Abstract
Aims
Having shown that Lumacaftor rescued the hERG trafficking defect in the induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two LQT2 patients, we tested whether the ...commercial association Lumacaftor + Ivacaftor (LUM + IVA) could shorten the QTc in the same two patients.
Methods and results
After hospital admission and 1 day of baseline recordings, half dose LUM + IVA was administered on Day 1, followed by full dose (LUM 800 mg + IVA 500 mg) for 7 days. A continuous 12-lead Holter ECG allowed a large number of blind QTc measurements. Lumacaftor + Ivacaftor shortened QTc significantly in both patients: in V6 from 551 ± 22 ms to 523 ± 35 ms in Patient 1 (Pt1) and from 472 ± 21 ms to 449 ± 20 ms in Patient 2 (Pt2); in DII from 562 ± 25 ms to 549 ± 35 ms in Pt1 and from 485 ± 32 ms to 452 ± 18 ms in Pt2. In both patients, the percentage of QTc values in the lower tertile increased strikingly: in V6 from 33% to 68% and from 33% to 76%; in DII from 33% to 50% and from 33% to 87%. In the wash-out period a rebound in QTc was observed. On treatment, both patients developed diarrhoea, Pt1 more than Pt2.
Conclusion
This represents the first attempt to validate in patients the in vitro results of a drug repurposing strategy for cardiovascular disorders. Lumacaftor + Ivacaftor shortened significantly the QTc in the two LQT2 patients with a trafficking defect, largely confirming the findings in their iPSC-CMs but with smaller quantitative changes. The findings are encouraging but immediate translation into clinical practice, without validation in more patients, would be premature.
BACKGROUND:The diagnosis of long QT syndrome (LQTS) is rather straightforward. We were surprised by realizing that, despite long-standing experience, we were making occasional diagnostic errors by ...considering as affected subjects that, over time, resulted as not affected. These individuals were all actively practicing sports, an observation which helped to design our study.
METHODS:We focused on subjects referred to our Center by Sports Medicine doctors with a suspicion of LQTS because of marked repolarization abnormalities on the ECG performed during the mandatory medical visit necessary in Italy to obtain the certificate of eligibility to practice sports. They all underwent our standard procedures involving both a resting and 12-lead ambulatory ECG, an exercise stress test, and genetic screening.
RESULTS:There were 310 such consecutive subjects, all actively practicing sports with many hours of intensive weekly training. Of them, 111 had a normal ECG, different cardiac diseases or were lost to follow-up and exited the study. Of the remaining 199, all with either clear QTc prolongation and/or typical repolarization abnormalities, 121 were diagnosed as affected based on combination of ECG abnormalities with positive genotyping (QTc 482±35 ms). Genetic testing was negative in 78 subjects but 45 were nonetheless diagnosed as affected by LQTS based on unequivocal ECG abnormalities (QTc 472±33 ms). The remaining 33, entirely asymptomatic and with a negative family history, following detraining showed an unexpected and practically complete normalization of the ECG abnormalities (their QTc shortened from 492±37 to 423±25 ms, p<0.001, and their Schwartz score went from 3.0 to 0.06). They were considered not affected by congenital LQTS and are henceforth referred to as “Cases”. Furthermore, among them, those who resume a similarly heavy physical training showed reappearance of the repolarization abnormalities.
CONCLUSIONS:It is not uncommon to suspect LQTS among individuals actively practicing sports, based on marked repolarization abnormalities. Among those who are genotype-negative, >40% normalize their ECG following detraining but the abnormalities tend to recur with resumption of training. These individuals are not affected by LQTS but could have a form of acquired LQTS. Care should be exercised to avoid diagnostic errors.
The prevalence of genetic arrhythmogenic diseases is unknown. For the long-QT syndrome (LQTS), figures ranging from 1:20 000 to 1:5000 were published, but none was based on actual data. Our objective ...was to define the prevalence of LQTS.
In 18 maternity hospitals, an ECG was performed in 44 596 infants 15 to 25 days old (43 080 whites). In infants with a corrected QT interval (QTc) >450 ms, the ECG was repeated within 1 to 2 weeks. Genetic analysis, by screening 7 LQTS genes, was performed in 28 of 31 (90%) and in 14 of 28 infants (50%) with, respectively, a QTc >470 ms or between 461 and 470 ms. A QTc of 451 to 460, 461 to 470, and >470 ms was observed in 177 (0.41%), 28 (0.06%), and 31 infants (0.07%). Among genotyped infants, disease-causing mutations were found in 12 of 28 (43%) with a QTc >470 ms and in 4 of 14 (29%) with a QTc of 461 to 470 ms. One genotype-negative infant (QTc 482 ms) was diagnosed as affected by LQTS on clinical grounds. Among family members of genotype-positive infants, 51% were found to carry disease-causing mutations. In total, 17 of 43 080 white infants were affected by LQTS, demonstrating a prevalence of at least 1:2534 apparently healthy live births (95% confidence interval, 1:1583 to 1:4350).
