results of methadone-users, healthy volunteers and congenital LQTS patients were compared. Methadone serum levels and doses were collected. The prognostic value of the test was evaluated after 4years of follow-up. ResultsThe QT-response of methadone-users to the “stand-up” test resembled that of healthy volunteers more than the response of LQTS-patients. Differences in the QTc of methadone treated patients and controls, which were statistically significant at baseline, became no longer significant after standing. Within 52months of follow-up, one patient had suffered unexplained death and one had documented ventricular tachycardia. ConclusionsThe QT-response of methadone-users to the “stand-up” test is similar to that of healthy volunteers, not to that of LQTS-patients.

Prevalence of early repolarization in congenital long QT syndrome. A combination of early and delayed repolarization

Introduction: Early Repolarization (ER) in Brugada or short QT syndrome is common and has been associated to a less favourable outcome. Even if apparently paradoxical, ER can also be seen in Long QT (LQT) but prevalence and correlations to other variables are unknown. Methods: 12 leads ECG of 41 LQT patients (21 men, 37±22 yo) were reviewed and compared to 97 matched controls (54 men, 39±24 yo) LQT patients were selected by a positive genetic testing (n=33) or by showing abnormal T wave and long QT interval spontaneously or during epinephrin infusion in patients without discovered genetic mutation (n=8). ER was defined by ≥ 1 mm J point elevation in the inferior or lateral leads with a notch or slurring pattern. Presence of ER was correlated to the clinical and ECG characteristics and to the results of genetic analysis. Results: QT was 406±52 msec in LQT patients and 354±42 in controls (p≤0.0001) (QTc 433±34 versus 386±26 msec, p≤0.0001). Two LQT patients presented with ressuscitated sudden death and 4 with syncope at the time of diagnosis. 14/41 LQT patients (34%) had ER compared to 14/97 (14%) controls (p=0.008). Heart rate was not different between patients and controls (64±10bpm versus 73±20bpm, p=0.14). ER was more frequent in men (12/21, 57%) compared to women (2/20, 10%) (p=0.004) but was not correlated to age (41±22 yo with ER versus 35±22bpm, p=0.4). ER was not correlated to symptoms or cardiac events (no ER in the 2 patients with SD and in 2/4 patients with syncope versus 12/35 in asymptomatic LQT patients, p=ns). There was a trend toward longer QT in patients with ER (427±40 versus 396±54 msec in V2, p=0.09) but there was no correlations between ER and corrected QT intervals. This can be explained by the lower heart rate in patients with ER (63±10 versus 75±18bpm, p=0.03). ER was not more often seen in patients with or without mutations (11/33 versus 3/8, p=0.8), but there was more frequent ER in case of HeRG mutations (9/17) than in case of KCNQ1 or KCNJ2 mutations (2/13 and 0/3) (p=0.04) Conclusion: ER is very common in LQT patients and is related to a male gender, to a longer QT duration and to a slower heart rate but not to age or to the corrected QT duration. ER does not seem to be correlated to cardiac events in this series but may be linked to HeRG mutations. Further studies are needed for demonstrating additional mutations/variants or the existence of an early transient voltage gradient due to altered kinetics in muted potassium channels with loss of function especially for HeRG mutations.

Novel Chemical Suppressors of Long QT Syndrome Identified by an In Vivo Functional Screen

Genetic long QT (LQT) syndrome is a life-threatening disorder caused by mutations that result in prolongation of cardiac repolarization. Recent work has demonstrated that a zebrafish model of LQT syndrome faithfully recapitulates several features of human disease, including prolongation of ventricular action potential duration, spontaneous early afterdepolarizations, and 2:1 atrioventricular block in early stages of development. Because of their transparency, small size, and absorption of small molecules from their environment, zebrafish are amenable to high-throughput chemical screens. We describe a small-molecule screen using the zebrafish KCNH2 mutant breakdance to identify compounds that can rescue the LQT type 2 phenotype. Zebrafish breakdance embryos were exposed to test compounds at 48 hours of development and scored for rescue of 2:1 atrioventricular block at 72 hours in a 96-well format. Only compounds that suppressed the LQT phenotype in 3 of 3 fish were considered hits. Screen compounds were obtained from commercially available small-molecule libraries (Prestwick and Chembridge). Initial hits were confirmed with dose-response testing and time-course studies. Optical mapping with the voltage-sensitive dye di-4 ANEPPS was performed to measure compound effects on cardiac action potential durations. Screening of 1200 small molecules resulted in the identification of flurandrenolide and 2-methoxy-N-(4-methylphenyl) benzamide (2-MMB) as compounds that reproducibly suppressed the LQT phenotype. Optical mapping confirmed that treatment with each compound caused shortening of ventricular action potential durations. Structure activity studies and steroid receptor knockdown suggest that flurandrenolide functions via the glucocorticoid signaling pathway. Using a zebrafish model of LQT type 2 syndrome in a high-throughput chemical screen, we have identified 2 compounds, flurandrenolide and the novel compound 2-MMB, as small molecules that rescue the zebrafish LQT type 2 syndrome by shortening the ventricular action potential duration. We provide evidence that flurandrenolide functions via the glucocorticoid receptor-mediated pathway. These 2 molecules and future discoveries from this screen should yield novel tools for the study of cardiac electrophysiology and may lead to novel therapeutics for human LQT patients.