This study provides the first data-based estimate of the prevalence of LQTS among whites. On the basis of the nongenotyped infants with QTc between 451 and 470 ms, we advance the hypothesis that this prevalence might be close to 1:2000. ECG-guided molecular screening can identify most infants affected by LQTS and unmask affected relatives, thus allowing effective preventive measures.
Acquired long QT syndrome (aLQTS) exhibits QT prolongation and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalaemia, or bradycardia. Sometimes, QTc remains prolonged despite ...elimination of triggers, suggesting the presence of an underlying genetic substrate. In aLQTS subjects, we assessed the prevalence of mutations in major LQTS genes and their probability of being carriers of a disease-causing genetic variant based on clinical factors.
We screened for the five major LQTS genes among 188 aLQTS probands (55 ± 20 years, 140 females) from Japan, France, and Italy. Based on control QTc (without triggers), subjects were designated 'true aLQTS' (QTc within normal limits) or 'unmasked cLQTS' (all others) and compared for QTc and genetics with 2379 members of 1010 genotyped congenital long QT syndrome (cLQTS) families. Cardiac symptoms were present in 86% of aLQTS subjects. Control QTc of aLQTS was 453 ± 39 ms, shorter than in cLQTS (478 ± 46 ms, P < 0.001) and longer than in non-carriers (406 ± 26 ms, P < 0.001). In 53 (28%) aLQTS subjects, 47 disease-causing mutations were identified. Compared with cLQTS, in 'true aLQTS', KCNQ1 mutations were much less frequent than KCNH2 (20% 95% CI 7-41% vs. 64% 95% CI 43-82%, P < 0.01). A clinical score based on control QTc, age, and symptoms allowed identification of patients more likely to carry LQTS mutations.
A third of aLQTS patients carry cLQTS mutations, those on KCNH2 being more common. The probability of being a carrier of cLQTS disease-causing mutations can be predicted by simple clinical parameters, thus allowing possibly cost-effective genetic testing leading to cascade screening for identification of additional at-risk family members.
Objectives The purpose of this study was to compare the efficacy of beta-blockers in congenital long QT syndrome (LQTS). Background Beta-blockers are the mainstay in managing LQTS. Studies comparing ...the efficacy of commonly used beta-blockers are lacking, and clinicians generally assume they are equally effective. Methods Electrocardiographic and clinical parameters of 382 LQT1/LQT2 patients initiated on propranolol (n = 134), metoprolol (n = 147), and nadolol (n = 101) were analyzed, excluding patients <1 year of age at beta-blocker initiation. Symptoms before therapy and the first breakthrough cardiac events (BCEs) were documented. Results Patients (56% female, 27% symptomatic, heart rate 76 ± 16 beats/min, QTc 472 ± 46 ms) were started on beta-blocker therapy at a median age of 14 years (interquartile range: 8 to 32 years). The QTc shortening with propranolol was significantly greater than with other beta-blockers in the total cohort and in the subset with QTc >480 ms. None of the asymptomatic patients had BCEs. Among symptomatic patients (n = 101), 15 had BCEs (all syncopes). The QTc shortening was significantly less pronounced among patients with BCEs. There was a greater risk of BCEs for symptomatic patients initiated on metoprolol compared to users of the other 2 beta-blockers combined, after adjustment for genotype (odds ratio: 3.95, 95% confidence interval: 1.2 to 13.1, p = 0.025). Kaplan-Meier analysis showed a significantly lower event-free survival for symptomatic patients receiving metoprolol compared to propranolol/nadolol. Conclusions Propranolol has a significantly better QTc shortening effect compared to metoprolol and nadolol, especially in patients with prolonged QTc. Propranolol and nadolol are equally effective, whereas symptomatic patients started on metoprolol are at a significantly higher risk for BCEs. Metoprolol should not be used for symptomatic LQT1 and LQT2 patients.
Risk Stratification in the Long-QT Syndrome Priori, Silvia G; Schwartz, Peter J; Napolitano, Carlo ...
New England journal of medicine/The New England journal of medicine,
05/2003, Letnik:
348, Številka:
19
Journal Article
Recenzirano
Odprti dostop
The most common causes of the inherited long-QT syndrome are mutations in either of two potassium-channel genes (at locus LQT1 or LQT2) or a sodium-channel gene (at locus LQT3). In this large study, ...the risk of syncope, cardiac arrest, or sudden death was influenced by the genotype of the patient, the duration of the QT interval (corrected for heart rate), and the patient's sex.
Risk influenced by genotype and duration of the QT.
The Romano–Ward variant of the long-QT syndrome is a genetically transmitted disorder characterized by prolonged ventricular repolarization that predisposes carriers to life-threatening arrhythmias.
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Almost 40 years after its initial description,
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,
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the natural history of the syndrome remains incompletely characterized and approaches to risk stratification are not well defined. These gaps in knowledge are largely due to the fact that the long-QT syndrome is uncommon, cardiac events may be separated by long periods without symptoms, and the initial manifestation may occur late in life. Five genes have been linked to the long-QT syndrome,
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,
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and studies of the genotype and . . .
Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (IVF). ...Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility, screening for disease-predisposing variants could improve IVF diagnostics.
The study included 76 Finnish and Italian patients with a mean age of 31.2years at the time of the VF event, collected between the years 1996–2016 and diagnosed with idiopathic, out-of-hospital VF. Using whole-exome sequencing (WES) and next-generation sequencing (NGS) approaches, we aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias of these patients. Combining the results from the two study populations, we identified pathogenic or likely pathogenic variants residing in the RYR2, CACNA1C and DSP genes in 7 patients (9%). Most of them (5, 71%) were found in the RYR2 gene, associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). These genetic findings prompted clinical investigations leading to disease reclassification. Additionally, in 9 patients (11.8%) we detected 10 novel or extremely rare (MAF<0.005%) variants that were classified as of unknown significance (VUS).
The results of our study suggest that a subset of patients originally diagnosed with IVF may carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies. Although misclassification of other cardiac channelopathies as IVF appears rare, our findings indicate that the possibility of CPVT as the underlying disease entity should be carefully evaluated in IVF patients.
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The efficacy of beta-blockers for treatment of patients with long QT syndrome type 3 (LQT3) has been repeatedly questioned, and it has been suggested that they might be detrimental for this genetic ...subgroup of patients with long QT syndrome (LQTS). The disquieting consequence has been that cardiologists confronted with LQT3 patients often do not even attempt pharmacologic therapy and implant cardioverter-defibrillators as first-choice treatment. However, the most recent clinical data indicate high efficacy of beta-blocker therapy in LQT3 patients.
The purpose of this study was to test the antiarrhythmic efficacy of beta-blockers in an established experimental model for LQT3.
After phenotypic validation of 65 ∆KPQ-SCN5A knock-in transgenic (TG) mice compared to 32 wild-type (WT) mice, we tested the effect of the arrhythmogenic cholinergic muscarinic agonist carbachol in 19 WT and 39 TG anesthetized mice, with and without pretreatment with propranolol given intraperitoneally.
At the same heart rates, TG mice had a markedly longer QT interval than WT mice. Whereas carbachol had minor arrhythmic effects in the WT mice, it produced ventricular tachycardia (VT) and ventricular fibrillation (VF) in 55% of 20 TG mice. By contrast, in none of 19 TG mice pretreated with propranolol did VT/VF occur after carbachol injection.
These experimental data indicate that, contrary to previous reports, beta-blockade effectively prevents VT/VF in a validated LQT3 model. Together with the most recent clinical data, these findings indicate that there is no reason for not initiating protective therapy with beta-blockers in LQT3 patients.
Abstract
Aims
Mutation type, location, dominant-negative I Ks reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent I Ks stimulation via protein kinase A (PKA) influence ...the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk.
Methods and results
Clinical and genetic data were obtained from 1316 LQT1 patients 450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341-neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 ± 33 vs. 490 ± 44 ms) but longer than the remaining LQT1 patient population (467 ± 41 ms) (P < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighbouring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; P < 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighbouring mutations, by the p.A341V-specific impairment of I Ks regulation. The differences between the p.A341-neighbouring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation.
Conclusion
KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent I Ks enhancement correlates with its phenotypic severity. Cellular studies providing further insights into I Ks-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management.
The management of long-QT syndrome (LQTS) patients who continue to have cardiac events (CEs) despite beta-blockers is complex. We assessed the long-term efficacy of left cardiac sympathetic ...denervation (LCSD) in a group of high-risk patients.
We identified 147 LQTS patients who underwent LCSD. Their QT interval was very prolonged (QTc, 543+/-65 ms); 99% were symptomatic; 48% had a cardiac arrest; and 75% of those treated with beta-blockers remained symptomatic. The average follow-up periods between first CE and LCSD and post-LCSD were 4.6 and 7.8 years, respectively. After LCSD, 46% remained asymptomatic. Syncope occurred in 31%, aborted cardiac arrest in 16%, and sudden death in 7%. The mean yearly number of CEs per patient dropped by 91% (P<0.001). Among 74 patients with only syncope before LCSD, all types of CEs decreased significantly as in the entire group, and a post-LCSD QTc <500 ms predicted very low risk. The percentage of patients with >5 CEs declined from 55% to 8% (P<0.001). In 5 patients with preoperative implantable defibrillator and multiple discharges, the post-LCSD count of shocks decreased by 95% (P=0.02) from a median number of 25 to 0 per patient. Among 51 genotyped patients, LCSD appeared more effective in LQT1 and LQT3 patients.
LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in high-risk LQTS patients when compared with pre-LCSD events. However, LCSD is not entirely effective in preventing cardiac events including sudden cardiac death during long-term follow-up. LCSD should be considered in patients with recurrent syncope despite beta-blockade and in patients who experience arrhythmia storms with an implanted defibrillator.
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