A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly.

The LQT1 locus (KCNQ1) has been correlated with the most common form of inherited long QT (LQT) syndrome. LQT patients suffer from syncopal episodes and high risk of sudden death. The KCNQ1 gene encodes KvLQT1 alpha-subunits, which together with auxiliary IsK (KCNE1, minK) subunits form IK(s) K(+) channels. Mutant KvLQT1 subunits may be associated either with an autosomal dominant form of inherited LQT, Romano-Ward syndrome, or an autosomal recessive form, Jervell and Lange-Nielsen syndrome (JLNS). We have identified a small domain between residues 589 and 620 in the KvLQT1 C-terminus, which may function as an assembly domain for KvLQT1 subunits. KvLQT1 C-termini do not assemble and KvLQT1 subunits do not express functional K(+) channels without this domain. We showed that a JLN deletion-insertion mutation at KvLQT1 residue 544 eliminates important parts of the C-terminal assembly domain. Therefore, JLN mutants may be defective in KvLQT1 subunit assembly. The results provide a molecular basis for the clinical observation that heterozygous JLN carriers show slight cardiac dysfunctions and that the severe JLNS phenotype is characterized by the absence of KvLQT1 channel.

The LQT syndromes--current status of molecular mechanisms.

Our knowledge on the molecular genetics of inherited cardiac arrhythmias is very recent in comparison to the advances of genetics achieved in other inherited cardiac disorders. This is related to the high mortality and early disease onset of these arrhythmias resulting in mostly small nucleus families. Thus, traditional genetic linkage studies that are based on the genetic information obtained from large multi-generation families were made difficult. In 1991, the first chromosomal locus for congenital long-QT (LQT) syndrome was identified on chromosome 11p15.5 (LQT1 locus) by linkage analysis. Meanwhile, the disease-causing gene at the LQT1 locus (KCNQ1), a gene encoding a K+ channel subunit of the IKs channel, and three other, major genes, all encoding cardiac ion channel components, have been identified. Taken together, LQT syndrome turned out to be a heterogeneous channelopathy. Moreover, the power of linkage studies to reveal the genetic causes of the LQT syndrome was also important to identify unknown but fundamental channel components that contribute to the ion currents tuning ventricular repolarization. In-vitro expression of the altered ion channel genes demonstrated in each case that the altered ion channel function produces prolongation of the action potential and thus the increasing propensity to ventricular tachyarrhythmias. Since these ion channels are pharmacological targets of many antiarrhythmic (and other) drugs, individual and potentially deleterious drug responses may be related to genetic variation in ion channel genes. Very recently, also in acquired LQT syndrome, which is a frequent clinical disorder in cardiology a genetic basis has been proposed in part since mutations in LQT genes have been specifically found. The discovery of ion channel defects in LQT syndrome represents the major achievement in our understanding and implies potential therapeutic options. The knowledge of the genomic structure of the LQT genes now offers the possibility to detect the underlying genetic defect in 80-90% of all patients. With this specific information, containing the type of ion channel (Na+ versus K+ channel) and electrophysiological alteration by the mutation (loss-of-function versus change-of-function mutation), gene-directed, elective drug therapies have been initiated in genotyped LQT patients. Based on preliminary data, that were supported by in vitro studies, this approach may be useful in recompensating the characteristic phenotypes in some LQT patients. Mutation detection is a new diagnostic tool which may become of more increasing importance in patients with a normal QTc or just a borderline prolongation of the QTc interval at presentation. These patients represent approximately 40% of all familial cases. Moreover, LQT3 syndrome and idiopathic ventricular fibrillation are allelic disorders and genetically overlap. In both mutations in the LQT3 gene SCN5A encoding the Na+ channel alpha-subunit for INa have been reported. Thus, the clinical nosology of inherited arrhythmias may be reconsidered after elucidation of the underlying molecular bases. Meanwhile, genotype-phenotype correlations in large families are on the way to evaluate intergene, interfamilial, and intrafamilial differences in the clinical phenotype reflecting gene specific, gene-site specific, and individual consequences of a given mutation. LQT syndrome is phenotypically heterogeneous due to the reduced penetrance and variable expressivity associated with the mutations. This paper discusses the current data on molecular genetics and genotype-phenotype correlations and the implications for diagnosis and treatment.